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It’s a weird thing that a ideology like socialism, which is supposed to promote cooperation, can sustain such anti-social behaviour as the one I’m lately seeing in the socialist reddit. Specifically, all hell broke loose after I posted my blog-reply over there.
I do not mind people criticizing my ideas and thoughts, this is how one learns but it’s amazing how much the administrators of that reddit have gone on a power-trip even by the small power provided to them for filtering out trolls and spammers.
it’s funny that even though I didn’t agree with Larry’s request to stop submitting his articles to reddit, mostly because I always consider that among the morons there might be some who will listen and have an interest in conversation, his assessment ended up forcing itself upon me. Lazy morons indeed do not care to see or hear conflicting opinions and will happily attempt to silence them so that nobody else will either.
This has become plainly true in the comments of that last post, where arguing about my article ensued. This very quickly escalated into a flamewar since, for these “socialists” anyone who does not think exactly the same way they do, is an enemy to be labeled and assaulted. The jump from “You’re saying something wrong” to “You are a wrong kind of person” in their minds is near-instantaneous.
But this is the wrong kind of attitude. When one says something wrong, our reaction should not be to insult the person. That does not achieve anything other than alienate and drive others away. Sure, if your purpose is to have only your own voice heard, like the moderators above, this can be a good tactic, but in the long run, you have only managed to burn more bridges behind you.
But is this mentality of “my way or the highway” useful? On the contrary by refusing to discuss points, even wrong points that others raise, in favour of calling them traitors or heretics, not only does not help them understand where their thinking has gotten astray but immediately erects a wall between you, effectively making sure that they will get defensive and ignore whatever you say.
This is what happened to me in my last post, while I got in with interest to discuss, the initial comments immediately flew off the handle, accusing me of being “anti-working class” and calling me a “Maniac”. And even though I should have known better than to rise to the bait, I went on the defensive and the flamewar began. More time was spent on accusing each other of douchebaggery than actually countering each other’s arguments.
And opinions we do not agree with are important as well, especially coming from people that do not have completely opposite kind of views. Controversial ideas is how we learn either to strengthen our own opinions or we change our mind when we cannot counter them. It is disheartening that this reddit tends to reward mostly orthodox views on marxism and punishes the heretics with obscurity.
This is simply groupthink. You do not learn anything new, nor do you get to think. You only get to reinforce what you already believe in. As long as an article is well written and raises a few points on the part of the author, it should never be downvoted. Ignored perhaps, and even upvoted if the ideas are well presented, even if wrong. But downvoting simply hides the opposing view away from others. We should treasure controversy, not attempt to silence it.
If our views are solid enough, controversy is not an issue. The arguments against it can be presented and the idea eviscerated. When libertarians and *shudder* Objectivists come here to argue with me, I do not accuse them of being exploitation supporters, horribly misguided or douchebags as this would only serve to drive them away. But that would mean that I have even less people to criticize me, and that’s just hurts myself.
Especially people who label themselves socialists should have so much more tolerance to each other. If we cannot have an argument within our own ranks, how do even attempt to take on the people who outright disagree for anything we stand for? If we waste all of our time fighting each other with such ferocity, is it any surprise that no pressure can be directed towards the real culprits?
This is the most common reason why the Anarchist and Socialist movements are much more hostile towards each other, than they are towards the Capitalists. From the first time I noticed that, my initial thoughts were “But we’re on the same side?! Why are people fighting others who have the same goal in mind?”. And yet, for some of the revolutionary socialists, anyone who does not follow the rigid tactics he believes in, is as bad as the enemy. For the Anarchist , because of the misunderstanding of how Marxists try to achieve Communism, they consider them hostile. The two opposing camps in the case, simply talk past each other, exchanging more insults than ideas and stabbing each other in the back more than lending a hand.
But back to our original subject. I do not expect to last much more in the socialist reddit. Bannination threats have already been implied and the willingness to do the act admitted, so I’m obviously on a tight rope for speaking my mind and daring to argue my position. Because of this, I decided to start my own subreddit where people like me, who value conversation and don’t fear opposing viewpoints, can meet.
If you’re tired of being bullied for not being a “true socialist” and prefer intelligent discussions over insultfests, hopefully you will consider joining me at Libertarian Socialism. It’s up to us to make it what the admins of Socialism /r/ won’t let happen.
That does not mean I’m quitting socialism /r/ just yet, but It’d be nice to have a conversation without the Marxist purists insulting everyone and then calling them whiners for pointing that out. Dogma and inability to consider progressive ideas are a recipe for stagnation and if that is what is necessary to be considered a Marxist, then I’m certainly not a Marxist.
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I am suffering from asthma allergic rhinitis and nose blocked problems I am using montek lc and doxyphilline tablets for 2 months is there permanent solutions in homeopathy I have also anxiety neurosis.
hello lybrate user, yes there is complete relief and (permanent)cure for allergies rhinitis, asthma in homeopathy.
Take homeopathic treatment for your overall health issues (allergic rhinitis, asthma, and anxiety neurosis).
It’s a safe, natural and highly effective treatment.It is a holistic way of treatment, homeopathic medicine is selected on the basis of thorough details of patient, like medical history, causes, routine, temperament etc..; such well selected medicine covers overall health issues and gives complete cure without any side effects.
you can message back for proper online homeopathic consultation and homeopathic remedy prescription.
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Zesty Cheese Dip
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Zesty Cheese Dip
This dip is perfect with our Soft Pretzel Bites, but it’s also delicious for dipping tortilla chips or your favorite veggies. You can certainly buy a jar of cheese dip in the store, but this dip is so much better; and, it doesn’t have any of those weird ingredients. It only takes a few minutes to make your own cheese dip and you have the added benefit of being able to adjust the heat to your preference.
Print Recipe
Zesty Cheese Dip
This Zesty Cheese Dip is perfect for dipping just about anything. Skip the processed cheese dips and make your own in a matter of minutes. Use it for chips, over nachos, or as a dip for pretzel bites or veggies.
Servings
cups
Ingredients
1/4cupunsalted butter
1/4cupall-purpose flour
2cupswhole milk
2cupsgrated sharp cheddar cheese
2Tbsphot sauce
1tspcayenne pepper
salt, to taste
ground pepper, to taste
Servings
cups
Ingredients
1/4cupunsalted butter
1/4cupall-purpose flour
2cupswhole milk
2cupsgrated sharp cheddar cheese
2Tbsphot sauce
1tspcayenne pepper
salt, to taste
ground pepper, to taste
Instructions
In a medium size saucepan over over medium heat, melt the butter. When the butter is melted, add the flour, stirring to combine with the butter until it forms a paste. Cook for 1 to 2 minutes. Slowly add the milk, whisking constantly
Slowly add the milk, whisking constantly. Cook for about 5 minutes, while continuing to whisk. The mixture should become smooth and thickened. Add the grated cheese and whisk until it is melted and the cheese dip is smooth. Whisk in the hot sauce and cayenne pepper. Season with salt and pepper, to taste. If you want to add a bit more kick to the cheese dip, add some additional hot sauce or cayenne pepper.
The cheese dip should be of a pourable consistency. If it gets too thick, whisk in a couple of drops of milk until the dip is thick, yet still pourable.
.
Recipe Notes
Tips:
You can make this zesty cheese dip ahead of time. Store in the refrigerator until needed, then warm in the microwave or on the stovetop. |
Sample records for meister stefan werner
The article contains some recollections on Werner Callebaut highlighting his personal character and his role in the community of historians, philosophers and sociologists of the life sciences. Werner Callebaut (1952-2014) was a real European philosopher. He was the Scientific Director of the Konrad Lorenz Institute for Evolution and Cognition Research (KLI, Klosterneuburg, Austria) and the President of the International Society for the History, Philosophy, and Social Studies of Biology. PMID:26350077
Werner states are paradigmatic examples of quantum states and play an innovative role in quantum information theory. In investigating the correlating capability of Werner states, we find the curious phenomenon that quantum correlations, as quantified by the entanglement of formation, may exceed the total correlations, as measured by the quantum mutual information. Consequently, though the entanglement of formation is so widely used in quantifying entanglement, it cannot be interpreted as a consistent measure of quantum correlations per se if we accept the folklore that total correlations are measured (or rather upper bounded) by the quantum mutual information.
Stefan Meyer was one of the pioneers in radioactivity research and director of the Vienna Radium Institute, the first institution in the world devoted exclusively to radioactivity. I give here a biographical sketch of Meyer and of some of his colleagues and an overview of the research activities at the Radium Institute.
Considers the contributions of Heinz Werner to developmental psychology and identifies the tensions between Werner's theory and the practices of contemporary developmental psychology. Core issues of Werner's psychology concern: (1) development as heuristic, rather than phenomenon; (2) developmental process analysis; and (3) conceptions of the…
Attempts to provide increased understanding of the nature and function of mystical preaching as a distinctive form of discourse by investigating the sermons of the medieval German mystic Meister Eckhart (1260-ca. 1327, 1329). (MH)
This paper generalizes the Stefan-Boltzmann law to include massive photons. A crucial ingredient to obtain the correct formula for the radiance is to realize that a massive photon does not travel at the speed of (massless) light. It follows that, contrary to what could be expected, the radiance is not proportional to the energy density times the speed of light.
This paper generalizes the Stefan-Boltzmann law to include massive photons. A crucial ingredient to obtain the correct formula for the radiance is to realize that a massive photon does not travel at the speed of (massless) light. It follows that, contrary to what could be expected, the radiance is not proportional to the energy density times the speed of light.
Werner Heisenberg was one of the greatest physicists of all times. When he started out as a young research worker, the world of physics was in a very confused and frustrating state, which Abraham Pais has described1 as: It was the spring of hope, it was the winter of despair using Charles Dickens' words in A Tale of Two Cities. People were playing a guessing game: There were from time to time great triumphs in proposing, through sheer intuition, make-shift schemes that amazingly explained some regularities in spectral physics, leading to joy. But invariably such successes would be followed by further work which reveal the inconsistency or inadequacy of the new scheme, leading to despair...
We formulate a Stefan problem on an evolving hypersurface and study the well posedness of weak solutions given L1 data. To do this, we first develop function spaces and results to handle equations on evolving surfaces in order to give a natural treatment of the problem. Then, we consider the existence of solutions for data; this is done by regularization of the nonlinearity. The regularized problem is solved by a fixed point theorem and then uniform estimates are obtained in order to pass to the limit. By using a duality method, we show continuous dependence, which allows us to extend the results to L1 data. PMID:26261364
The symmetric Werner states for n qubits, important in the study of quantum nonlocality and useful for applications in quantum information, have a surprisingly simple and elegant structure in terms of tensor products of Pauli matrices. Further, each of these states forms a unique local unitary equivalence class, that is, no two of these states are interconvertible by local unitary operations.
The life of the Vienna-born writer Stefan Zweig, whose centenary will be on November 28th, 1981, is portrayed in the light of some external data. His works - mainly novellas - in which the theme of suicide plays a central role, are briefly presented, and his preference for describing psychological borderline and extreme states is stressed. One of his first poems and his last one - more than forty years lie between them - are discussed with reference to his depression and suicidal tendencies. Zweig, who at least since the First World war had been periodically suffering from depressions, was looked after and in a sense also treated by his first wife Friderike von Winternitz, until he had to leave his home in Salzburg in 1935. In 1939, he divorced from his wife and married his sickly secretary, Lotte Altmann, who suffered from asthma and depression. After prolonged stays in England, North and South America he settled in Petropolis near Rio de Janeiro in Brasil, where he spent the last months of his life. Zweig was the second son of a dominating, self-willed mother and a dignified, almost "motherly" father. He felt his childhood to have been constricted and hemmed in. His narcissism, which has played an essential role in relation to his suicide, has its roots in his childhood. Direct as well as indirect hints at suicide were not lacking during the last two years of Zweig's life, which were increasingly filled with depression and anxiety. The preface to his autobiography "The World of Yesterday" may be interpreted as an indirect announcement of suicide. On February 22nd, 1942, Zweig committed suicide together with his second wife in Petropolis. PMID:7034194
The paper deals with interdiffusion in a two-component fluid (also called binary or mutual diffusion) near isothermal equilibrium. The historical approach of Maxwell and Stefan, developed in an ideal gaseous mixture, is updated by introducing the chemical potentials of the components subsequently devised by Gibbs, which enable one to implement the Maxwell-Stefan picture of interdiffusion in an arbitrary fluid mixture. The pattern of the interdiffusion law reduces to Fick's in the high-dilution limit, but care should be taken of the reference frame in which the laws of diffusion are written. For a third-year university student, the assets of the modern Maxwell-Stefan description, besides its simplicity and inborn connection with thermodynamics, are (i) manifest Galilean invariance (the principle of relativity of motion); (ii) straightforward compatibility with fluid dynamics; and (iii) simple generalization to a multicomponent fluid in future, graduate-level studies. The value of the mutual-diffusion coefficient, which is not given by the macroscopic description, was calculated by Stefan in an ideal gaseous mixture and found to be independent of the composition. That independence is often observed in real mixtures and is taken as evidence against the mean-free-path account of diffusion. Yet a mixture of components of disparate masses shows a dependence of the mutual-diffusion coefficient on its composition, and we examine why Stefan's calculation can be invalid for this mixture.
What follows is a description of several activities involving the Stefan-Boltzmann radiation law that can provide laboratory experience beyond what is normally found in traditional introductory thermodynamics experiments on thermal expansion, specific heat, and heats of transformation. The activities also provide more extensive coverage of and…
Over 40 renowned scientists from all around the world discuss the work and influence of Werner Heisenberg. The papers result from the symposium held by the Alexander von Humboldt-Stiftung on the occasion of the 100th anniversary of Heisenberg's birth, one of the most important physicists of the 20th century and cofounder of modern-day quantum mechanics. Taking atomic and laser physics as their starting point, the scientists illustrate the impact of Heisenberg's theories on astroparticle physics, high-energy physics and string theory right up to processing quantum information.
Human fibroblast cells from two different progeroid syndromes, Werner syndrome (WS) and progeria, were established as immortalized cell lines by transfection with plasmid DNA containing the SV40 early region. The lineage of each immortalized cell line was confirmed by VNTR analysis. Each of the immortalized cell lines maintained its original phenotype of slow growth. DNA repair ability of these cells was also studied by measuring sensitivity to killing by uv or the DNA-damaging drugs methyl methansulfonate, bleomycin, and cis-dichlorodiamine platinum. The results showed that both WS and progeria cells have normal sensitivity to these agents.
We propose a theoretical scheme of quantum nondemolition measurement of two-qubit Werner state. We discuss our scheme with the two qubits restricted in a local place and then extend the scheme to the case in which two qubits are separated. We also consider the experimental realization of our scheme based on cavity quantum electrodynamics. It is very interesting that our scheme is robust against the dissipative effects introduced by the probe process. We also give a brief interpretation of our scheme finally.
We consider a nonlinear one-dimensional Stefan problem for a semi-infinite material x > 0, with phase change temperature T f . We assume that the heat capacity and the thermal conductivity satisfy a Storm's condition, and we assume a convective boundary condition at the fixed face x = 0. A unique explicit solution of similarity type is obtained. Moreover, asymptotic behavior of the solution when {h→ + ∞} is studied.
Werner's syndrome (WS) is a rare autosomal recessive disorder, characterised by skin changes prematurely during adolescence. An unusual case of WS was found in a 27-year-old pregnant woman who presented to the hospital with a history of uncontrolled hypertension at 32 weeks of gestation. All clinical features corresponding to WS (early aging of skin, hair loss, blurred vision and diabetes type 2) appeared to match with the prospective diagnosis, which was confirmed later with genetic testing. The pregnancy became complicated due to oligohydramnios and therefore a caesarean section was carried out in order to preserve the fetus. Despite all implemented efforts, the patient died intraoperative as a result of cardiac arrest and its complications. Successfully, the newborn survived and it was further investigated to exclude this condition. PMID:24302663
By Nathalie Walker, Guest Writer Editor’s note: This article represents one student’s perspective on her experiences as a Werner H. Kirsten student intern. Failure isn’t just a possibility, it is a certainty; yet failure is what leads you to success. Above all else, that is what I will retain from my experience in the Werner H. Kirsten Student Intern Program (WHK SIP).
A 52-year-old man with Werner Syndrome (WS) was admitted to our hospital for the treatment of skin ulcers on his thighs. Routine chest radiography revealed an abnormal shadow in the left upper lung field. Computed tomography (CT) revealed a poorly demarcated homogeneous mass (diameter, 4 cm) in the S1 + 2 lung area; no pleural effusion was observed. CT-guided percutaneous needle biopsy revealed the presence of an adenocarcinoma. Other imaging studies did not reveal any lymph-node involvement or presence of metastatic lesions. The patient was diagnosed with stage IB adenocarcinoma (T2N0M0), and a left upper lobectomy was successfully carried out; postoperative wound healing was steady and uneventful, with no obvious ulcer formation. Primary lung cancers very rarely develop in patients with WS; non-epithelial tumors are usually observed in such patients. Patients with WS usually develop severe skin problems, such as refractory skin ulcers in the extremities; however, our patient did not develop any skin-related complications after surgery. As the expected lifespan of patients with WS is increasing, we need to pay attention not only to the rare non-epithelial malignancy, but also cancer. Further, the expected short lifespan of patients with WS, as well as the possibility of skin-related problems after surgery, should not be considered while deciding whether to take the option of surgery in the case of malignancy. PMID:20887625
The biography of the psychiatrist and neurologist Werner Villinger reflects the ambivalence of the history of German psychiatry during the first half of the twentieth century. Politically committed to the national conservatives, he was attracted by many elements of National Socialist (Nazi) ideology. Still, he joined the party rather late and reluctantly. Villinger was a eugenist by firm conviction. While he still argued against hasty legal regulation of eugenic sterilisations in the Weimar Republic, he strongly moved for translating the law on preventing hereditarily ill progeny into reality in the institution of von Bodelschwingh in Bethel. Since 1941, Villinger, who had become a professor for psychiatry and neurology in Breslau in the meantime, acted as an expert in the framework of the National Socialist "euthanasia" programme. At the same time, however, he supported the quiet diplomacy of Rev. von Bodelschwingh in his attempt to terminate the mass murder. Villinger was also involved in criminal experiments with human beings. After 1945, he successfully continued his career in the Federal Republic of Germany. He never confronted his past during the Third Reich. PMID:12430048
A thermodynamically consistent two-phase Stefan problem with temperature-dependent surface tension and with or without kinetic undercooling is studied. It is shown that these problems generate local semiflows in well-defined state manifolds. If a solution does not exhibit singularities, it is proved that it exists globally in time and converges towards an equilibrium of the problem. In addition, stability and instability of equilibria is studied. In particular, it is shown that multiple spheres of the same radius are unstable if surface heat capacity is small; however, if kinetic undercooling is absent, they are stable if surface heat capacity is sufficiently large.
Werner Syndrome (WS, ICD-10 E34.8, ORPHA902) and Atypical Werner Syndrome (AWS, ICD-10 E34.8, ORPHA79474) are very rare inherited syndromes characterized by premature aging. While approximately 90% of WS individuals have any of a range of mutations in the WRN gene, there exists a clinical subgroup in which the mutation occurs in the LMNA/C gene in heterozygosity. Although both syndromes exhibit an age-related pleiotropic phenotype, AWS manifests the onset of the disease during childhood, while major symptoms in WS appear between the ages of 20 and 30. To study the molecular mechanisms of progeroid diseases provides a useful insight into the normal aging process. Main changes found were the decrease in Cu/Zn and Mn SOD activities in the three cell lines. In AWS, both mRNA SOD and protein levels were also decreased. Catalase and glutathione peroxidases decrease, mainly in AWS. Glutaredoxin (Grx) and thioredoxin (Trx) protein expression was lower in the three progeroid cell lines. Grx and Trx were subjected to post-transcriptional regulation, because protein expression was reduced although mRNA levels were not greatly affected in WS. PMID:24799429
The ‘Werner gap’ is the range of relevant parameters characterizing a quantum state for which it is both entangled and admits a local hidden variable model. Werner showed that the gap becomes maximal for entanglement mixed with white noise if subsystems have infinitely many levels. Here we study pure entangled states mixed with simple coloured noise modelled as a single pure product state. We provide an explicit local hidden variable model for quantum correlations of some states of this family and provide hints that there is probably a model for all quantum predictions. This demonstrates essentially a maximal Werner gap already for just two qubits. Additionally to its fundamental interest, the study has implications for quantum computation and communication. This article is part of a special issue of Journal of Physics A: Mathematical and Theoretical devoted to ‘50 years of Bell’s theorem’.
Pairwise quantum correlations in the ground state of an N-spins antiferromagnetic Heisenberg chain are investigated. By varying the exchange coupling between two neighboring sites, it is possible to reversibly drive spins from entangled to disentangled states. For even N, the two-spin density matrix is written in the form of a Werner state, allowing identification of its single parameter with the usual spin-spin correlation function. The N = 4 chain is identified as a promising system for practical demonstrations of non-classical correlations and the realization of Werner states in familiar condensed matter systems. Fabrication and measurement ingredients are within current capabilities.
VIEW OF PIEDMONT AVENUE AND MEDIAN. REPLICATING WERNER HEGEMANN PHOTO TAKEN CIRCA 1909 SEEN FROM TRAFFIC CIRCLE AT CHANNING WAY LOOKING NW. Photograph by Fredrica Drotos and Michael Kelly, July 9, 2006 - Piedmont Way & the Berkeley Property Tract, East of College Avenue between Dwight Way & U.C. Memorial Stadium, Berkeley, Alameda County, CA
VIEW OF PIEDMONT AVENUE AT BANCROFT WAY, REPLICATING WERNER HEGEMANN PHOTO CIRCA 1909, SEEN FROM WEST SIDE OF PIEDMONT LOOKING NORTH. Photograph by Fredrica Drotos and Michael Kelly, July 9, 2006 - Piedmont Way & the Berkeley Property Tract, East of College Avenue between Dwight Way & U.C. Memorial Stadium, Berkeley, Alameda County, CA
Generalizing the two-qubit purification method of Bennett et al. (Phys. Rev. Lett. 76, 722-725 1996), we present a three-qubit protocol, to purify partially entangled pairs of generalized Werner states, with application of controlled-not gates, projective measurements and Pauli rotations. The protocol is simple and recyclable and the fidelity of the purified states converge rapidly to 1, after a few cycles.
Due to the universality of blackbody radiation the constant in the Stefan-Boltzmann law connecting the energy density and temperature of blackbody radiation is either a universal constant, or built out of several universal constants. Since the Stefan-Boltzmann law follows from thermodynamics and classical electrodynamics this constant must involve the speed of light and the Boltzmann constant. However, a dimensional analysis points to the existence of an additional universal constant not present in the two classical theories giving birth to the Stefan-Boltzmann law. In the most elementary version this constant has the dimension of an action and is thereby proportional to Planck’s constant. We point out this unusual phenomenon of the combination of two classical laws creating a quantum law and speculate about its deeper origin.
Herlyn-Werner-Wunderlich (HWW) syndrome is a rare congenital disorder of the Müllerian ducts in which there is uterus didelphys, obstructed hemivagina and unilateral renal agenesis. The most common presentation is an abdominal mass secondary to hematocolpos, pain and dysmenorrhea. However, in some cases, such as the one we present here, menses are normal due to an obstructed hemivagina, and diagnosis can be delayed. We describe evaluation and surgical management of a 13-year-old girl with this condition who was diagnosed by computed tomography (CT) scan and confirmed by pelvic ultrasound and surgical exploration, as well as a review of the literature. PMID:25992503
The psychiatrist and medical historian Werner Leibbrand resigned from the Berlin Medical Association after the seizure of power in protest against the exclusion of Jewish colleagues and lost both the license to practice as well as his professional position in the public health service. After the end of the war the American military authorities appointed him as expert witness for the prosecution in the Nürnberg Doctors Trial. In addition to a biographical review, Leibbrand's resolute although still undisputed attitude as ethical expert in the trials will be roughly outlined. PMID:23942580
The multiphoton states generated by high-gain spontaneous parametric down-conversion (SPDC) in the presence of large losses are investigated theoretically and experimentally. The explicit form for the two-photon output state has been found to exhibit a Werner structure very resilient to losses for any value of the nonlinear gain parameter g. The theoretical results are found to be in agreement with experimental data obtained by 'entanglement witness' methods and by the quantum tomography of the state generated by a high-g SPDC.
We study quantum strategies in games of incomplete information using a formalism of game theory based on multi-sector probability matrix. We analyze an extension of the well-known game of Battle of Sexes using an extended Werner-like state focusing in how its mixedness and entanglement affect the Bayesian Nash payoffs of the player. It is shown that entanglement is needed to outperform classical payoffs but not all entangled states are useful due to the presence of mixedness. A threshold for the mixedness parameter and the minimum entanglement value were found.
Salva and Tarzia, [N.N. Salva, D.A. Tarzia, J. Math. Anal. Appl. 379 (2011) 240 - 244], gave explicit solutions of a similarity type for a class of free boundary problem for a semi-infinite material. In this paper, through an elementary approach and less stringent assumption on data, we obtain more general results than those given by their central result, and thereby construct explicit solutions for a wider class of Stefan problems with a type of variable heat flux boundary conditions. Further, explicit solutions of certain forced one-phase Stefan problems are given.
Werner's syndrome (WS) is an autosomal recessive genetic disorder caused by loss of function mutation in wrn and is a useful model of premature in vivo ageing. Cellular senescence is a plausible causal mechanism of mammalian ageing and, at the cellular level, WS fibroblasts show premature senescence resulting from a combination of telomeric attrition and replication fork stalling. Over 90% of WS fibroblast cultures achieve <20 population doublings (PD) in vitro compared to wild type human fibroblast cultures. It has been proposed that some cell types, capable of proliferation, will fail to show a premature senescence phenotype in response to wrn mutations. To test this hypothesis, human dermal keratinocytes (derived from both WS and wild type patients) were cultured long term. WS Keratinocytes showed a replicative lifespan in excess of 100 population doublings but maintained functional growth arrest mechanisms based on p16 and p53. The karyotype of the cells was superficially normal and the cultures retained markers characteristic of keratinocyte holoclones (stem cells) including p63 expression and telomerase activity. Accordingly we conclude that, in contrast to WS fibroblasts, WS keratinocytes do not demonstrate slow growth rates or features of premature senescence. These findings suggest that the epidermis is among the tissue types that do not display symptoms of premature ageing caused by loss of function of wrn. This is in support that Werner's syndrome is a segmental progeroid syndrome. PMID:27492502
In this work we study Podolsky electromagnetism in thermodynamic equilibrium. We show that a Podolsky mass-dependent modification to the Stefan-Boltzmann law is induced and we use experimental data to limit the possible values for this free parameter.
An exact solution of a heat conduction problem with the effect of latent heat of solidification (Stefan problem) is derived. The solution of the one dimensional Stefan problem for a finite liquid phase initially existing in a semi-infinite body is applied to evaluate temperature fields produced by laser or electron beam welding. The solution of the model has not been available before, as Carslaw and Jaeger [{ital Conduction of Heat in Solids}, 2nd ed. (Oxford University Press, New York, 1959)] pointed out. The heat conduction calculations are performed using thermal properties of carbon steel, and the comparison of the Stefan problem with a simplified linear heat conduction model reveals that the solidification rate and cooling curve over 1273 K significantly depend on which model (Stefan or linear heat conduction problem) is applied, and that the type of the thermal model applied has little meaning for cooling curve below 1273 K. Since the heat conduction problems with a phase change arise in many important industrial fields, the solution derived in this study is ready to be used not only for welding but also for other industrial applications. {copyright} {ital 1997 American Institute of Physics.}
Werner syndrome (WS) is the canonical adult human progeroid (‘premature aging’) syndrome. Patients with this autosomal recessive Mendelian disorder display constitutional genomic instability and an elevated risk of important age-associated diseases including cancer. Remarkably few analyses of WS patient tissue and tumors have been performed to provide insight into WS disease pathogenesis or the high risk of neoplasia. We used autopsy tissue from four mutation-typed WS patients to characterize pathologic and genomic features of WS, and to determine genomic features of three neoplasms arising in two of these patients. The results of these analyses provide new information on WS pathology and genomics; provide a first genomic characterization of neoplasms arising in WS; and provide new histopathologic and genomic data to test several popular models of WS disease pathogenesis. PMID:27559010
Inner-shell ionization cross sections used in Particle-Induced X-ray Elemental (PIXE) analyses are routinely calculated in the ECPSSR [W. Brandt, G. Lapicki, Phys. Rev. A 23 (1981) 1717-1729] theory and/or semiempirical formulas scaled to that theory. Thirty years after the passing of Werner Brandt, with recognition of his seminal contributions to other research on positron physics and stopping power problems, the work and articles that progressed into the ECPSSR theory for inner-shell ionization by protons and heavier ions are recalled as Brandt's past legacy to the PIXE community. Applications of the ECPSSR and its evolution into the ECUSAR [G. Lapicki, Nucl. Instr. Meth. B 189 (2002) 8-20] theory over the last three decades are reviewed with perspectives on Brandt's present legacy.
XRCC4-like factor (XLF) is involved in non-homologous end joining-mediated repair of DNA double-strand breaks (DSBs). Mutations in the WRN gene results in the development of Werner syndrome (WS), a rare autosomal recessive disorder characterized by premature ageing and genome instability. In the present study, it was identified that XLF protein levels were lower in WRN-deficient fibroblasts, compared with normal fibroblasts. Depletion of WRN in HeLa cells led to a decrease of XLF mRNA and its promoter activity. Chromatin immunoprecipitation assays demonstrated that WRN was associated with the XLF promoter. Depletion of XLF in normal human fibroblasts increased the percentage of β-galactosidase (β-gal) staining-positive cells, indicating acceleration in cellular senescence. Taken together, the results suggest that XLF is a transcriptional target of WRN and may be involved in the regulation of cellular senescence. PMID:24626809
Werner syndrome (WS) is the canonical adult human progeroid ('premature aging') syndrome. Patients with this autosomal recessive Mendelian disorder display constitutional genomic instability and an elevated risk of important age-associated diseases including cancer. Remarkably few analyses of WS patient tissue and tumors have been performed to provide insight into WS disease pathogenesis or the high risk of neoplasia. We used autopsy tissue from four mutation-typed WS patients to characterize pathologic and genomic features of WS, and to determine genomic features of three neoplasms arising in two of these patients. The results of these analyses provide new information on WS pathology and genomics; provide a first genomic characterization of neoplasms arising in WS; and provide new histopathologic and genomic data to test several popular models of WS disease pathogenesis. PMID:27559010
In a celebrated paper [Optics Communications 179, 447, 2000], A.O. Pittenger and M.H. Rubin presented for the first time a sufficient and necessary condition of separability for the generalized Werner states. Inspired by their ideas, we generalized their method to a more general case. We obtain a sufficient and necessary condition for the separability of a specific class of N d-dimensional system (qudits) states, namely special generalized Werner state (SGWS): W{sup [d{sup N}]}(v)=(1-v)(I{sup (N)})/(d{sup N}) +v|{psi}{sub d}{sup N}>={sigma}{sub i=0}{sup d-1}{alpha}{sub i}|i...i> is an entangled pure state of N qudits system and {alpha}{sub i} satisfies two restrictions: (i) {sigma}{sub i=0}{sup d-1}{alpha}{sub i}{alpha}{sub i}*=1; (ii) Matrix 1/d (I{sup (1)}+T{sigma}{sub i{ne}}{sub j}{alpha}{sub i}|i>
Present work is an attempt to compare quantum discord and quantum entanglement of quasi-Werner states formed with the four bipartite entangled coherent states (ECS) used recently for quantum teleportation of a qubit encoded in superposed coherent state. Out of these, the quasi-Werner states based on maximally ECS due to its invariant nature under local operation is independent of measurement basis and mean photon numbers, while for quasi-Werner states based on non-maximally ECS, it depends upon measurement basis as well as on mean photon number. However, for large mean photon numbers since non-maximally ECS becomes almost maximally entangled therefore dependence of quantum discord for non-maximally ECS based quasi-Werner states on the measurement basis disappears.
Werner Kolhörster belonged to the outstanding German scholars in cosmic ray and particle astrophysics, prior to World War II. But the wide fame of Victor F. Hess overshadows largely his merits nowadays.
Hutchinson-Gilford progeria syndrome (HGPS) and Werner's syndrome are representative types of progeroid syndrome. LMNA (Lamin A/C) gene mutation with atypical Werner's syndrome have recently been reported. Atypical Werner's syndrome with the severe metabolic complications, the extent of the lipodystrophy is associated with A133L mutation in the LMNA gene and these patients present with phenotypically heterogeneous disorders. We experienced a 15-yr-old Korean female with progeroid features, generalized lipodystrophy, hypertriglyceridemia, fatty liver, steatohepatitis, and type 2 diabetes mellitus. Skin fibroblasts from the patient showed marked abnormal nuclear morphology, compared with that from normal persons. Gene analysis revealed that this patient had T506del of exon 2 in the LMNA gene. We report here the first case of atypical Werner's syndrome with frameshift mutation that was caused by T506del. PMID:19270485
We demonstrate the generation of a Werner-like state from a single semiconductor quantum dot. The tomographic analysis with temporal gating brings us to a systematic understanding of the relation between the time evolution of quantum correlation and a set of parameters characterizing the exciton states, including fine-structure splitting and cross-dephasing time. The Werner state relates the Bell's parameter in the Clauser, Horne, Shimony, and Holt inequality with a fidelity, which facilitates the evaluation of nonlocality.
On the base of the Holm model, we represent two phase spherical Stefan problem and its analytical solution, which can serve as a mathematical model for diverse thermo-physical phenomena in electrical contacts. Suggested solution is obtained from integral error function and its properties which are represented in the form of series whose coefficients have to be determined. Convergence of solution series is proved.
Comments are made on the ball lightning paper of Stephan and Massey [Stefan, K.D., Massey, N., 2008. Burning molten metallic sphere: One class of ball lightning? Journal of Atmospheric and Solar-Terrestrial Physics 70, 1589-1596] that describes their [`]welding drop' theory. An alternative theory is offered based on combustion inside an atmospheric vortex. The [`]vortex fireball' hypothesis has good explanatory capability in regard to published ball lightning properties.
This paper explores the mathematical formulations of Fick and Maxwell-Stefan diffusion in the context of polymer electrolyte membrane fuel cell cathode gas diffusion layers. The simple Fick law with a diagonal diffusion matrix is an approximation of Maxwell-Stefan. Formulations of diffusion combined with mass-averaged Darcy flow are considered for three component gases. For this application, the formulations can be compared computationally in a simple, one dimensional setting. Despite the models' seemingly different structure, it is observed that the predictions of the formulations are very similar on the cathode when air is used as oxidant. The two formulations give quite different results when the Nitrogen in the air oxidant is replaced by helium (this is often done as a diagnostic for fuel cells designs). The two formulations also give quite different results for the anode with a dilute Hydrogen stream. These results give direction to when Maxwell-Stefan diffusion, which is more complicated to implement computationally in many codes, should be used in fuel cell simulations.
Placed in the bottom of a vertical tube open at the top, volatile liquid (species 1) evaporates at a rate set by diffusion of vapour through the carrier gas (species 2). In the textbook solution, due to J. Stefan, species 2 is assumed to be stationary, but numerical solutions of the governing equations show that species 2, in fact, recirculates (Mills and Chang 2013; and references therein). But although Stefan's solution is based on an incorrect assumption, the same numerical solutions show that it predicts the evaporation rate to within a few percent (Mills and Chang, below eq.12). Assuming the ratio L / a of tube length to radius to be large, we use lubrication theory to give an elementary solution determining the velocity profiles for each species, including the effect of slip. It is shown that, in the limit as L / a --> ∞ , the Stefan solution correctly determines the total evaporation rate; this conclusion is independent of the precise form of the boundary condition placed on the species velocities at the tube wall.
Background: Uterus didelphys and blind hemivagina associated with ipsilateral renal agenesis are collectively known as Herlyn-Werner-Wunderlich syndrome (HWWS). In the literature, the syndrome often appears as a single case report or as a small series. In our study, we reviewed the characteristics of all HWWS patients at Peking Union Medical College Hospital (PUMCH) and suggested a new classification for this syndrome because the clinical characteristics differed significantly between the completely and incompletely obstructed vaginal septum. This new classification allows for earlier diagnosis and treatment. Methods: From January 1986 to March 2013, all diagnosed cases of HWWS at PUMCH were reviewed. A retrospective long-term follow-up study of the clinical presentation, surgical prognosis, and pregnancy outcomes was performed. Statistical analyses were performed using SPSS, version 15.0 (IBM, Armonk, NY, USA). Between-group comparisons were performed using the χ2 test, Fisher's exact test, and the t-test. The significance level for all analyses was set at P < 0.05. Results: The clinical data from 79 patients with HWWS were analyzed until March 31, 2013. According to our newly identified characteristics, we recommend that the syndrome be classified by the complete or incomplete obstruction of the hemivagina as follows: Classification 1, a completely obstructed hemivagina and Classification 2, an incompletely obstructed hemivagina. The clinical details associated with these two types are distinctly different. Conclusions: HWWS patients should be differentiated according to these two classifications. The two classifications could be generalized by gynecologists world-wide. PMID:25591566
Population III (Pop III) stars can regulate star formation in the primordial Universe in several ways. They can ionize nearby haloes, and even if their ionizing photons are trapped by their own haloes, their Lyman-Werner (LW) photons can still escape and destroy H2 in other haloes, preventing them from cooling and forming stars. LW escape fractions are thus a key parameter in cosmological simulations of early reionization and star formation but have not yet been parametrized for realistic haloes by halo or stellar mass. To do so, we perform radiation hydrodynamical simulations of LW UV escape from 9-120 M⊙ Pop III stars in 105-107 M⊙ haloes with ZEUS-MP. We find that photons in the LW lines (i.e. those responsible for destroying H2 in nearby systems) have escape fractions ranging from 0 to 85 per cent. No LW photons escape the most massive halo in our sample, even from the most massive star. Escape fractions for photons elsewhere in the 11.18-13.6 eV energy range, which can be redshifted into the LW lines at cosmological distances, are generally much higher, being above 60 per cent for all but the least massive stars in the most massive haloes. We find that shielding of H2 by neutral hydrogen, which has been neglected in most studies to date, produces escape fractions that are up to a factor of 3 smaller than those predicted by H2 self-shielding alone.
Obstructed hemivagina and ipsilateral renal anomaly (OHVIRA), also known as Herlyn-Werner-Wunderlich syndrome, is a rare syndrome with only a few hundred reported cases described since 1922. Only a handful of these cases have been associated with pyocolpos. Mullerian duct anomalies have an incidence of 2–3%. While OHVIRA constitutes 0.16–10% of these Mullerian duct anomalies. Symptoms usually present shortly after menarche when hematocolpos develops during menstruation resulting in dysmenorrhea and a pelvic mass. The pelvic mass is the collection of blood products within the obstructed hemivagina. The first study in the diagnostic work-up is usually ultrasonography, which typically demonstrates a pelvic fluid collection which can simulate other disease processes thus confounding the diagnosis. MRI findings of the pelvis reveal a didelphic uterus. Imaging of the abdomen reveals agenesis of the ipsilateral kidney. MRI is beneficial in characterizing the didelphic uterus and vaginal septum for pre-operative planning. Understanding the imaging findings, in conjunction with the clinical presentation, is critical for early diagnosis in attempting to prevent complications such as endometriosis or adhesions from chronic infections with subsequent infertility. PMID:22690286
Obstructed hemivagina and ipsilateral renal anomaly (OHVIRA), also known as Herlyn-Werner-Wunderlich syndrome, is a rare syndrome with only a few hundred reported cases described since 1922. Only a handful of these cases have been associated with pyocolpos. Mullerian duct anomalies have an incidence of 2-3%. While OHVIRA constitutes 0.16-10% of these Mullerian duct anomalies. Symptoms usually present shortly after menarche when hematocolpos develops during menstruation resulting in dysmenorrhea and a pelvic mass. The pelvic mass is the collection of blood products within the obstructed hemivagina. The first study in the diagnostic work-up is usually ultrasonography, which typically demonstrates a pelvic fluid collection which can simulate other disease processes thus confounding the diagnosis. MRI findings of the pelvis reveal a didelphic uterus. Imaging of the abdomen reveals agenesis of the ipsilateral kidney. MRI is beneficial in characterizing the didelphic uterus and vaginal septum for pre-operative planning. Understanding the imaging findings, in conjunction with the clinical presentation, is critical for early diagnosis in attempting to prevent complications such as endometriosis or adhesions from chronic infections with subsequent infertility. PMID:22690286
We address an open question about the existence of entangled continuous-variable (CV) Werner states with positive partial transpose (PPT). We prove that no such state exists by showing that all PPT CV Werner states are separable. The separability follows by observing that these CV Werner states can be approximated by truncating the states into a finite-dimensional convex mixture of product states. In addition, the constituents of the product states comprise a generalized non-Gaussian measurement which gives, rather surprisingly, a strictly tighter upper bound on quantum discord than photon counting. These results uncover the presence of only negative partial transpose entanglement and illustrate the complexity of more general nonclassical correlations in this paradigmatic class of genuine non-Gaussian quantum states.
The contributions to this special issue of Chemical Physics report on new developments in the quantum-chemical calculation of electron correlation, relativistic effects and/or molecular properties. The 75th birthday of Professor Werner Kutzelnigg, which was celebrated a few months ago, triggered the idea to dedicate a special issue of Chemical Physics to these topics. The idea has been made real by the guest editors of this special issue together with, of course, the contributors. To the three research fields just mentioned, Werner Kutzelnigg has made important contributions throughout his scientific career, which becomes obvious when we go through the list of his 20 most-cited papers. We feel tempted to do so although Werner Kutzelnigg himself has expressed a rather critical attitude toward measuring scientific output with bibliometric tools [1].
We derive the quantitative modulus of continuity which we conjecture to be optimal for solutions of the p-degenerate two-phase Stefan problem. Even in the classical case p = 2, this represents a twofold improvement with respect to the early 1980's state-of-the-art results by Caffarelli- Evans (Arch Rational Mech Anal 81(3):199-220, 1983) and DiBenedetto (Ann Mat Pura Appl 103(4):131-176, 1982), in the sense that we discard one logarithm iteration and obtain an explicit value for the exponent α( n, p).
The classical one-phase Stefan problem (without surface tension) allows for a continuum of steady-state solutions, given by an arbitrary (but sufficiently smooth) domain together with zero temperature. We prove global-in-time stability of such steady states, assuming a sufficient degree of smoothness on the initial domain, but without any a priori restriction on the convexity properties of the initial shape. This is an extension of our previous result (Hadžić & Shkoller 2014 Commun. Pure Appl. Math. 68, 689–757 (doi:10.1002/cpa.21522)) in which we studied nearly spherical shapes. PMID:26261359
A classical laboratory experiment to verify the Stefan-Boltzmann radiation law with the tungsten filaments of commercial incandescent lamps has been fully revisited, collecting a fairly large amount of data with a computer-controlled four-channel power supply. In many cases, the total power dissipated by the lamp is well described by a sum of two power-law terms, with one exponent very close to 4, as predicted by the radiation law, and the other very close to 1, as for simple heat conduction. This result was true even for filament surfaces with a shiny metallic appearance, whose emissivity should vary with temperature.
The development of organic and physical chemistry as specialist fields, during the middle and end of the 19th century respectively, left inorganic behind as a decidedly less highly regarded subfield of chemistry. Despite Alfred Werner's groundbreaking studies of coordination chemistry in the early 20th century, that inferior status remained in place - particularly in the US - until the 1950s, when the beginnings of a resurgence that eventually restored its parity with the other subfields can be clearly observed. This paper explores the extent to which Werner's heritage - both direct, in the form of academic descendants, and indirect - contributed to those advances. PMID:24983802
A Schur complement formulation that utilizes a linear iterative solver is derived to solve a free-boundary, Stefan problem describing steady-state phase change via the Isotherm-Newton approach, which employs Newton's method to simultaneously and efficiently solve for both interface and field equations. This formulation is tested alongside more traditional solution strategies that employ direct or iterative linear solvers on the entire Jacobian matrix for a two-dimensional sample problem that discretizes the field equations using a Galerkin finite-element method and employs a deforming-grid approach to represent the melt-solid interface. All methods demonstrate quadratic convergence for sufficiently accurate Newton solves, but the two approaches utilizing linear iterative solvers show better scaling of computational effort with problem size. Of these two approaches, the Schur formulation proves to be more robust, converging with significantly smaller Krylov subspaces than those required to solve the global system of equations. Further improvement of performance are made through approximations and preconditioning of the Schur complement problem. Hence, the new Schur formulation shows promise as an affordable, robust, and scalable method to solve free-boundary, Stefan problems. Such models are employed to study a wide array of applications, including casting, welding, glass forming, planetary mantle and glacier dynamics, thermal energy storage, food processing, cryosurgery, metallurgical solidification, and crystal growth.
Medieval medicine and pharmacy were the subjects of numerous researches. The enviable level of health culture and social care of the diseased and debilitated people of the Serbian medieval state was far advanced for the time. However, there are scarce written records of the conditions. The purpose of this paper is to point out the conditions which enabled the foundation of the first Serbian hospitals, development of scientific medicine and spiritual culture in medieval Serbian lands. Favourable conditions for the development of medieval medicine are linked with the arrival of the Nemanjić dynasty to the throne of the Serbian medieval state, i.e. Stefan Nemanja, and later with the life and work of his son Prince Rastko Nemanjić - Saint Sava. The wide field of activity of the Grand Prince Stefan Nemanja included the creation of stable and independent state ("the unifier of all Serbian lands") with a significant and shrewd political activity (vassal to Byzantine Emperor Manuel Comnenus, participation in great alliances against Byzantium), building of churches, defender of the Orthodox Christianity, foundation of the first Serbian hospital outside of borders of Serbian state in Hilandar monastery, social care about people and cultivating literary activity. PMID:22650117
A big honor for small objects: The Nobel Prize in Chemistry 2014 was jointly awarded to Eric Betzig, Stefan Hell, and William E. Moerner "for the development of super-resolved fluorescence microscopy". This Highlight describes how the field of super-resolution microscopy developed from the first detection of a single molecule in 1989 to the sophisticated techniques of today. PMID:25371081
Solution of the heat equation in a spherical domain with two free boundaries (two-phase Stefan problem) when one of the subdomains degenerates at the initial time is considered. The use of conventional finite-difference methods in these cases is not expedient because of the degenerate domain. The solution is found in the form of combination of Integral Error functions series, [M. Sarsengeldin, and S. Kharin, Filomat, (2016), (in Press)] and then recurrent solvability of nonlinear algebraic equations for determining the coefficients of the series is proved. Such problems are of practical interest for the simulation of laser material processing as well for the modeling of thermal effects of electric arc that ignites during the opening of electric contacts [S. N. Kharin, and M. Sarsengeldin, Influence of contact materials on phenomena in a short electrical arc, in Key Engineering Materials, Trans tech publications, Islamabad, Pakistan, 2012, pp. 321-329].
Herlyn-Werner-Wunderlich (HWW) syndrome is a very rare congenital anomaly of the urogenital tract resulting from maldevelopment of both Mullerian and Wolffian ducts. It is characterized by the triad of uterus didelphys, obstructed hemivagina and ipsilateral renal agenesis. It generally presents at puberty shortly following menarche with the symptom of acute pelvic pain. Management of these cases is surgical and consists mainly of vaginoplasty with excision of the vaginal septum in order to release the obstruction and prevent the long term complication of recurrent pyocolpos and infertility. We report here a case of Herlyn-Werner-Wunderlich syndrome in a 13-year-old adolescent girl, emphasizing the role of imaging in the accurate and prompt diagnosis of this rare developmental urogenital anomaly. Only a few hundred such cases have been reported in literature till date. PMID:26155531
Herlyn-Werner-Wunderlich syndrome is characterized by a triad of uterine didelphys, obstructed hemivagina, and ipsilateral renal agenesis. The syndrome should be suspected in any young woman with abdominal pain or cyclic dysmenorrhea, and radiologic evidence of müllerian duct and renal anomalies. Herein is presented the case of a 25-year-old woman with a rare variant of Herlyn-Werner-Wunderlich syndrome, characterized by an anomalous connection between the 2 endocervical canals, who underwent hemivaginal septum resection to relieve progressively worsening dysmenorrhea. The right hemivaginal septum was resected medially from the left cervix and laterally off the right vaginal wall. Hydrodissection between the hemivaginal septum and right cervix facilitated surgical resection. After resection of the hemivaginal septum there was complete resolution of dysmenorrhea and no recurrence of hematometra or hematocolpos. PMID:24858986
Herlyn-Werner-Wunderlich (HWW) syndrome is a very rare congenital anomaly of the urogenital tract resulting from maldevelopment of both Mullerian and Wolffian ducts. It is characterized by the triad of uterus didelphys, obstructed hemivagina and ipsilateral renal agenesis. It generally presents at puberty shortly following menarche with the symptom of acute pelvic pain. Management of these cases is surgical and consists mainly of vaginoplasty with excision of the vaginal septum in order to release the obstruction and prevent the long term complication of recurrent pyocolpos and infertility. We report here a case of Herlyn-Werner-Wunderlich syndrome in a 13-year-old adolescent girl, emphasizing the role of imaging in the accurate and prompt diagnosis of this rare developmental urogenital anomaly. Only a few hundred such cases have been reported in literature till date. PMID:26155531
This paper follows Werner Heisenberg and Carl Friedrich von Weizsäcker during their fifty-year friendship from 1926, when they first met in Copenhagen, to Heisenberg's death in Munich in 1976. The relationship underwent profound changes during that period, as did physics, philosophy, and German society and politics, all of which exerted important influences on their lives, work, and interactions with each other. The nature of these developments and their impact are explored in this paper.
Multicomponent diffusional mechanisms in the ternary LiCl-KCl system are elucidated using the Green-Kubo formalism and equilibrium molecular dynamics simulations. The Maxwell-Stefan (MS) diffusion matrix is evaluated from the Onsager dynamical matrix that contains the diffusion flux correlation functions. From the temporal behavior of the correlation functions, we observe that the Li-Li and Li-Cl ion pairs have a pronounced cage dynamics that remains noticeably strong even at high temperatures. Even though the Onsager coefficients, which are the time integrals of the diffusion flux correlation functions, portray a relatively smooth variation across various compositions and temperatures, we observe a sign change and a divergent-like behavior for the MS diffusivity of the K-Li ion pair at a temperature of ˜1100 K for the eutectic composition, and at a KCl mole fraction of ˜0.49 at 1043 K. Negative MS diffusivities, while unusual, are however shown to satisfy the nonnegative entropic constraints.
Jožef Stefan Institute recently commissioned a high brightness H- ion beam injection system for its existing tandem accelerator facility. Custom developed by High Voltage Engineering Europa, the multicusp ion source has been tuned to deliver at the entrance of the Tandetron™ accelerator H- ion beams with a measured brightness of 17.1 A m-2 rad-2 eV-1 at 170 μA, equivalent to an energy normalized beam emittance of 0.767 π mm mrad MeV1/2. Upgrading the accelerator facility with the new injection system provides two main advantages. First, the high brightness of the new ion source enables the reduction of object slit aperture and the reduction of acceptance angle at the nuclear microprobe, resulting in a reduced beam size at selected beam intensity, which significantly improves the probe resolution for micro-PIXE applications. Secondly, the upgrade strongly enhances the accelerator up-time since H and He beams are produced by independent ion sources, introducing a constant availability of 3He beam for fusion-related research with NRA. The ion beam particle losses and ion beam emittance growth imply that the aforementioned beam brightness is reduced by transport through the ion optical system. To obtain quantitative information on the available brightness at the high-energy side of the accelerator, the proton beam brightness is determined in the nuclear microprobe beamline. Based on the experience obtained during the first months of operation for micro-PIXE applications, further necessary steps are indicated to obtain optimal coupling of the new ion source with the accelerator to increase the normalized high-energy proton beam brightness at the JSI microprobe, currently at 14 A m-2 rad-2 eV-1, with the output current at 18% of its available maximum.
A neonate with a prenatal diagnosis of left renal agenesis was born at 33 weeks gestation. A postnatal abdominal ultrasound confirmed the absence of the left kidney and revealed two non-divergent hemiuteri, consistent with the diagnosis of Herlyn-Werner-Wunderlich syndrome. During admission, significant axial hypotonia was noted, warranting additional investigations. Brain ultrasounds and MRI were normal, as were a preliminary metabolic study and comparative genomic hybridisation array. DNA methylation testing confirmed the diagnosis of Prader-Willi syndrome. The baby was discharged after 70 days, breast feeding and with modest hypotonia improvement. PMID:26491004
Herlyn-Werner-Wunderlich syndrome (HWWS), characterized by uterus didelphys, obstructed hemivagina, and ipsilateral renal agenesis, is an uncommon combined Mullerian and mesonephric duct anomaly, and its presentation in adulthood is even rarer. We report here a 22-year-old female presenting with primary infertility where magnetic resonance imaging (MRI) suggested the diagnosis of HWWS with endometriosis. In a patient of infertility with endometriosis and unilateral renal agenesis, diagnosis of HWWS should be suspected and MRI is the investigation of choice for such anomalies. PMID:24347855
An enthalpy transforming scheme is proposed to convert the energy equation into a nonlinear equation with the enthalpy, E, being the single dependent variable. The existing control-volume finite-difference approach is modified so it can be applied to the numerical performance of Stefan problems. The model is tested by applying it to a three-dimensional freezing problem. The numerical results are in agreement with those existing in the literature. The model and its algorithm are further applied to a three-dimensional moving heat source problem showing that the methodology is capable of handling complicated phase-change problems with fixed grids.
Herlyn-Werner-Wunderlich syndrome (HWWS) is a rare congenital mullerian anomaly consisting of uterus didelphys, hemivaginal septum, and unilateral renal agenesis [1,2]. Most authors reported cases of Herlyn-Werner-Wunderlich syndrome with prepuberal or postpuberal onset with cyclical abdominal pain and a vaginal mass (3-8). Only six cases are reported in Literature with early onset of this syndrome under 5 years (9-14). Our case is about 3 years old girl, with all the features of this syndrome who came to our attention for lower abdominal mass. The aim of this article is to share our experience and focus the attention on the importance of high level of suspicion of HWWS in neonatal period to early diagnosis and treatment. The possible early presentation of this syndrome should be suspected in all neonates (females) with renal agenesia confirmed postnatally or with prenatal diagnosis. It is common, in fact, an error of evaluation with planning of removal of mass, that can damage patients in term of chance for a successful reproductive outcome. For all these reasons, our team consider HWWS as differential diagnosis in newborn with prenatal ultrasonography of a cystic mass behind the urinary bladder in the absence of a kidney and plan a pelvic ultrasound (with aim to identify an uterus, normal or dydhelfus, and presence or absence of pelvic mass), an examination under anesthesia and cystoscopy and vaginoscopy, if it is necessary. A high level of suspicion, indeed, is the key to early diagnosis. PMID:25932973
Atypical progeroid syndrome (APS), including atypical Werner syndrome (AWS), is a progeroid syndrome involving heterozygous mutations in the LMNA gene encoding the nuclear protein lamin A/C. We report the first Japanese case of APS/AWS with a LMNA mutation (p.D300N). A 53-year-old Japanese man had a history of recurrent severe cardiovascular diseases as well as brain infarction and hemorrhages. Although our APS/AWS patient had overlapping features with Werner syndrome (WS), such as high-pitched voice, scleroderma, lipoatrophy and atherosclerosis, several cardinal features of WS, including short stature, premature graying/alopecia, cataract, bird-like face, flat feet, hyperkeratosis on the soles and diabetes mellitus, were absent. In immunofluorescence staining and electron microscopic analyses of the patient's cultured fibroblasts, abnormal nuclear morphology, an increase in small aggregation of heterochromatin and a decrease in interchromatin granules in nuclei of fibroblasts were observed, suggesting that abnormal nuclear morphology and chromatin disorganization may be associated with the pathogenesis of APS/AWS. PMID:25327215
The formation of the first stars is an exciting frontier area in astronomy. Early redshifts (z ˜ 20) have become observationally promising as a result of a recently recognized effect of a supersonic relative velocity between the dark matter and gas. This effect produces prominent structure on 100 comoving Mpc scales, which makes it much more feasible to detect 21-cm fluctuations from the epoch of first heating. We use semi-numerical hybrid methods to follow for the first time the joint evolution of the X-ray and Lyman-Werner radiative backgrounds, including the effect of the supersonic streaming velocity on the cosmic distribution of stars. We incorporate self-consistently the negative feedback on star formation induced by the Lyman-Werner radiation, which dissociates molecular hydrogen and thus suppresses gas cooling. We find that the feedback delays the X-ray heating transition by Δz ˜ 2, but leaves a promisingly large fluctuation signal over a broad redshift range. The large-scale power spectrum is predicted to reach a maximal signal-to-noise ratio of S/N ˜ 3-4 at z ˜ 18 (for a projected first-generation instrument), with S/N >1 out to z ˜ 22-23. We hope to stimulate additional numerical simulations as well as observational efforts focused on the epoch prior to cosmic reionization.
Segmental progeroid syndromes are rare, heterogeneous disorders characterized by signs of premature aging affecting more than one tissue or organ. A prototypic example is the Werner syndrome (WS), caused by biallelic germline mutations in the Werner helicase gene (WRN). While heterozygous lamin A/C (LMNA) mutations are found in a few nonclassical cases of WS, another 10%–15% of patients initially diagnosed with WS do not have mutations in WRN or LMNA. Germline POLD1 mutations were recently reported in five patients with another segmental progeroid disorder: mandibular hypoplasia, deafness, progeroid features syndrome. Here, we describe eight additional patients with heterozygous POLD1 mutations, thereby substantially expanding the characterization of this new example of segmental progeroid disorders. First, we identified POLD1 mutations in patients initially diagnosed with WS. Second, we describe POLD1 mutation carriers without clinically relevant hearing impairment or mandibular underdevelopment, both previously thought to represent obligate diagnostic features. These patients also exhibit a lower incidence of metabolic abnormalities and joint contractures. Third, we document postnatal short stature and premature greying/loss of hair in POLD1 mutation carriers. We conclude that POLD1 germline mutations can result in a variably expressed and probably underdiagnosed segmental progeroid syndrome. PMID:26172944
Segmental progeroid syndromes are rare, heterogeneous disorders characterized by signs of premature aging affecting more than one tissue or organ. A prototypic example is the Werner syndrome (WS), caused by biallelic germline mutations in the Werner helicase gene (WRN). While heterozygous lamin A/C (LMNA) mutations are found in a few nonclassical cases of WS, another 10%-15% of patients initially diagnosed with WS do not have mutations in WRN or LMNA. Germline POLD1 mutations were recently reported in five patients with another segmental progeroid disorder: mandibular hypoplasia, deafness, progeroid features syndrome. Here, we describe eight additional patients with heterozygous POLD1 mutations, thereby substantially expanding the characterization of this new example of segmental progeroid disorders. First, we identified POLD1 mutations in patients initially diagnosed with WS. Second, we describe POLD1 mutation carriers without clinically relevant hearing impairment or mandibular underdevelopment, both previously thought to represent obligate diagnostic features. These patients also exhibit a lower incidence of metabolic abnormalities and joint contractures. Third, we document postnatal short stature and premature greying/loss of hair in POLD1 mutation carriers. We conclude that POLD1 germline mutations can result in a variably expressed and probably underdiagnosed segmental progeroid syndrome. PMID:26172944
4-Hydroxy-2-nonenal (HNE) is a reactive α,β-unsaturated aldehyde generated during oxidative stress and subsequent peroxidation of polyunsaturated fatty acids. Here, Werner protein (WRN) was identified as a novel target for modification by HNE. Werner syndrome arises through mutations in the WRN gene that encodes the RecQ DNA helicase which is critical for maintaining genomic stability. This hereditary disease is associated with chromosomal instability, premature aging and cancer predisposition. WRN appears to participate in the cellular response to oxidative stress and cells devoid of WRN display elevated levels of oxidative DNA damage. We demonstrated that helicase/ATPase and exonuclease activities of HNE-modified WRN protein were inhibited both in vitro and in immunocomplexes purified from the cell extracts. Sites of HNE adduction in human WRN were identified at Lys577, Cys727, His1290, Cys1367, Lys1371 and Lys1389. We applied in silico modeling of the helicase and RQC domains of WRN protein with HNE adducted to Lys577 and Cys727 and provided a potential mechanism of the observed deregulation of the protein catalytic activities. In light of the obtained results, we postulate that HNE adduction to WRN is a post-translational modification, which may affect WRN conformational stability and function, contributing to features and diseases associated with premature senescence. PMID:25170083
Werner Heisenberg was one of the greatest physicists of the 20th century. He participated as a front rank actor in the shaping of a good part of XXth century physics and directly witnessed most of the intellectual struggles which led to what he called “Wandlungen in den Grundlagen der exakten Naturwissenschaft”. This expression is borrowed from one of the many talks and writings he devoted to the analysis of the scientific and philosophical implications of his, and his fellows physicists, findings. Indeed, Heisenberg's scientific activity increasingly reflected his more general intellectual views. This makes him another magnificent representative of a glorious linage going from the remote times of modern science to Einstein, Bohr and the like. This “philosophical” vein started early in his scientific life, and got stronger with time, prompted by the highly demanding scientific, but also social and political context of his mature years.
We ascertain, following ideas of Arnesen, Bose, and Vedral concerning thermal entanglement [Phys. Rev. Lett. 87 (2001) 017901] and using the statistical tool called entropic non-triviality [P.W. Lamberti, M.T. Martin, A. Plastino, O.A. Rosso, Physica A 334 (2004) 119], that there is a one-to-one correspondence between (i) the mixing coefficient x of a Werner state, on the one hand, and (ii) the temperature T of the one-dimensional Heisenberg two-spin chain with a magnetic field B along the z-axis, on the other one. This is true for each value of B below a certain critical value B. The pertinent mapping depends on the particular B-value one selects within such a range.
The following short biography recalls Professor Dr. Dr. h.c. Werner Schäfer, emeritus professor and director of the Medical Biology Department of the Max-Planck-Institut für Virusforschung in Tübingen and scientific member of the Max-Planck Society who died on 25th April 2000. He was one of the most distinguished pioneers of animal virology and one of the great personalities who since the Second World War have helped German science to regain its international reputation. In a brief synopsis the important results of his work on the viruses he used as models to conduct his research have been portrayed. As a result of Schäfer's scientific conception to gain insights into the functional characteristics of viruses by looking at their structure, the field of virology has taken new directions and founded a school whose pupils try to continue his successful and much honoured life's work. PMID:10955000
Herlyn-Werner-Wunderlich (HWW) syndrome is a rare müllerian duct anomaly with uterus didelphys, unilateral obstructed hemivagina, and ipsilateral renal agenesis. Patients with this syndrome generally present after menarche with pelvic pain and mass and, rarely, primary infertility in later years. Strong suspicion and knowledge of this syndrome are mandatory for an accurate diagnosis. A 14-year-old female patient presented with acute retention of urine and abdominopelvic pain. Her condition was diagnosed with the use ultrasonography and magnetic resonance imaging as a case of HWW syndrome. She was treated with vaginal hemiseptal resection. The HWW syndrome should be considered among the differential diagnoses in girls with renal anomalies presenting with pelvic mass, symptoms of acute abdominal pain, and acute urinary retention. PMID:24378860
Quantum information processing is largely dependent on the robustness of non-classical correlations, such as entanglement and quantum discord. However, all the realistic quantum systems are thermodynamically open and lose their coherence with time through environmental interaction. The time evolution of quantum entanglement, discord, and the respective classical correlation for a single, spin-1/2 particle under spin and energy degrees of freedom, with an initial Werner state, has been investigated in the present study. The present intra-particle system is considered to be easier to produce than its inter-particle counterpart. Experimentally, this type of system may be realized in the well-known Penning trap. The most stable correlation was identified through maximization of a system-specific global objective function. Quantum discord was found to be the most stable, followed by the classical correlation. Moreover, all the correlations were observed to attain highest robustness under initial Bell state, with minimum possible dephasing and decoherence parameters.
We redescribe Cyrtodactylus lateralis (Werner) on the basis of new specimens. Cyrtodactylus lateralis is a prehensile-tailed species, known from scattered lowland to mid-elevation localities in northern Sumatra. The prehensile-tailed Cyrtodactylus are more speciose and have a wider distribution than previously thought. This group includes a mainland SE Asian clade consisting of C. elok, C. interdigitalis, and C. brevipalmatus and an insular clade containing C. durio, C. lateralis, C. nuaulu, C. serratus, C. spinosus, and C. stresemanni. However, a distinctive color pattern in the Wallacean and Papuan species and uncertainty surrounding the type locality of C. stresemanni raise unresolved questions about the inclusiveness of the insular clade. DNA sequence data supports a close relationship between C. elok and C. interdigitalis, but also reveals that C. lateralis and C. durio are not closely related to these species. PMID:27394838
Werner syndrome (WS, MIM#277700) is a very rare autosomal recessive disorder. WS clinical signs include altered distribution of subcutaneous fat, juvenile bilateral cataracts, a mask-like face and bird-like nose, trophic ulcers of the feet, diabetes mellitus, and premature atherosclerosis. The habitus is characteristic, with short stature, stocky trunk and slender extremities. WS frequency has been roughly estimated to be 1: 100,000 in Japan and 1: 1,000,000-1: 10,000,000 outside of Japan. The only exception to the latter data can be seen in the clustering of WS in Sardinia. Since 2001, 5 new cases have been observed: 4 members of the same family and 1 sporadic case. Therefore, since 1982 the total number of cases described in North Sardinia amounts to 18: 15 are familial (11 members of the same family group) and 3 sporadic. A short clinical description of the 5 new cases is reported. PMID:17478382
The entanglement evolution of the bipartite quantum system which is initially prepared in extended Werner-like state under the influence of independent or collective noisy channels are investigated by solving the master equation in Lindblad form. With the aid of the concurrence, we find that the initial state can preserve more entanglement in certain region when it is transmitted through the collective Pauli σ x or σ y noisy channel than the corresponding independent noisy channel. For the Pauli σ z or the depolarizing channel, however, the collective decoherence can speed up the process of entanglement decay. Meanwhile, we show that the purity of initial state has a great influence on the region which the entanglement can be preserved.
Obstructive mullerian anomalies give rise to a spectrum of clinical presentations and are uncommon in routine gynecologic practice. The patient usually becomes symptomatic in early reproductive years. Recurrent pelvic pain, dysmenorrhea, enlarging abdominopelvic mass, and abnormal vaginal discharge are the common presenting symptoms. We describe a rare case of a mullerian anomaly getting diagnosed 13 years after attaining menarche during the evaluation of postabortal sepsis. Patient presented 2 weeks following evacuation carried out for missed abortion, with acute abdominal pain, fever and foul smelling discharge per vaginum. The anomaly was identified as uterus didelphys with obstructed left hemivagina and ipsilateral renal agenesis (Herlyn-Werner-Wunderlich syndrome) complicated by pyocolpos. She was successfully managed by single-stage transvaginal septum resection under laparoscopic control. PMID:26085755
Herlyn-Werner-Wunderlich (HWW) syndrome is an uncommon combined müllerian duct anomalies (MDAs) and mesonephric duct malformation of female urogenital tract characterized by uterus didelphys and obstructed hemi-vagina and ipsilateral renal agenesis (OHVIRA) syndrome. We present a rare and unusual case of this syndrome in a 19 year-old female who suffered from hypomenorrhoea and abdominal pain. She had an obstructed hemi-vagina on right side which led to marked distention of ipsilateral cervix, while proximal hemi-vagina compressed the contralateral side causing its partial obstruction resulting in hypomenorrhoea. Understanding the imaging findings of this rare condition is important for early diagnosis in order to prevent complications which may lead to infertility. PMID:27123211
Herlyn-Werner-Wunderlich (HWW) syndrome is an uncommon combined müllerian duct anomalies (MDAs) and mesonephric duct malformation of female urogenital tract characterized by uterus didelphys and obstructed hemi-vagina and ipsilateral renal agenesis (OHVIRA) syndrome. We present a rare and unusual case of this syndrome in a 19 year-old female who suffered from hypomenorrhoea and abdominal pain. She had an obstructed hemi-vagina on right side which led to marked distention of ipsilateral cervix, while proximal hemi-vagina compressed the contralateral side causing its partial obstruction resulting in hypomenorrhoea. Understanding the imaging findings of this rare condition is important for early diagnosis in order to prevent complications which may lead to infertility. PMID:27123211
Uterovaginal duplication with obstructed hemivagina and ipsilateral renal agenesis is referred to as the Herlyn-Werner-Wunderlich (HWW) syndrome. A 17 year old woman presented with right pelvic pain and dysmenorrhea, present since menarche at 13 and worsening over the past year. Ultrasound examination revealed a right pelvic mass (5×5 cm), double endometrial echoes, and hematocolpos. A right pelvic mass, agenesis of the right kidney, double uterus, and blind hemivagina with hematocolpos were detected by magnetic resonance imaging and intravenous pyelography. A right tubo-ovarian abscess with dense adhesions and a double uterus were observed on diagnostic laparoscopy. Adhesiolysis was carried out and purulent material irrigated. After a course of antibiotics, a vaginal septum resection was performed and the pyocolpos drained. She remained symptom free after four months of follow-up. Prompt and accurate diagnosis and treatment of this syndrome can significantly improve the lives of sufferers and prevent future complications. PMID:24591910
The maximum lifespan potential is a constitutional feature of speciation and must be subject to polygenic controls acting both in the domain of development and in the domain of the maintenance of macromolecular integrity. The enormous genetic heterogeneity that characterizes our own species, the complexities of numerous nature-nurture interactions, and the quantitative and qualitative variations of the senescent phenotype that are observed suggest that precise patterns of aging in each of us may be unique. Patterns of aging may also differ sharply among species (for example, semelparous vs. multiparous mammals). Some potential common denominators, however, allow one to identify progeroid syndromes in man that could lead to the elucidation of important pathways of gene action. (The suffix "-oid" means "like"; it does not mean identity.) Unimodal progeroid syndromes (eg., familial dementia of the Alzheimer type, an autosomal dominant) can help us understand the pathogenesis of a particular aspect of the senescent phenotype of man. Segmental progeroid syndromes (eg. the Werner syndrome, an autosomal recessive) may be relevant to multiple aspects of the senescent phenotype. Some results of research on the Werner syndrome may be interpreted as support for "peripheral" as opposed to "central" theories of aging; they are consistent with the view that gene action in the domain of development (adolescence, in this instance) can set the stage for patterns of aging in the adult; they point to the importance of mesenchymal cell populations in the pathogenesis of age-related disorders; finally, they underscore the role of chromosomal instability, especially in the pathogenesis of neoplasia. PMID:3909765
The diffusion process in a multicomponent system can be formulated in a general form by the generalized Maxwell-Stefan equations. This formulation is able to describe the diffusion process in different systems, such as, for instance, bulk diffusion (in the gas, liquid, and solid phase) and diffusion in microporous materials (membranes, zeolites, nanotubes, etc.). The Maxwell-Stefan equations can be solved analytically (only in special cases) or by numerical approaches. Different numerical strategies have been previously presented, but the number of diffusing species is normally restricted, with only few exceptions, to three in bulk diffusion and to two in microporous systems, unless simplifications of the Maxwell-Stefan equations are considered. In the literature, a large effort has been devoted to the derivation of the analytic expression of the elements of the Fick-like diffusion matrix and therefore to the symbolic inversion of a square matrix with dimensions n x n (n being the number of independent components). This step, which can be easily performed for n = 2 and remains reasonable for n = 3, becomes rapidly very complex in problems with a large number of components. This paper addresses the problem of the numerical resolution of the Maxwell-Stefan equations in the transient regime for a one-dimensional system with a generic number of components, avoiding the definition of the analytic expression of the elements of the Fick-like diffusion matrix. To this aim, two approaches have been implemented in a computational code; the first is the simple finite difference second-order accurate in time Crank-Nicolson scheme for which the full mathematical derivation and the relevant final equations are reported. The second is based on the more accurate backward differentiation formulas, BDF, or Gear's method (Shampine, L. F. ; Gear, C. W. SIAM Rev. 1979, 21, 1.), as implemented in the Livermore solver for ordinary differential equations, LSODE (Hindmarsh, A. C. Serial
NaF-ZrF4 is used as a waste incinerator and as a coolant in Generation IV reactors.Structural and dynamical properties of molten NaF-ZrF4 system were studied along with Onsagercoefficients and Maxwell-Stefan (MS) Diffusivities applying Green-Kubo formalism and molecular dynamics (MD) simulations. The zirconium ions are found to be 8 fold coordinated with fluoride ions for all temperatures and concentrations. All the diffusive flux correlations show back-scattering. Even though the MS diffusivities are expected to depend very lightly on the composition because of decoupling of thermodynamic factor, the diffusivity ĐNa-F shows interesting behavior with the increase in concentration of ZrF4. This is because of network formation in NaF-ZrF4. Positive entropy constraints have been plotted to authenticate negative diffusivities observed.
It has recently been suggested (S.B. Giddings (2016) [2]) that the Hawking black-hole radiation spectrum originates from an effective quantum "atmosphere' which extends well outside the black-hole horizon. In particular, comparing the Hawking radiation power of a (3 + 1)-dimensional Schwarzschild black hole of horizon radius rH with the familiar Stefan-Boltzmann radiation power of a (3 + 1)-dimensional flat space perfect blackbody emitter, Giddings concluded that the source of the Hawking semi-classical black-hole radiation is a quantum region outside the Schwarzschild black-hole horizon whose effective radius rA is characterized by the relation Δr ≡rA -rH ∼rH. It is of considerable physical interest to test the general validity of Giddings's intriguing conclusion. To this end, we study the Hawking radiation of (D + 1)-dimensional Schwarzschild black holes. We find that the dimensionless radii rA /rH which characterize the black-hole quantum atmospheres, as determined from the Hawking black-hole radiation power and the (D + 1)-dimensional Stefan-Boltzmann radiation law, are a decreasing function of the number D + 1 of spacetime dimensions. In particular, it is shown that radiating (D + 1)-dimensional Schwarzschild black holes are characterized by the relation (rA -rH) /rH ≪ 1 in the large D ≫ 1 regime. Our results therefore suggest that, at least in some physical cases, the Hawking emission spectrum originates from quantum excitations very near the black-hole horizon.
The vacuum ultraviolet electron-impact-induced fluorescence emissions of H2 were studied for the Lyman and Werner band systems in the range of 120-170 nm, using an optical system containing a photomultiplier and a spectrometer, over an energy range from threshold to 400 eV. The emission cross sections for the Lyman and Werner transitions at 100 eV are determined. The cross-section ratio is in excellent agreement with theoretical calculations and experimental data for the optical oscillator strengths. The cross-section for cascading to the B state is stated as a percentage of the total emission cross section at both 100 and 300 eV, increasing substantially at 20 eV. The vibrational population distribution of the B state is found to be a function of electron-impact energy as the importance of cascading relative to direct excitation changes with electron-impact energy.
Herlyn-Werner-Wunderlich (HWW) syndrome is a rare variant of Müllerian duct anomalies consisting of uterine didelphys, obstructed hemivagina, and ipsilateral renal agenesis. Patients with HWW syndrome are usually asymptomatic until menarche, when they present with acute lower abdominal pain. Here we report a case of a female newborn with right renal agenesis diagnosed during the pregnancy. The patient presented with a protruding mass over the vaginal introitus that was associated with an obstructed hemivagina and uterine didelphys. PMID:22348499
Luminous quasars detected at redshifts z > 6 require that the first black holes form early and grow to ~109 solar masses within one Gyr. Our work uses cosmological simulations to study the formation and early growth of direct collapse black holes. In the pre-reionization epoch, molecular hydrogen (H2) causes gas to fragment and form Population III stars, but Lyman-Werner radiation can suppress H2 formation and allow gas to collapse directly into a massive black hole. The critical flux required to inhibit H2 formation, Jcrit, is hotly debated, largely due to the uncertainties in the source radiation spectrum, H2 self-shielding, and collisional dissociation rates. Here, we test the power of the direct collapse model in a non-uniform Lyman-Werner radiation field, using an updated version of the SPH+N-body tree code Gasoline with H2 non-equilibrium abundance tracking, H2 cooling, and a modern SPH implementation. We vary Jcrit from 30 to 104 J21 to study the effect on seed black holes, focusing on black hole formation as a function of environment, halo mass, metallicity, and proximity of the Lyman-Werner source. We discuss the constraints on massive black hole occupation fraction in the quasar epoch, and implications for reionization, high-redshift X-ray background radiation, and gravitational waves.
Background Laminopathies, due to mutations in LMNA, encoding A type-lamins, can lead to premature ageing and/or lipodystrophic syndromes, showing that these diseases could have close physiopathological relationships. We show here that lipodystrophy and extreme insulin resistance can also reveal the adult progeria Werner syndrome linked to mutations in WRN, encoding a RecQ DNA helicase. Methods We analysed the clinical and biological features of two women, aged 32 and 36, referred for partial lipodystrophic syndrome which led to the molecular diagnosis of Werner syndrome. Cultured skin fibroblasts from one patient were studied. Results Two normal-weighted women presented with a partial lipodystrophic syndrome with hypertriglyceridemia and liver steatosis. One of them had also diabetes. Both patients showed a peculiar, striking lipodystrophic phenotype with subcutaneous lipoatrophy of the four limbs contrasting with truncal and abdominal fat accumulation. Their oral glucose tolerance tests showed extremely high levels of insulinemia, revealing major insulin resistance. Low serum levels of sex-hormone binding globulin and adiponectin suggested a post-receptor insulin signalling defect. Other clinical features included bilateral cataracts, greying hair and distal skin atrophy. We observed biallelic WRN null mutations in both women (p.Q748X homozygous, and compound heterozygous p.Q1257X/p.M1329fs). Their fertility was decreased, with preserved menstrual cycles and normal follicle-stimulating hormone levels ruling out premature ovarian failure. However undetectable anti-müllerian hormone and inhibin B indicated diminished follicular ovarian reserve. Insulin-resistance linked ovarian hyperandrogenism could also contribute to decreased fertility, and the two patients became pregnant after initiation of insulin-sensitizers (metformin). Both pregnancies were complicated by severe cervical incompetence, leading to the preterm birth of a healthy newborn in one case, but to a
Purpose. To examine the promoter methylation and histone modification of WRN (Werner syndrome gene), a DNA repair gene, and their relationship with the gene expression in age-related cataract (ARC) lens. Methods. We collected the lenses after cataract surgery from 117ARC patients and 39 age-matched non-ARC. WRN expression, DNA methylation and histone modification around the CpG island were assessed. The methylation status of Human-lens-epithelium cell (HLEB-3) was chemically altered to observe the relationship between methylation and expression of WRN. Results. The WRN expression was significantly decreased in the ARC anterior lens capsules comparing with the control. The CpG island of WRN promoter in the ARC anterior lens capsules displayed hypermethylation comparing with the controls. The WRN promoter was almost fully methylated in the cortex of ARC and control lens. Acetylated H3 was lower while methylated H3-K9 was higher in ARC anterior lens capsules than that of the controls. The expression of WRN in HLEB-3 increased after demethylation of the cells. Conclusions. A hypermethylation in WRN promoter and altered histone modification in anterior lens capsules might contribute to the ARC mechanism. The data suggest an association of altered DNA repair capability in lens with ARC pathogenesis. PMID:26509079
Herlyn-Werner-Wunderlich syndrome (HWWS) is a congenital Müllerian duct anomaly characterized by uterine didelphys, obstructed hemivagina, and ipsilateral renal agenesis. Little is reported about spinal deformity associated with this syndrome. This study presents a case of scoliosis occurring in the setting of HWWS and explores the possible association between the 2 diseases. A previously unreported scoliosis in HWWS is described. The patient is a 12-year-old Chinese female with scoliosis that underwent a posterior correction at thoracic 5-thoracic 12 (T5-T12) levels, using the Moss-SI (Johnson & Johnson, American) spinal system. At 24-month follow-up, the patient was clinically pain free and well balanced. Plain radiographs showed solid spine fusion with no loss of deformity correction. Six months after scoliosis correction surgery, the patient went to our clinics for the treatment of HWWS. She was performed a vaginal septum resection and detected with pyocolpos. Her follow-up was symptom free at the fourth postoperative month. The prevalence of scoliosis among patients with HWWS was 8.57% that is much higher than the incidence of congential scoliosis among general population (1/1000). To the best of our knowledge, this is the first report of HWWS with thoracic scoliosis. During surgery, surgeons and anesthesiologists must pay particular attention to the Müllerian duct anomaly and renal agenesis associated with HWWS. There is a potential association between congenital scoliosis and HWWS. PMID:25526433
Herlyn-Werner-Wunderlich syndrome (HWWS) is a rare congenital anomaly of the female urogenital tract that associates Müllerian duct anomalies with mesonephric duct anomalies. The triad of uterus didelphys, obstructed hemivagina, and ipsilateral renal agenesis characterizes this syndrome. Patients generally present with non-specific symptoms after menarche. Pelvic pain, dysmenorrhea, and palpable mass due to hematocolpos or hematometra are the most common findings. Pyohematocolpos and pyosalpinx may appear as acute complications, while endometriosis and pelvic adhesions constitute potential long-term complications. When a prenatal diagnosis of unilateral renal agenesis in newborn girls is known, a gynecological imaging study should be performed to exclude uterine and vaginal abnormalities. These patients should be followed up to ensure that a timely surgical correction is performed. The diagnosis of HWWS is difficult due to the lack of specific symptoms or findings upon physical examination. An accurate imaging description of these congenital anomalies is crucial to guide patients toward surgical treatment, relieving acute complications, and preserving the normal fertility. The authors provide a pictorial review of the magnetic resonance imaging and ultrasonography findings of the HWWS with correlation to embryological, clinical, and surgical features. PMID:25852048
Werner syndrome (WS) is a premature aging disorder that mainly affects tissues derived from mesoderm. We have recently developed a novel human WS model using WRN-deficient human mesenchymal stem cells (MSCs). This model recapitulates many phenotypic features of WS. Based on a screen of a number of chemicals, here we found that Vitamin C exerts most efficient rescue for many features in premature aging as shown in WRN-deficient MSCs, including cell growth arrest, increased reactive oxygen species levels, telomere attrition, excessive secretion of inflammatory factors, as well as disorganization of nuclear lamina and heterochromatin. Moreover, Vitamin C restores in vivo viability of MSCs in a mouse model. RNA sequencing analysis indicates that Vitamin C alters the expression of a series of genes involved in chromatin condensation, cell cycle regulation, DNA replication, and DNA damage repair pathways in WRN-deficient MSCs. Our results identify Vitamin C as a rejuvenating factor for WS MSCs, which holds the potential of being applied as a novel type of treatment of WS. PMID:27271327
Loss of WRN function causes Werner Syndrome, characterized by increased genomic instability, elevated cancer susceptibility and premature aging. Although WRN is subject to acetylation, phosphorylation and sumoylation, the impact of these modifications on WRN’s DNA metabolic function remains unclear. Here, we examined in further depth the relationship between WRN acetylation and its role in DNA metabolism, particularly in response to induced DNA damage. Our results demonstrate that endogenous WRN is acetylated somewhat under unperturbed conditions. However, levels of acetylated WRN significantly increase after treatment with certain DNA damaging agents or the replication inhibitor hydroxyurea. Use of DNA repair-deficient cells or repair pathway inhibitors further increase levels of acetylated WRN, indicating that induced DNA lesions and their persistence are at least partly responsible for increased acetylation. Notably, acetylation of WRN correlates with inhibition of DNA synthesis, suggesting that replication blockage might underlie this effect. Moreover, WRN acetylation modulates its affinity for and activity on certain DNA structures, in a manner that may enhance its relative specificity for physiological substrates. Our results also show that acetylation and deacetylation of endogenous WRN is a dynamic process, with sirtuins and other histone deacetylases contributing to WRN deacetylation. These findings advance our understanding of the dynamics of WRN acetylation under unperturbed conditions and following DNA damage induction, linking this modification not only to DNA damage persistence but also potentially to replication stalling caused by specific DNA lesions. Our results are consistent with proposed metabolic roles for WRN and genomic instability phenotypes associated with WRN deficiency. PMID:24965941
Werner syndrome (WS) is a severe recessive disorder characterized by premature aging, cancer predisposition and genomic instability. The gene mutated in WS encodes a bi-functional enzyme called WRN that acts as a RecQ-type DNA helicase and a 3′-5′ exonuclease, but its exact role in DNA metabolism is poorly understood. Here we show that WRN physically interacts with the MSH2/MSH6 (MutSα), MSH2/MSH3 (MutSβ) and MLH1/PMS2 (MutLα) heterodimers that are involved in the initiation of mismatch repair (MMR) and the rejection of homeologous recombination. MutSα and MutSβ can strongly stimulate the helicase activity of WRN specifically on forked DNA structures with a 3′-single-stranded arm. The stimulatory effect of MutSα on WRN-mediated unwinding is enhanced by a G/T mismatch in the DNA duplex ahead of the fork. The MutLα protein known to bind to the MutS α–heteroduplex complexes has no effect on WRN-mediated DNA unwinding stimulated by MutSα, nor does it affect DNA unwinding by WRN alone. Our data are consistent with results of genetic experiments in yeast suggesting that MMR factors act in conjunction with a RecQ-type helicase to reject recombination between divergent sequences. PMID:17715146
For the coherent understanding of heat acclimatization in tropical natives, we compared ethnic differences between tropical and temperate natives during resting, passive and active heating conditions. Experimental protocols included: (1) a resting condition (an air temperature of 28°C with 50% RH), (2) a passive heating condition (28°C with 50% RH; leg immersion in a hot tub at a water temperature of 42°C), and (3) an active heating condition (32°C with 70% RH; a bicycle exercise). Morphologically and physically matched tropical natives (ten Malaysian males, MY) and temperate natives (ten Japanese males, JP) participated in all three trials. The results saw that: tropical natives had a higher resting rectal temperature and lower hand and foot temperatures at rest, smaller rise of rectal temperature and greater temperature rise in bodily extremities, and a lower sensation of thirst during passive and active heating than the matched temperate natives. It is suggested that tropical natives' homeostasis during heating is effectively controlled with the improved stability in internal body temperature and the increased capability of vascular circulation in extremities, with a lower thirst sensation. The enhanced stability of internal body temperature and the extended thermoregulatory capability of vascular circulation in the extremities of tropical natives can be interpreted as an interactive change to accomplish a thermal dynamic equilibrium in hot environments. These heat adaptive traits were explained by Wilder's law of initial value and Werner's process and controller adaptation model. PMID:21437607
Summary Werner syndrome (WS) patients exhibit premature aging predominantly in mesenchyme-derived tissues, but not in neural lineages, a consequence of telomere dysfunction and accelerated senescence. The cause of this lineage-specific aging remains unknown. Here, we document that reprogramming of WS fibroblasts to pluripotency elongated telomere length and prevented telomere dysfunction. To obtain mechanistic insight into the origin of tissue-specific aging, we differentiated iPSCs to mesenchymal stem cells (MSCs) and neural stem/progenitor cells (NPCs). We observed recurrence of premature senescence associated with accelerated telomere attrition and defective synthesis of the lagging strand telomeres in MSCs, but not in NPCs. We postulate this “aging” discrepancy is regulated by telomerase. Expression of hTERT or p53 knockdown ameliorated the accelerated aging phenotypein MSC, whereas inhibition of telomerase sensitized NPCs to DNA damage. Our findings unveil a role for telomerase in the protection of accelerated aging in a specific lineage of stem cells. PMID:24749076
Purpose. To examine the promoter methylation and histone modification of WRN (Werner syndrome gene), a DNA repair gene, and their relationship with the gene expression in age-related cataract (ARC) lens. Methods. We collected the lenses after cataract surgery from 117ARC patients and 39 age-matched non-ARC. WRN expression, DNA methylation and histone modification around the CpG island were assessed. The methylation status of Human-lens-epithelium cell (HLEB-3) was chemically altered to observe the relationship between methylation and expression of WRN. Results. The WRN expression was significantly decreased in the ARC anterior lens capsules comparing with the control. The CpG island of WRN promoter in the ARC anterior lens capsules displayed hypermethylation comparing with the controls. The WRN promoter was almost fully methylated in the cortex of ARC and control lens. Acetylated H3 was lower while methylated H3-K9 was higher in ARC anterior lens capsules than that of the controls. The expression of WRN in HLEB-3 increased after demethylation of the cells. Conclusions. A hypermethylation in WRN promoter and altered histone modification in anterior lens capsules might contribute to the ARC mechanism. The data suggest an association of altered DNA repair capability in lens with ARC pathogenesis. PMID:26509079
Progeroid syndromes show features of accelerated ageing and are used as models for human ageing, of which Werner syndrome (WS) is one of the most widely studied. WS fibroblasts show accelerated senescence that may result from p38 MAP kinase activation since it is prevented by the p38 inhibitor SB203580. Thus, small molecule inhibition of p38-signalling may be a therapeutic strategy for WS. To develop this approach issues such as the in vivo toxicity and kinase selectivity of existing p38 inhibitors need to be addressed, so as to strengthen the evidence that p38 itself plays a critical role in mediating the effect of SB203580, and to find an inhibitor suitable for in vivo use. In this work we used a panel of different p38 inhibitors selected for: (1) having been used successfully in vivo in either animal models or human clinical trials; (2) different modes of binding to p38; and (3) different off-target kinase specificity profiles, in order to critically address the role of p38 in the premature senescence seen in WS cells. Our findings confirmed the involvement of p38 in accelerated cell senescence and identified p38 inhibitors suitable for in vivo use in WS, with BIRB 796 the most effective. PMID:27136566
Progeroid syndromes show features of accelerated ageing and are used as models for human ageing, of which Werner syndrome (WS) is one of the most widely studied. WS fibroblasts show accelerated senescence that may result from p38 MAP kinase activation since it is prevented by the p38 inhibitor SB203580. Thus, small molecule inhibition of p38-signalling may be a therapeutic strategy for WS. To develop this approach issues such as the in vivo toxicity and kinase selectivity of existing p38 inhibitors need to be addressed, so as to strengthen the evidence that p38 itself plays a critical role in mediating the effect of SB203580, and to find an inhibitor suitable for in vivo use. In this work we used a panel of different p38 inhibitors selected for: (1) having been used successfully in vivo in either animal models or human clinical trials; (2) different modes of binding to p38; and (3) different off-target kinase specificity profiles, in order to critically address the role of p38 in the premature senescence seen in WS cells. Our findings confirmed the involvement of p38 in accelerated cell senescence and identified p38 inhibitors suitable for in vivo use in WS, with BIRB 796 the most effective. PMID:27136566
The organic component of the vapor phase of a porous medium contaminated by an immiscible organic liquid can be significant enough to violate the condition of a dilute species diffusing in a bulk phase assumed by Fick's Law. The Stefan-Maxwell equations provide a more comprehensive model for quantifying steady state transport for a vapor phase composed of arbitrary proportions of its constituents. The application of both types of models to the analysis of column experiments demonstrates that use of a Fickian-based transport model can lead to significant overestimates of soil tortuosity constants. Further, the physical displacement of naturally occurring gases (e.g., O{sub 2}), predicted by the Stefan-Maxwell model but not by application of Fick's Law, can be attributed improperly to a sink term such as microbial degradation in a Fickian-based transport model.
Fickian, Stefan-Maxwell and dusty-gas model have been widely used in modeling mass transfer in porous electrodes of solid oxide fuel cells. Suwanwarangkul et al. (J. Power Sources 122 (2003) 9-18) implement a survey for performance comparison among these models to predict the concentration overpotential of a solid oxide fuel cell anode. In their work, the flux ratio of species is calculated by Graham's law and contradictorily the equimolar counter transport is used for isobaric assumption. Focused on the flux-ratio approaches and usually neglected pressure gradient, a comparison between Fickian, Stefan-Maxwell and dusty-gas model is done again in this article. The dusty gas model combined with the 'Stoich' flux-ratio approach, i.e. the species flux is dictated by its stoichiometry of the electrochemical reaction, is validated to make the best performance. And all models by the 'Graham' flux-ratio approach, i.e. the flux of species satisfies Graham's law, underestimate the concentration overpotential when the molecular weights of species are quite different. The extended Stefan-Maxwell model is an alternative, although it generally exaggerates the role of Knudsen diffusion. The effect of pore size on the Knudsen diffusion and pressure gradient is also discussed.
Applying Green–Kubo formalism and equilibrium molecular dynamics (MD) simulations, we have studied the dynamic correlation, Onsager coeeficients and Maxwell–Stefan (MS) Diffusivities of molten salt LiF-BeF{sub 2}, which is used as coolant in high temperature reactor. All the diffusive flux correlations show back-scattering or cage dynamics which becomes pronouced at higher temperature. Although the MS diffusivities are expected to depend very lightly on the composition due to decoupling of thermodynamic factor, the diffusivity Đ{sub Li-F} and Đ{sub Be-F} decreases sharply for higher concentration of LiF and BeF{sub 2} respectively. Interestingly, all three MS diffusivities have highest magnitude for eutectic mixture at 1000K (except Đ{sub Be-F} at lower LiF mole fraction) which is desirable from coolant point of view. Although the diffusivity for positive-positive ion pair is negative it is not in violation of the second law of thermodynamics as it satisfies the non-negative entropic constraints.
In this work our main objective is to compute Dynamical correlations, Onsager coefficients and Maxwell-Stefan (MS) diffusivities for molten salt LiF-KF mixture at various thermodynamic states through Green-Kubo formalism for the first time. The equilibrium molecular dynamics (MD) simulations were performed using BHM potential for LiF-KF mixture. The velocity autocorrelations functions involving Li ions reflect the endurance of cage dynamics or backscattering with temperature. The magnitude of Onsager coefficients for all pairs increases with increase in temperature. Interestingly most of the Onsager coefficients has almost maximum magnitude at the eutectic composition indicating the most dynamic character of the eutectic mixture. MS diffusivity hence diffusion for all ion pairs increases in the system with increasing temperature. Smooth variation of the diffusivity values denies any network formation in the mixture. Also, the striking feature is the noticeable concentration dependence of MS diffusivity between cation-cation pair, ĐLi-K which remains negative for most of the concentration range but changes sign to become positive for higher LiF concentration. The negative MS diffusivity is acceptable as it satisfies the non-negative entropy constraint governed by 2nd law of thermodynamics. This high diffusivity also vouches the candidature of molten salt as a coolant.
Decontamination of polymers exposed to chemical warfare agents (CWA) often proceeds by application of a liquid solution. Absorption of some decontaminant components proceed concurrently with extraction of the CWA, resulting in multicomponent diffusion in the polymer. In this work, the Maxwell-Stefan equations were used with the Flory-Huggins model of species activity to mathematically describe the transport of two species within a polymer. This model was used to predict the extraction of the nerve agent O-ethyl S-[2(diisopropylamino)ethyl] methylphosphonothioate (VX) from a silicone elastomer into both water and methanol. Comparisons with experimental results show good agreement with minimal fitting of model parameters from pure component uptake data. Reaction of the extracted VX with sodium hydroxide in the liquid-phase was also modeled and used to predict the overall rate of destruction of VX. Although the reaction proceeds more slowly in the methanol-based solution compared to the aqueous solution, the extraction rate is faster due to increasing VX mobility as methanol absorbs into the silicone, resulting in an overall faster rate of VX destruction.
A Müser-type engine model can be taken as a particular case of a Curzon-Ahlborn thermal cycle, when the upper thermal conductance is finite and the lower one is infinite. In addition, the upper heat exchange is given by the Stefan-Boltzmann law. That model is suitable to thermodynamically describe some aspects of energy converters as solar cells and photosynthetic systems. In the present article, we call n-Müser engine to an engine of the Müser type in which the T4 heat transfer law is substituted by a Tn-law, being n > 0 a real number. Here, we show that if we use the so-called ecological criterion of merit to optimize finite-time heat engines to compare the thermodynamic performance of the n-Müser engines under approximate terrestrial conditions (see below), we obtain that n = 4 accomplishes the best performance. This same result was obtained by using data from the rest of planets of the solar system.
Two PhD theses (Alexander Gordienko, 1912; Johannes Angerstein, 1914) and a dissertation in partial fulfillment of a PhD thesis (H. S. French, Zurich, 1914) are reviewed that deal with hitherto unpublished UV-vis spectroscopy work of coordination compounds in the group of Alfred Werner. The method of measurement of UV-vis spectra at Alfred Werner's time is described in detail. Examples of spectra of complexes are given, which were partly interpreted in terms of structure (cis ↔ trans configuration, counting number of bands for structural relationships, and shift of general spectral features by consecutive replacement of ligands). A more complete interpretation of spectra was hampered at Alfred Werner's time by the lack of a light absorption theory and a correct theory of electron excitation, and the lack of a ligand field theory for coordination compounds. The experimentally difficult data acquisitions and the difficult spectral interpretations might have been reasons why this method did not experience a breakthrough in Alfred Werner's group to play a more prominent role as an important analytical method. Nevertheless the application of UV-vis spectroscopy on coordination compounds was unique and novel, and witnesses Alfred Werner's great aptitude and keenness to always try and go beyond conventional practice. PMID:24983805
Swiss microbial geneticist, Werner Arber shared the 1978 Nobel Prize in Physiology or Medicine with Hamilton Smith and Daniel Nathans for their discovery of restriction endonucleases. Werner Arber was born in Granichen, Switzerland in 1929. Following a public school education, he entered the Swiss Polytechnical School in Zurich in 1949, working toward a diploma in natural sciences. There, his first research experience involved isolating and characterizing an isomer of chlorine. Following graduation in 1953, Arber joined a graduate program at the University of Geneva, taking on an assistanceship in electron microscopy (EM), in which he studied gene transfer in the bacterial virus (bacteriophage) lambda. Eventually encountering limitations with EM as a tool, he began using microbial genetics as a methodology for his studies. The study of microbial genetics had been possible for a relatively short time: DNA had been discovered to carry genetic information only a decade before he d entered the field. After earning his Ph.D. in 1958, Arber continued to develop skills in microbial genetics, working with colleagues in the United States for a short time before returning to Geneva at beginning of 1960. There, he continued working on lambda transduction in E. coli, but found that the virus would not efficiently propagate. Recalling research done seven years earlier by Joe Bertani and Jean Weigle on "host-controlled restriction-modification", he realized there must be a host-controlled modification of the invading DNA, and sought to identify the mechanism. Based on Grete Kallengerger s work that demonstrated degradation of both irradiated and non-irradiated phage lambda following injection in a host, Arber and his graduate student, Daisy Dussoix further investigated the fate of DNA, and found that restriction and modification (later determined to be postreplicative nuclotide methylation) directly affected DNA, but did not cause mutations. They also found that theses were
Swiss microbial geneticist, Werner Arber shared the 1978 Nobel Prize in Physiology or Medicine with Hamilton Smith and Daniel Nathans for their discovery of restriction endonucleases. Werner Arber was born in Granichen, Switzerland in 1929. Following a public school education, he entered the Swiss Polytechnical School in Zurich in 1949, working toward a diploma in natural sciences. There, his first research experience involved isolating and characterizing an isomer of chlorine. Following graduation in 1953, Arber joined a graduate program at the University of Geneva, taking on an assistanceship in electron microscopy (EM), in which he studied gene transfer in the bacterial virus (bacteriophage) lambda. Eventually encountering limitations with EM as a tool, he began using microbial genetics as a methodology for his studies. The study of microbial genetics had been possible for a relatively short time: DNA had been discovered to carry genetic information only a decade before he d entered the field. After earning his Ph.D. in 1958, Arber continued to develop skills in microbial genetics, working with colleagues in the United States for a short time before returning to Geneva at beginning of 1960. There, he continued working on lambda transduction in E. coli, but found that the virus would not efficiently propagate. Recalling research done seven years earlier by Joe Bertani and Jean Weigle on "host-controlled restriction-modification", he realized there must be a host-controlled modification of the invading DNA, and sought to identify the mechanism. Based on Grete Kallengerger s work that demonstrated degradation of both irradiated and non-irradiated phage lambda following injection in a host, Arber and his graduate student, Daisy Dussoix further investigated the fate of DNA, and found that restriction and modification (later determined to be postreplicative nuclotide methylation) directly affected DNA, but did not cause mutations. They also found that theses were
Werner syndrome (WS) is an autosomal recessive disease with a complex phenotype that is suggestive of accelerated aging. WS is caused by mutations in a gene, WRN, that encodes a predicted 1,432-amino-acid protein with homology to DNA and RNA helicases. Previous work identified four WS mutations in the 3{prime} end of the gene, which resulted in predicted truncated protein products of 1,060-1,247 amino acids but did not disrupt the helicase domain region (amino acids 569-859). Here, additional WS subjects were screened for mutations, and the intron-exon structure of the gene was determined. A total of 35 exons were defined, with the coding sequences beginning in the second exon. Five new WS mutations were identified: two nonsense mutations at codons 369 and 889; a mutation at a splice-junction site, resulting in a predicted truncated protein of 760 amino acids; a 1-bp deletion causing a frameshift; and a predicted truncated protein of 391 amino acids. Another deletion is >15 kb of genomic DNA, including exons 19-23; the predicted protein is 1,186 amino acids long. Four of these new mutations either partially disrupt the helicase domain region or result in predicted protein products completely missing the helicase region. These results confirm that mutations in the WRN gene are responsible for WS. Also, the location of the mutations indicates that the presence or absence of the helicase domain does not influence the WS phenotype and suggests that WS is the result of complete loss of function of the WRN gene product. 63 refs., 1 fig., 5 tabs.
Members of the RecQ family of helicases are known for their roles in DNA repair, replication, and recombination. Mutations in the human RecQ helicases, WRN and BLM, cause Werner and Bloom syndromes, which are diseases characterized by genome instability and an increased risk of cancer. While WRN contains both a helicase and an exonuclease domain, the Drosophila melanogaster homolog, WRNexo, contains only the exonuclease domain. Therefore the Drosophila model system provides a unique opportunity to study the exonuclease functions of WRN separate from the helicase. We created a null allele of WRNexo via imprecise P-element excision. The null WRNexo mutants are not sensitive to double-strand break-inducing reagents, suggesting that the exonuclease does not play a key role in homologous recombination-mediated repair of DSBs. However, WRNexo mutant embryos have a reduced hatching frequency and larvae are sensitive to the replication fork-stalling reagent, hydroxyurea (HU), suggesting that WRNexo is important in responding to replication stress. The role of WRNexo in the HU-induced stress response is independent of Rad51. Interestingly, the hatching defect and HU sensitivity of WRNexo mutants do not occur in flies containing an exonuclease-dead copy of WRNexo, suggesting that the role of WRNexo in replication is independent of exonuclease activity. Additionally, WRNexo and Blm mutants exhibit similar sensitivity to HU and synthetic lethality in combination with mutations in structure-selective endonucleases. We propose that WRNexo and BLM interact to promote fork reversal following replication fork stalling and in their absence regressed forks are restarted through a Rad51-mediated process. PMID:24709634
Age-associated minor inflammation: inflammageing may explain human ageing mechanism(s). Our previous study reported a significant increase in the serum level of highly sensitive C-reactive protein (hsCRP) with normal ageing and the patients with Werner syndrome (WS). To further study the minor inflammatory condition associated with ageing, another possible ageing biomarker: matrix metalloproteinase-9 (MMP9) was examined in the sera from 217 normal Japanese individuals aged between 1 and 100 years and 41 mutation-proven Japanese WS aged between 32 and 70 years. MMP9 was assayed by ELISA. The serum level of MMP9 was elevated significantly (p < 0.001) with normal ageing from both sexes as hsCRP. In contrast to normal ageing, the serum MMP9 level in WS decreased significantly with calendar age (p < 0.05). The MMP9 level (ng/mL) in WS (147.2 ± 28.5) was not significantly different in comparison with those from age-matched normal adult population aged between 25 and 70 years (109.1 ± 9.4), nor normal elderly population aged between 71 and 100 years (179.9 ± 16.1). Although both normal ageing and WS were associated with minor inflammation, the inflammatory parameters such as serum MMP9 and hsCRP changed differently between normal ageing and WS. The WS-specific chronic inflammation including skin ulcer and diabetes mellitus may contribute the different behavior of both ageing biomarkers from normal ageing. PMID:27195193
Werner syndrome (WS) is an autosomal recessive disorder characterized by the premature occurrence of many age-related features. Previously, the WS gene (WRN) was mapped between D8S131 and D8S87, in an 8.3-cM interval. In this study, regions of homozygosity in 36 WS patients from inbred families were searched for by genotyping for 35 dinucleotide repeat polymorphic markers to narrow down the W-RN critical region. The region most consistently homozygous in these patients was between the D8S1219/D8S1220 cluster and D8S278, within a 4.4-cM interval. For 16 markers mapped in this interval, 24 WS patients (22 Japanese patients and 2 Caucasian patients) in whom consanguinity failed to be proved were also genotyped, under the assumption that some of these patients might still be from consanguineous marriages. The data were analyzed by Fisher`s exact test with a 2 x 2 contingency table for the 22 Japanese patients, excluding the 2 Caucasian patients. The frequencies of homozygosity in the 22 patients at 10 of 16 markers tested were significantly higher than those detected in the general population. Analysis of homozygosity patterns indicated that the region most consistently homozygous was between D8S1445 and D8S278. Thus the WRN locus is most likely between the two markers D8S1445 and D8S278, in a 1.6-cM interval. 49 refs., 4 tabs.
The first generation of stars produces a background of Lyman-Werner (LW) radiation which can photodissociate molecular hydrogen, increasing the mass of dark matter haloes required to host star formation. Previous studies have determined the critical mass required for efficient molecular cooling with a constant LW background. However, the true background is expected to increase rapidly at early times. Neglecting this evolution could underestimate star formation in small haloes that may have started to cool in the past when the LW intensity was much lower. Background evolution is a large source of uncertainty in pre-reionization predictions of the cosmological 21cm signal, which can be observed with future radio telescopes. To address this, we perform zero-dimensional one-zone calculations that follow the density, chemical abundances, and temperature of gas in the central regions of dark matter haloes, including hierarchical growth and an evolving LW background. We begin by studying the physics of haloes subjected to a background that increases exponentially with redshift. We find that when the intensity increases more slowly than JLW(z)∝10-z/5, cooling in the past is a relatively small effect. We then self-consistently compute the cosmological LW background over z = 15-50 and find that cooling in the past due to an evolving background has a modest impact. Finally, we compare these results to three-dimensional hydrodynamical cosmological simulations with varying LW histories. While only a small number of haloes were simulated, the results are consistent with our one-zone calculations.
Summary Age-associated minor inflammation: inflammageing may explain human ageing mechanism(s). Our previous study reported a significant increase in the serum level of highly sensitive C-reactive protein (hsCRP) with normal ageing and the patients with Werner syndrome (WS). To further study the minor inflammatory condition associated with ageing, another possible ageing biomarker: matrix metalloproteinase-9 (MMP9) was examined in the sera from 217 normal Japanese individuals aged between 1 and 100 years and 41 mutation-proven Japanese WS aged between 32 and 70 years. MMP9 was assayed by ELISA. The serum level of MMP9 was elevated significantly (p < 0.001) with normal ageing from both sexes as hsCRP. In contrast to normal ageing, the serum MMP9 level in WS decreased significantly with calendar age (p < 0.05). The MMP9 level (ng/mL) in WS (147.2 ± 28.5) was not significantly different in comparison with those from age-matched normal adult population aged between 25 and 70 years (109.1 ± 9.4), nor normal elderly population aged between 71 and 100 years (179.9 ± 16.1). Although both normal ageing and WS were associated with minor inflammation, the inflammatory parameters such as serum MMP9 and hsCRP changed differently between normal ageing and WS. The WS-specific chronic inflammation including skin ulcer and diabetes mellitus may contribute the different behavior of both ageing biomarkers from normal ageing. PMID:27195193
Asymmetric obstructed uterus didelphys (Herlyn-Werner-Wunderlich syndrome), also known as obstructed hemivagina with ipsilateral renal agenesis syndrome, is a rare congenital müllerian duct anomaly. Herein we present a case report of incomplete Herlyn-Werner-Wunderlich syndrome, with absence of the hemivaginal septum, diagnosed in a 12-year-old girl. Treatment of the severe pain using an analgesic agent was ineffective. Therefore, laparoscopic metroplastic surgery via the modified Strassman procedure was performed. After surgery, the patient no longer reported dysmenorrhea. PMID:23465264
In this paper, we investigate the dynamical behaviour of entanglement in terms of concurrence in a bipartite system subjected to an external magnetic field under the action of dissipative environments in the extended Werner-like initial state. The interesting phenomenon of entanglement sudden death as well as sudden birth appears during the evolution process. We analyse in detail the effect of the purity of the initial entangled state of two qubits via Heisenberg XY interaction on the apparition time of entanglement sudden death and entanglement sudden birth. Furthermore, the conditions on the conversion of entanglement sudden death and entanglement sudden birth can be generalized when the initial entangled state is not pure. In particular, a critical purity of the initial mixed entangled state exists, above which entanglement sudden birth vanishes while entanglement sudden death appears. It is also noticed that stable entanglement, which is independent of different initial states of the qubits (pure or mixed state), occurs even in the presence of decoherence. These results arising from the combination of the extended Werner-like initial state and dissipative environments suggest an approach to control and enhance the entanglement even after purity induced sudden birth, death and revival.
In this paper, we study the influence of Dzyaloshinskii-Moriya (DM) interaction on quantum correlations in two-qubit Werner states and maximally entangled mixed states (MEMS). We consider our system as a closed system of a qubit pair and one auxiliary qubit, which interact with any one of the qubit of the pair through DM interaction. We show that DM interaction, taken along any direction ( x or y or z), does not affect two-qubit Werner states. On the other hand, the MEMS are affected by x and z components of DM interaction and remain unaffected by the y component. Further, we find that the state (i.e., probability amplitude) of auxiliary qubit does not affect the quantum correlations in both the states, and only DM interaction strength influences the quantum correlations. So one can avoid the intention to prepare the specific state of auxiliary qubit to manipulate the quantum correlations in both the states. We mention here that avoiding the preparation of state can contribute to cost reduction in quantum information processing. We also observe the phenomenon of entanglement sudden death in the present study.
Genes that play a role in the senescent arrest of cellular replication are likely to be overexpressed in human diploid fibroblasts (HDF) derived from subjects with Werner syndrome (WS) because these cells have a severely curtailed replicative life span. To identify some of these genes, a cDNA library was constructed from WS HDF after they had been serum depleted and repleted (5 days in medium containing 1% serum followed by 24 h in medium containing 20% serum). Differential screening of 7,500 colonies revealed 102 clones that hybridized preferentially with [32P]cDNA derived from RNA of WS cells compared with [32P]cDNA derived from normal HDF. Cross-hybridization and partial DNA sequence determination identified 18 independent gene sequences, 9 of them known and 9 unknown. The known genes included alpha 1(I) procollagen, alpha 2(I) procollagen, fibronectin, ferritin heavy chain, insulinlike growth factor-binding protein-3 (IGFBP-3), osteonectin, human tissue plasminogen activator inhibitor type I, thrombospondin, and alpha B-crystallin. The nine unknown clones included two novel gene sequences and seven additional sequences that contained both novel segments and the Alu class of repetitive short interspersed nuclear elements; five of these seven Alu+ clones also contained the long interpersed nuclear element I (KpnI) family of repetitive elements. Northern (RNA) analysis, using the 18 sequences as probes, showed higher levels of these mRNAs in WS HDF than in normal HDF. Five selected mRNAs studied in greater detail [alpha 1(I) procollagen, fibronectin, insulinlike growth factor-binding protein-3, WS3-10, and WS9-14] showed higher mRNA levels in both WS and late-passage normal HDF than in early-passage normal HDF at various intervals following serum depletion/repletion and after subculture and growth from sparse to high-density confluent arrest. These results indicate that senescence of both WS and normal HDF is accompanied by overexpression of similar sets of
The MCNP4B Monte Carlo transport code is used in a feasibility study of the epithermal neutron boron neutron capture therapy facility in the thermalizing column of the 250-kW TRIGA Mark II reactor at the Jozef Stefan Institute (JSI). To boost the epithermal neutron flux at the reference irradiation point, the efficiency of a fission plate with almost 1.5 kg of 20% enriched uranium and 2.3 kW of thermal power is investigated. With the same purpose in mind, the TRIGA reactor core setup is optimized, and standard fresh fuel elements are concentrated partly in the outermost ring of the core. Further, a detailed parametric study of the materials and dimensions for all the relevant parts of the irradiation facility is carried out. Some of the standard epithermal neutron filter/moderator materials, as well as 'pressed-only' low-density Al{sub 2}O{sub 3} and AlF{sub 3}, are considered. The proposed version of the BNCT facility, with PbF{sub 2} as the epithermal neutron filter/moderator, provides an epithermal neutron flux of {approx}1.1 x 10{sup 9} n/cm{sup 2}.s, thus enabling patient irradiation times of <60 min. With reasonably low fast neutron and photon contamination ([overdot]D{sub nfast}/{phi}{sub epi} < 5 x 10{sup -13} Gy.cm{sup 2}/n and [overdot]D{sub {gamma}} /{phi}{sub epi} < 3 x 10{sup -13} Gy.cm{sup 2}/n), the in-air performances of the proposed beam are comparable to all existing epithermal BNCT facilities. The design presents an equally efficient alternative to the BNCT beams in TRIGA reactor thermal columns that are more commonly applied. The cavity of the dry cell, a former JSI TRIGA reactor spent-fuel storage facility, adjacent to the thermalizing column, could rather easily be rearranged into a suitable patient treatment room, which would substantially decrease the overall developmental costs.
Werner syndrome (WS) is a progeroid or premature aging syndrome characterized by early onset of age-related pathologies and cancer. The average life expectancy of affected people is 52.8 years and tends to increase. The major causes of death are malignancy and myocardial infarction. Increased telomere attrition and decay are thought to play a causative role in the clinical and pathological manifestations of the disease. Although telomere length, with or without germline mutation, is known to be associated with interstitial lung disease, the latter is not associated with WS. To the best of our knowledge, we report the first case describing a WS patient with fatal ILD. This case suggests that older patients with WS could develop ILD. Clinical outcome of WS patients may thus be improved by counselling them regarding smoking cessation or other exposure and by proposing antifibrotic therapy. PMID:26788395
Microwave-assisted Suzuki-Miyaura cross-coupling reactions have been employed towards the synthesis of three different MAPKAPK2 (MK2) inhibitors to study accelerated aging in Werner syndrome (WS) cells, including the cross-coupling of a 2-chloroquinoline with a 3-pyridinylboronic acid, the coupling of an aryl bromide with an indolylboronic acid and the reaction of a 3-amino-4-bromopyrazole with 4-carbamoylphenylboronic acid. In all of these processes, the Suzuki-Miyaura reaction was fast and relatively efficient using a palladium catalyst under microwave irradiation. The process was incorporated into a rapid 3-step microwave-assisted method for the synthesis of a MK2 inhibitor involving 3-aminopyrazole formation, pyrazole C-4 bromination using N-bromosuccinimide (NBS), and Suzuki-Miyaura cross-coupling of the pyrazolyl bromide with 4-carbamoylphenylboronic acid to give the target 4-arylpyrazole in 35% overall yield, suitable for study in WS cells. PMID:26046488
Among many applications quantum weak measurements have been shown to be important in exploring fundamental physics issues, such as the experimental violation of the Heisenberg uncertainty relation and the Hardy paradox, and have also technological implications in quantum optics, quantum metrology and quantum communications, where the precision of the measurement is as important as the precision of quantum state preparation. The theory of weak measurement can be formulated using the pre-and post-selected quantum systems, as well as using the weak measurement operator formalism. In this work, we study the quantum discord (QD) of quasi-Werner mixed states based on bipartite entangled coherent states using the weak measurements operator, instead of the projective measurement operators. We then compare the quantum discord for both kinds of measurement operators, in terms of the entanglement quality, the latter being measured using the concept of concurrence. It's found greater quantum correlations using the weak measurement operators.
The thermal entanglement and teleportation of a thermally mixed entangled state of a two-qubit Heisenberg XXX chain under the Dzyaloshinski-Moriya (DM) anisotropic antisymmetric interaction through a noisy quantum channel given by a Werner state is investigated. The dependences of the thermal entanglement of the teleported state on the DM coupling constant, the temperature and the entanglement of the noisy quantum channel are studied in detail for both the ferromagnetic and the antiferromagnetic cases. The result shows that a minimum entanglement of the noisy quantum channel must be provided in order to realize the entanglement teleportation. The values of fidelity of the teleported state are also studied for these two cases. It is found that under certain conditions, we can transfer an initial state with a better fidelity than that for any classical communication protocol.
Werner Syndrome (WS) is a rare inherited disease characterized by premature aging and increased propensity for cancer. Mutations in the WRN gene can be of several types, including nonsense mutations, leading to a truncated protein form. WRN is a RecQ family member with both helicase and exonuclease activities, and it participates in several cell metabolic pathways, including DNA replication, DNA repair, and telomere maintenance. Here, we reported a novel homozygous WS mutation (c.3767 C > G) in 2 Argentinian brothers, which resulted in a stop codon and a truncated protein (p.S1256X). We also observed increased WRN promoter methylation in the cells of patients and decreased messenger WRN RNA (WRN mRNA) expression. Finally, we showed that the read-through of nonsense mutation pharmacologic treatment with both aminoglycosides (AGs) and ataluren (PTC-124) in these cells restores full-length protein expression and WRN functionality. PMID:25830902
Abstract Leptodira nycthemera Werner, 1901, was described from a specimen collected in Ecuador. No information on the holotype was published after its description. In the most recent review of Leptodeira, Leptodira nycthemera was considered to be a synonym of Leptodeira annulata annulata, although the author emphasized that the holotype was lost and did not include the pholidotic data from the original description in his account of Leptodeira annulata annulata. Since this review, a number of authors have accepted this synonymy. Recently, analyzing specimens of Leptodeira in the Museum für Naturkunde, Berlin, Germany, we discovered the holotype of Leptodira nycthemera. This holotype is re-described here, and its correct identity is determined. Based on the analysis of meristic characters and the color of the holotype, we recognize Leptodira nycthemera as a junior synonym of Oxyrhopus petolarius. PMID:26085798
Background Herlyn-Werner-Wunderlich (HWW) syndrome is a very rare congenital anomaly of the urogenital tract involving Müllerian ducts and Wolffian structures, and it is characterized by the triad of didelphys uterus, obstructed hemivagina and ipsilateral renal agenesis. It generally occurs at puberty and exhibits non-specific and variable symptoms with acute or pelvic pain shortly following menarche, causing a delay in the diagnosis. Moreover, the diagnosis is complicated by the infrequency of this syndrome, because Müllerian duct anomalies (MDA) are infrequently encountered in a routine clinical setting. Cases presentation two cases of HWW syndrome in adolescents and a differential diagnosis for one case of a different MDA, and the impact of magnetic resonance (MR) imaging technology to achieve the correct diagnosis. Conclusions MR imaging is a very suitable diagnostic tool in order to perform the correct diagnosis of HWW syndrome. PMID:22405336
Herlyn-Werner-Wunderlich syndrome (HWWS) is a müllerian duct anomaly typically associated with a uterus didelphys with two cervices and two vaginas, one of which is obstructed. A remarkable case of HWWS with contralateral duplex kidneys and duplication of ureters is described, which, to our knowledge, is a rarely reported variant to date. For this congenital anomaly, a strong suspicion and knowledge of HWWS are essential for a precise diagnosis. PMID:24481003
Microwave-assisted synthesis of the pyrazolyl ketone p38 MAPK inhibitor RO3201195 in 7 steps and 15% overall yield, and the comparison of its effect upon the proliferation of Werner Syndrome cells with a library of pyrazolyl ketones, strengthens the evidence that p38 MAPK inhibition plays a critical role in modulating premature cellular senescence in this progeroid syndrome and the reversal of accelerated ageing observed in vitro on treatment with SB203580. PMID:26611938
One of the best ways to demonstrate the performance and capabilities of testing laboratories is to participate successfully in different international comparison schemes and proficiency tests. The overview of all results of such schemes in the field of high resolution gamma-ray spectrometry where the Laboratory for Radioactivity Measurements (LMR) of the Jožef Stefan Institute (JSI), Slovenia, participated in years 1986-2014 is presented. Different schemes are compared, strong points and drawbacks of different providers and schemes regarding evaluation procedures, determination of reference values, reporting time, sets of radionuclides included in the samples and range of activities of different radionuclides are discussed. One of the main conclusions is that the comparison and proficiency test samples normally contain substantially larger activities than are usually detected in environmental samples. Therefore the capability of determination of activities close to detection limits is usually covered only by few schemes. PMID:26706285
The Saccharomyces cerevisiae SGS1 gene is homologous to Escherichia coli RecQ and the human BLM and WRN proteins that are defective in the cancer-prone disorder Bloom's syndrome and the premature aging disorder Werner's syndrome, respectively. While recQ mutants are deficient in conjugational recombination and DNA repair, Bloom's syndrome cell lines show hyperrecombination. Bloom's and Werner's syndrome cell lines both exhibit chromosomal instability. sgs1Δ strains show mitotic hyperrecombination, as do Bloom's cells. This was manifested as an increase in the frequency of interchromosomal homologous recombination, intrachromosomal excision recombination, and ectopic recombination. Hyperrecombination was partially independent of both RAD52 and RAD1. Meiotic recombination was not increased in sgs1Δ mutants, although meiosis I chromosome missegregation has been shown to be elevated. sgs1Δ suppresses the slow growth of a top3Δ strain lacking topoisomerase III. Although there was an increase in subtelomeric Y' instability in sgs1Δ strains due to hyperrecombination, no evidence was found for an increase in the instability of terminal telomeric sequences in a top3Δ or a sgs1Δ strain. This contrasts with the telomere maintenance defects of Werner's patients. We conclude that the SGS1 gene product is involved in the maintenance of genome stability in S. cerevisiae. PMID:8913739
In this paper, the main outlines of the discussions between Niels Bohr with Albert Einstein, Werner Heisenberg, and Erwin Schroedinger during 1920-1927 are treated. From the formulation of quantum mechanics in 1925-1926 and wave mechanics in 1926, there emerged Born's statistical interpretation of the wave function in summer 1926, and on the basis of the quantum mechanical transformation theory - formulated in fall 1926 by Dirac, London, and Jordan - Heisenberg formulated the uncertainty principle in early 1927. At the Volta Conference in Como in September 1927 and at the fifth Solvay Conference in Brussels the following month, Bohr publicly enunciated his complementarity principle, which had been developing in his mind for several years. The Bohr-Einstein discussions about the consistency and completeness of quantum mechanics and of physical theory as such - formally begun in October 1927 at the fifth Solvay Conference and carried on at the sixth Solvay Conference in October 1930 - were continued during the next decades. All these aspects are briefly summarized.
The direct collapse model of supermassive black hole seed formation requires that the gas cools predominantly via atomic hydrogen. To this end we simulate the effect of an anisotropic radiation source on the collapse of a halo at high redshift. The radiation source is placed at a distance of 3 kpc (physical) from the collapsing object and is set to emit monochromatically in the center of the Lyman-Werner (LW) band. The LW radiation emitted from the high redshift source is followed self-consistently using ray tracing techniques. Due to self-shielding, a small amount of H2 is able to form at the very center of the collapsing halo even under very strong LW radiation. Furthermore, we find that a radiation source, emitting >1054 (~ 103 J21) photons s-1, is required to cause the collapse of a clump of M ~ 105 M ⊙. The resulting accretion rate onto the collapsing object is ~0.25 M ⊙ yr-1. Our results display significant differences, compared to the isotropic radiation field case, in terms of the H2 fraction at an equivalent radius. These differences will significantly affect the dynamics of the collapse. With the inclusion of a strong anisotropic radiation source, the final mass of the collapsing object is found to be M ~ 105 M ⊙. This is consistent with predictions for the formation of a supermassive star or quasi-star leading to a supermassive black hole.
Werner syndrome (WS) is an autosomal recessive disorder, characterized as a progeroid syndrome, previously mapped to the 8p 11.2-21.1 region. Because WS is so rare, and because many patients are from consanguineous marriages, fine localization of the gene by traditional meiotic mapping methods is unlikely to succeed. Here the authors present the results of a search for a region that exhibits linkage disequilibrium with the disorder, under the assumption that identification of such a region may provide an alternative method of narrowing down the location of WRN, the gene responsible for WS. They present allele frequencies in Japanese and Caucasian cases and controls for D8S137, D8S131, D8S87, D8S278, D8S259, D8S283, fibroblast growth factor receptor 1, ankyrin 1, D8S339, and two polymorphisms in glutathione reductase (GSR), covering [approximately] 16.5 cM in total. They show that three of the markers examined - D8S339 and both polymorphisms in the GSR locus - show strong statistically significant evidence of disequilibrium with WRN in the Japanese population but not in the Caucasian population. In addition, they show that a limited number of haplotypes are associated with the disease in both populations and that these haplotypes define clusters of apparently related haplotypes that may identify as many as eight or nine independent WRN mutations in these two populations. 36 refs., 1 fig., 4 tabs.
Herlyn-Werner-Wunderlich (HWW) syndrome is a rare developmental anomaly that is consists of uterus didelphys with obstructed hemivagina and ipsilateral renal agenesis. This rare entity is the spectrum of Mullerian duct anomalies (MDA) accompanied by developmental anomaly of one of Wolffian ducts. The present report demonstrated HWW syndrome and reviewed literatures in term of embryological etiology, clinical manifestation, radiographic findings and surgical management. In this case report is a 11-year-old girl presented with chronic pelvic pain. She had menarche at the age of 10 and her menstrual cycles were regular with moderate dysmenorrhea. Physical examination revealed palpable pelvic mass with tenderness. Transabdominal ultrasonography (US) and Magnetic resonance imaging (MRI) demonstrated uterine didelphys with right-sided hematometrocolpos and absent right kidney. Right hematosalpinx was also detected due to distal tubal occlusion from adhesion. These preoperative images can verify all of the features of this syndrome and correctly anticipated diagnosis was achieved. The patient underwent laparoscopic right tubal drainage with lysis of pelvic adhesion and hysteroscopic resection of vaginal septum. Her symptoms were improved uneventfully. In conclusion, HWW syndrome exhibits unique clinical presentation with characteristic radiographic findings and symptom can be relieved dramatically after receiving appropriate surgical management. PMID:23513478
Werner Ernst Reichardt was born on January 30, 1924 in Berlin and at age 19 was drafted into the Luftwaffe and assigned to an electronic signals section laboratory. He became an active member of a resistance group and supplied radios for the movement in Germany. He emerged from the ashes of the Second World War and dedicated his scientific life to the development of the newborn specialty of biological physics. Following graduation from the Technische Hochschule Charlottenburg, he did a fellowship at CalTech under Max Delbrück. On returning to Germany he joined the Max Planck Institut and later became Director of the Max Planck Institut für Biologische Kybernetik in Tübingen, West Germany. Reichardt was one of the founders of the quantitative study of visually controlled orientation in animals. His work is very nearly unique in its close dialectic between elegant non-linear mathematical theory and quantitative experimental test of their predictions. During the 1950s Reichardt and his collaborators jointly developed an autocorrelation model (i.e. the firing rate of the involved visual neurones is closely correlated with the features of the pattern stimulating them) of how moving patterns are perceived by motion detectors in the visual system of the fly. This was the first mathematical description of a biological abstraction process. His findings apply to vertebrate vision, including motion detection and figure-ground description in human vision. His Max Planck Institute became a world renowned center for the computational approach to information processing by the nervous system. At his retirement party from the Institute he founded, Reichardt died on the evening of September 11th, 1992. PMID:11108122
Werner syndrome (WS) is a premature aging disorder caused by mutations in a RecQ-family DNA helicase, WRN. Mice lacking part of the helicase domain of the WRN orthologue exhibit many phenotypic features of WS, including metabolic abnormalities and a shorter mean life span. In contrast, mice lacking the entire Wrn protein (i.e. Wrn null mice) do not exhibit a premature aging phenotype. In this study, we used a targeted mass spectrometry-based metabolomic approach to identify serum metabolites that are differentially altered in young Wrn helicase mutant and Wrn null mice. An antibody-based quantification of 43 serum cytokines and markers of cardiovascular disease risk complemented this study. We found that Wrn helicase mutants exhibited elevated and decreased levels, respectively, of the anti-inflammatory cytokine IL-10 and the pro-inflammatory cytokine IL-18. Wrn helicase mutants also exhibited an increase in serum hydroxyproline and plasminogen activator inhibitor-1, markers of extracellular matrix remodeling of the vascular system and inflammation in aging. We also observed an abnormal increase in the ratio of very long chain to short chain lysophosphatidylcholines in the Wrn helicase mutants underlying a peroxisome perturbation in these mice. Remarkably, the Wrn mutant helicase protein was mislocalized to the endoplasmic reticulum and the peroxisomal fractions in liver tissues. Additional analyses with mouse embryonic fibroblasts indicated a severe defect of the autophagy flux in cells derived from Wrn helicase mutants compared to wild type and Wrn null animals. These results indicate that the deleterious effects of the helicase-deficient Wrn protein are mediated by the dysfunction of several cellular organelles. PMID:26447695
XPG is a structure-specific endonuclease required for nucleotide excision repair (NER). XPG incision defects result in the cancer-prone syndrome xeroderma pigmentosum, whereas truncating mutations of XPG cause the severe postnatal progeroid developmental disorder Cockayne syndrome. We show that XPG interacts directly with WRN protein, which is defective in the premature aging disorder Werner syndrome, and that the two proteins undergo similar sub-nuclear redistribution in S-phase and co-localize in nuclear foci. The co-localization was observed in mid- to late-S-phase, when WRN moves from nucleoli to nuclear foci that have been shown to contain protein markers of both stalled replication forks and telomeric proteins. We mapped the interaction between XPG and WRN to the C-terminal domains of each and show that interaction with the C-terminal domain of XPG strongly stimulates WRN helicase activity. WRN also possesses a competing DNA single-strand annealing activity that, combined with unwinding, has been shown to coordinate regression of model replication forks to form Holliday junction/chicken foot intermediate structures. We tested whether XPG stimulated WRN annealing activity and found that XPG itself has intrinsic strand annealing activity that requires the unstructured R- and C-terminal domains, but not the conserved catalytic core or endonuclease activity. Annealing by XPG is cooperative, rather than additive, with WRN annealing. Taken together, our results suggest a novel function for XPG in S-phase that is at least in part carried out coordinately with WRN, and which may contribute to the severity of the phenotypes that occur upon loss of XPG.
Werner syndrome (WS) is a premature aging disorder caused by mutations in a RecQ-family DNA helicase, WRN. Mice lacking part of the helicase domain of the WRN orthologue exhibit many phenotypic features of WS, including metabolic abnormalities and a shorter mean life span. In contrast, mice lacking the entire Wrn protein (i.e. Wrn null mice) do not exhibit a premature aging phenotype. In this study, we used a targeted mass spectrometry-based metabolomic approach to identify serum metabolites that are differentially altered in young Wrn helicase mutant and Wrn null mice. An antibody-based quantification of 43 serum cytokines and markers of cardiovascular disease risk complemented this study. We found that Wrn helicase mutants exhibited elevated and decreased levels, respectively, of the anti-inflammatory cytokine IL-10 and the pro-inflammatory cytokine IL-18. Wrn helicase mutants also exhibited an increase in serum hydroxyproline and plasminogen activator inhibitor-1, markers of extracellular matrix remodeling of the vascular system and inflammation in aging. We also observed an abnormal increase in the ratio of very long chain to short chain lysophosphatidylcholines in the Wrn helicase mutants underlying a peroxisome perturbation in these mice. Remarkably, the Wrn mutant helicase protein was mislocalized to the endoplasmic reticulum and the peroxisomal fractions in liver tissues. Additional analyses with mouse embryonic fibroblasts indicated a severe defect of the autophagy flux in cells derived from Wrn helicase mutants compared to wild type and Wrn null animals. These results indicate that the deleterious effects of the helicase-deficient Wrn protein are mediated by the dysfunction of several cellular organelles. PMID:26447695
The direct collapse model of supermassive black hole seed formation requires that the gas cools predominantly via atomic hydrogen. To this end we simulate the effect of an anisotropic radiation source on the collapse of a halo at high redshift. The radiation source is placed at a distance of 3 kpc (physical) from the collapsing object and is set to emit monochromatically in the center of the Lyman-Werner (LW) band. The LW radiation emitted from the high redshift source is followed self-consistently using ray tracing techniques. Due to self-shielding, a small amount of H{sub 2} is able to form at the very center of the collapsing halo even under very strong LW radiation. Furthermore, we find that a radiation source, emitting >10{sup 54} (∼ 10{sup 3} J{sub 21}) photons s{sup –1}, is required to cause the collapse of a clump of M ∼ 10{sup 5} M {sub ☉}. The resulting accretion rate onto the collapsing object is ∼0.25 M {sub ☉} yr{sup –1}. Our results display significant differences, compared to the isotropic radiation field case, in terms of the H{sub 2} fraction at an equivalent radius. These differences will significantly affect the dynamics of the collapse. With the inclusion of a strong anisotropic radiation source, the final mass of the collapsing object is found to be M ∼ 10{sup 5} M {sub ☉}. This is consistent with predictions for the formation of a supermassive star or quasi-star leading to a supermassive black hole.
We have determined the mitotic stability of microsatellite alleles and allele lengths in SV40-immortalized Werner syndrome (WS) and control cell lines. The impetus for this work was presence of a mutator phenotype in WS cells and cell lines and the association between a DNA mismatch repair deficit and microsatellite length instability in a heritable human tumor syndrome. Thus the identification of microsatellite length instability in WS cells might provide a clue to the primary biochemical defect in WS and a partial explanation for the mutator phenotype and the elevated cancer risk of WS patients. Five microsatellite loci (D2S123, D10S197, D10S141, D8S255, and D8S87) were PCR genotyped in 88 independent clones derived from four SV40-immortalized fibroblast cell lines (two WS lines: WV1 and PSV811; and two control lines: GM637 and GM639). Stable allele lengths were transmitted from cell line to clones in every case. WS cell line WV1 contained a preexisting faint third D2S123 allele which was transmitted with the other two D2S123 alleles to a majority of WV1 clones. In contrast, microsatellite allele loss was common: complete absence of one of two alleles was seen in 30% of control and in 3% of WS clones. Complete allele loss likely results from a clonal population being derived from a cell lacking a microsatellite allele. Altered relative band intensities in clones compared to parental lines were very common in both WS and control backgrounds (40% of all clones). This suggests that allele loss is common and continues upon post-cloning cell culture. These allele losses are likely to be a consequence of the genetic instability that accompanies SV40 immortalization. These results indicate that SV40-immortalized cell lines are genetically heterogeneous, and that the genotypes of individual clones may incompletely represent the genomes of the primary cells from which they were derived.
Herlyn-Werner-Wunderlich (HWW) syndrome is a rare developmental anomaly that includes uterus didelphys with obstructed hemivagina and ipsilateral renal agenesis. A 13-year-old girl presented with chronic abdominal pain. Magnetic resonance imaging revealed uterus didelphys, hematometrocolpos and renal agenesis on the right side with imperforate hymen. Subsequently the patient was found to have Mullerian duct anomalies. CA 19-9 level was high. At laparoscopy combined with vaginoscopy hematocolpos was drained following which she improved clinically and CA 19-9 level returned to normal. PMID:26816677
Herlyn-Werner-Wunderlich (HWW) syndrome is a rare developmental anomaly that includes uterus didelphys with obstructed hemivagina and ipsilateral renal agenesis. A 13-year-old girl presented with chronic abdominal pain. Magnetic resonance imaging revealed uterus didelphys, hematometrocolpos and renal agenesis on the right side with imperforate hymen. Subsequently the patient was found to have Mullerian duct anomalies. CA 19-9 level was high. At laparoscopy combined with vaginoscopy hematocolpos was drained following which she improved clinically and CA 19-9 level returned to normal. PMID:26816677
We report the case of a female neonate with ipsilateral renal agenesis and uterus didelphys with blind hemivagina, also known as Herlyn-Werner-Wunderlich (HWW) syndrome. Prenatal sonography revealed the absence of the left kidney and a retrovesical cystic lesion suspected as hydrometrocolpos. Postnatal evaluation confirmed that the cystic lesion was a hydrocolpos associated with double uterus and blind hemivagina (HWW syndrome). HWW syndrome can be suspected prenatally if a retrovesical cystic lesion is detected in a female fetus with unilateral absence of kidney. PMID:22678931
This article announces the recipient of the 2014 inaugural Werner Kalow Responsible Innovation Prize in Global Omics and Personalized Medicine by the Pacific Rim Association for Clinical Pharmacogenetics (PRACP): Bernard Lerer, professor of psychiatry and director of the Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. The Werner Kalow Responsible Innovation Prize is given to an exceptional interdisciplinary scholar who has made highly innovative and enduring contributions to global omics science and personalized medicine, with both vertical and horizontal (transdisciplinary) impacts. The prize is established in memory of a beloved colleague, mentor, and friend, the late Professor Werner Kalow, who cultivated the idea and practice of pharmacogenetics in modern therapeutics commencing in the 1950s. PRACP, the prize's sponsor, is one of the longest standing learned societies in the Asia-Pacific region, and was founded by Kalow and colleagues more than two decades ago in the then-emerging field of pharmacogenetics. In announcing this inaugural prize and its winner, we seek to highlight the works of prize winner, Professor Lerer. Additionally, we contextualize the significance of the prize by recalling the life and works of Professor Kalow and providing a brief socio-technical history of the rise of pharmacogenetics and personalized medicine as a veritable form of 21(st) century scientific practice. The article also fills a void in previous social science analyses of pharmacogenetics, by bringing to the fore the works of Kalow from 1995 to 2008, when he presciently noted the rise of yet another field of postgenomics inquiry--pharmacoepigenetics--that railed against genetic determinism and underscored the temporal and spatial plasticity of genetic components of drug response, with invention of the repeated drug administration (RDA) method that estimates the dynamic heritabilities of drug response. The prize goes a long way
The rate of cooling of domesticated pig bones is investigated within the temperature range of 20°C-320°C. Within the afore-mentioned temperature range, it was found that different behaviors in the rate of cooling were taking place. For bones reaching a temperature within the lower temperature range of 20°C-50°C, it was found that the rate of cooling is mostly governed by the empirical Newton's law of cooling. It is also shown that a transition is taking place somewhere within 50°C-100°C, where both the heat conduction equation and Newton's law apply. As bones can be raised at a fairly high temperature before burning, it was found that the rate of cooling within the range 125°C-320°C is mostly behaving according to the heat conduction equation and Stefan-Boltzmann radiation law. A pulsed CO2 laser was used to heat the bones up to a given temperature and the change of temperature as a function of time was recorded by non-contact infrared thermometer during the cooling period. PMID:24688807
The rate of cooling of domesticated pig bones is investigated within the temperature range of 20°C-320°C. Within the afore-mentioned temperature range, it was found that different behaviors in the rate of cooling were taking place. For bones reaching a temperature within the lower temperature range of 20°C-50°C, it was found that the rate of cooling is mostly governed by the empirical Newton’s law of cooling. It is also shown that a transition is taking place somewhere within 50°C-100°C, where both the heat conduction equation and Newton’s law apply. As bones can be raised at a fairly high temperature before burning, it was found that the rate of cooling within the range 125°C-320°C is mostly behaving according to the heat conduction equation and Stefan-Boltzmann radiation law. A pulsed CO2 laser was used to heat the bones up to a given temperature and the change of temperature as a function of time was recorded by non-contact infrared thermometer during the cooling period. PMID:24688807
A yeast artificial chromosome (YAC), P1, and cosmid clone contig was constructed for the Werner syndrome (WRN) region of chromosome 8p12-p21 and used to clone a candidate gene for WRN. This region also possibly contains a familial breast cancer locus. The contig was initiated by isolating YACs for the glutathione reductase (GSR) gene and extended in either direction by walking techniques. Sequence-tagged site (STS) markers were generated from subclones of 2 GSR YACs and used to identify P1 and cosmid clones. Additional STSs were generated from P1 and cosmid clones and from potential expressed sequences identified by cDNA selection and exon amplification methods. The final contig was assembled by typing 17 YACs, 20 P1 clones, and 109 cosmids for 54 STS markers. The WRN region could be spanned by 2 nonchimeric YACs covering approximately 1.4 Mb. A P1/cosmid contig was established covering the core 700-800 kb of the WRN region. Fifteen new short tandem repeat polymorphisms and 2 biallelic polymorphic markers were identified and included as STSs in the contig. Analysis of these markers in Werner syndrome subjects demonstrates that the candidate WRN gene is in a region of linkage disequilibrium. 47 refs., 2 figs., 3 tabs.
Modulation of DNA repair proteins by small molecules has attracted great interest. An in vitro helicase activity screen was used to identify molecules that modulate DNA unwinding by Werner syndrome helicase (WRN), mutated in the premature aging disorder Werner syndrome. A small molecule from the National Cancer Institute Diversity Set designated NSC 19630 [1-(propoxymethyl)-maleimide] was identified that inhibited WRN helicase activity but did not affect other DNA helicases [Bloom syndrome (BLM), Fanconi anemia group J (FANCJ), RECQ1, RecQ, UvrD, or DnaB). Exposure of human cells to NSC 19630 dramatically impaired growth and proliferation, induced apoptosis in a WRN-dependent manner, and resulted in elevated γ-H2AX and proliferating cell nuclear antigen (PCNA) foci. NSC 19630 exposure led to delayed S-phase progression, consistent with the accumulation of stalled replication forks, and to DNA damage in a WRN-dependent manner. Exposure to NSC 19630 sensitized cancer cells to the G-quadruplex-binding compound telomestatin or a poly(ADP ribose) polymerase (PARP) inhibitor. Sublethal dosage of NSC 19630 and the chemotherapy drug topotecan acted synergistically to inhibit cell proliferation and induce DNA damage. The use of this WRN helicase inhibitor molecule may provide insight into the importance of WRN-mediated pathway(s) important for DNA repair and the replicational stress response. PMID:21220316
Applying Green-Kubo formalism and equilibrium molecular dynamics (MD) simulations, we have studied for the first time the dynamic correlation, Onsager coefficients, and Maxwell-Stefan (MS) diffusivities of molten salt LiF-BeF2, which is a potential candidate for a coolant in a high temperature reactor. We observe an unusual composition dependence and strikingly a crossover in sign for all the MS diffusivities at a composition of around 7% of LiF where the MS diffusivity between cation-anion pair (Đ(BeF) and Đ(LiF)) jumps from positive to negative value while the MS diffusivity between cation-cation pair (Đ(LiBe)) becomes positive from a negative value. Even though the negative MS diffusivities have been observed for electrolyte solutions between cation-cation pair, here we report negative MS diffusivity between cation-anion pair where Đ(BeF) shows a sharp rise around 66% of BeF2, reaches maximum value at 70% of BeF2, and then decreases almost exponentially with a sign change for BeF2 around 93%. For low mole fraction of LiF, Đ(BeF) follows the Debye-Huckel theory and rises with the square root of LiF mole fraction similar to the MS diffusivity between cation-anion pair in aqueous solution of electrolyte salt. Negative MS diffusivities while unusual are, however, shown to satisfy the non-negative entropy constraints at all thermodynamic states as required by the second law of thermodynamics. We have established a strong correlation between the structure and dynamics and predict that the formation of flouride polyanion network between Be and F ions and coulomb interaction is responsible for sharp variation of the MS diffusivities which controls the multicomponent diffusion phenomenon in LiF-BeF2 which has a strong impact on the performance of the reactor. PMID:26192629
Abstract This article announces the recipient of the 2014 inaugural Werner Kalow Responsible Innovation Prize in Global Omics and Personalized Medicine by the Pacific Rim Association for Clinical Pharmacogenetics (PRACP): Bernard Lerer, professor of psychiatry and director of the Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. The Werner Kalow Responsible Innovation Prize is given to an exceptional interdisciplinary scholar who has made highly innovative and enduring contributions to global omics science and personalized medicine, with both vertical and horizontal (transdisciplinary) impacts. The prize is established in memory of a beloved colleague, mentor, and friend, the late Professor Werner Kalow, who cultivated the idea and practice of pharmacogenetics in modern therapeutics commencing in the 1950s. PRACP, the prize's sponsor, is one of the longest standing learned societies in the Asia-Pacific region, and was founded by Kalow and colleagues more than two decades ago in the then-emerging field of pharmacogenetics. In announcing this inaugural prize and its winner, we seek to highlight the works of prize winner, Professor Lerer. Additionally, we contextualize the significance of the prize by recalling the life and works of Professor Kalow and providing a brief socio-technical history of the rise of pharmacogenetics and personalized medicine as a veritable form of 21st century scientific practice. The article also fills a void in previous social science analyses of pharmacogenetics, by bringing to the fore the works of Kalow from 1995 to 2008, when he presciently noted the rise of yet another field of postgenomics inquiry—pharmacoepigenetics—that railed against genetic determinism and underscored the temporal and spatial plasticity of genetic components of drug response, with invention of the repeated drug administration (RDA) method that estimates the dynamic heritabilities of drug response. The prize goes a
A molten salt mixture of lithium fluoride and thorium fluoride (LiF-ThF4) serves as a fuel as well as a coolant in the most sophisticated molten salt reactor (MSR). Here, we report for the first time dynamic correlations, Onsager coefficients, Maxwell-Stefan (MS) diffusivities, and the concentration dependence of density and enthalpy of the molten salt mixture LiF-ThF4 at 1200 K in the composition range of 2-45% ThF4 and also at eutectic composition in the temperature range of 1123-1600 K using Green-Kubo formalism and equilibrium molecular dynamics simulations. We have observed an interesting oscillating pattern for the MS diffusivity for the cation-cation pair, in which ĐLi-Th oscillates between positive and negative values with the amplitude of the oscillation reducing as the system becomes rich in ThF4. Through the velocity autocorrelation function, vibrational density of states, radial distribution function analysis, and structural snapshots, we establish an interplay between the local structure and multicomponent dynamics and predict that formation of negatively charged [ThFn](4-n) clusters at a higher ThF4 mole % makes positively charged Li(+) ions oscillate between different clusters, with their range of motion reducing as the number of [ThFn](4-n) clusters increases, and finally Li(+) ions almost get trapped at a higher ThF4% when the electrostatic force on Li(+) exerted by various surrounding clusters gets balanced. Although reports on variations of density and enthalpy with temperature exist in the literature, for the first time we report variations of the density and enthalpy of LiF-ThF4 with the concentration of ThF4 (mole %) and fit them with the square root function of ThF4 concentration, which will be very useful for experimentalists to obtain data over a range of concentrations from fitting the formula for design purposes. The formation of [ThFn](4-n) clusters and the reduction in the diffusivity of the ions at a higher ThF4% may limit the
In this paper, the main outlines of the discussions between Niels Bohr with Albert Einstein, Werner Heisenberg, and Erwin Schrödinger during 1920 1927 are treated. From the formulation of quantum mechanics in 1925 1926 and wave mechanics in 1926, there emerged Born's statistical interpretation of the wave function in summer 1926, and on the basis of the quantum mechanical transformation theory—formulated in fall 1926 by Dirac, London, and Jordan—Heisenberg formulated the uncertainty principle in early 1927. At the Volta Conference in Como in September 1927 and at the fifth Solvay Conference in Brussels the following month, Bohr publicly enunciated his complementarity principle, which had been developing in his mind for several years. The Bohr-Einstein discussions about the consistency and completeness of qnautum mechanics and of physical theory as such—formally begun in October 1927 at the fifth Solvay Conference and carried on at the sixth Solvay Conference in October 1930—were continued during the next decades. All these aspects are briefly summarized.
Sir William Harvey (1578-1657), who had many precursors, discovered blood circulation in 1628 after a significant number of anatomic dissection of cadavers; his studies were continued by Sir Christopher Wren and Daniel Johann Major. The first central vein catheterization was performed on a horse by Stephen Hales, an English Vicar. In 1844, a century later, the French biologist Claude Bernard attempted the first carotid artery cannulation and repeated the procedure in the jugular vein, again on a horse. He was first to report the complications now well known to be associated with this maneuver. In 1929 Werner Forssmann tried cardiac catheterization on himself, but could not investigate the procedure further since his findings were rejected and ridiculed by colleagues. His work was continued by André Frédéric Cournand and Dickinson Woodruff Richards Jr in the United States. In 1956 the three physicians shared the Nobel Prize for Medicine for their studies on vascular and cardiac systems. The genius and the perseverance of the three physicians paved the way towards peripheral and central catheter vein placement, one of the most frequently performed maneuvers in hospitals. Its history still remains unknown to most and deserves a short description. PMID:21983826
Classical Hutchinson-Gilford progeria syndrome (HGPS) is caused by LMNA mutations that generate an alternatively spliced form of lamin A, termed progerin. HGPS patients present in early childhood with atherosclerosis and striking features of accelerated aging. We report on two pedigrees of adult-onset coronary artery disease with progeroid features, who were referred to our International Registry of Werner Syndrome (WS) because of clinical features consistent with the diagnosis. No mutations were identified in the WRN gene that is responsible for WS, among these patients. Instead, we found two novel heterozygous mutations at the junction of exon 10 and intron 11 of the LMNA gene. These mutations resulted in the production of progerin at a level substantially lower than that of HGPS. Our findings indicate that LMNA mutations may result in coronary artery disease presenting in the fourth to sixth decades along with short stature and a progeroid appearance resembling WS. The absence of early-onset cataracts in this setting should suggest the diagnosis of progeroid laminopathy. This study illustrates the evolving genotype-phenotype relationship between the amount of progerin produced and the age of onset among the spectrum of restrictive dermopathy, HGPS, and atypical forms of WS. PMID:22065502
Werner syndrome (WS) is an autosomal recessive disorder characterized by premature onset of a number of age-related diseases. The gene for WS, WRN, has been mapped to the 8p11.1-21.1 region with further localization through linkage disequilibrium mapping. Here we present the results of linkage disequilibrium and ancestral haplotype analyses of 35 markers to further refine the location of WRN. We identified an interval in this region in which 14 of 18 markers tested show significant evidence of linkage disequilibrium in at least one of the two populations tested. Analysis of extended and partial haplotypes covering 21 of the markers studied supports the existence of both obligate and probable ancestral recombinant events which localize WRN almost certainly to the interval between DSS2196 and D8S2186, and most likely to the narrower interval between D8S2168 and D8S2186. These haplotype analyses also suggest that there are multiple WRN mutations in each of the two populations under study. We also present a comparison of approaches to performing disequilibrium tests with multiallelic markers, and show that some commonly used approximations for such tests perform poorly in comparison to exact probability tests. Finally, we discuss some of the difficulties introduced by the high mutation rate at microsatellite markers which influence our ability to use ancestral haplotype analysis to localize disease genes. 51 refs., 6 figs., 7 tabs.
Atypical progeroid syndrome (APS), including atypical Werner syndrome (AWS), is a disorder of premature ageing caused by mutation of the lamin A gene, the same causal gene involved in Hutchinson-Gilford syndrome (HGS). We previously reported the first Japanese case of APS/AWS with a LMNA mutation (p.D300N). Recently, it has been reported that UVA induced abnormal truncated form of lamin A, called progerin, as well as HGS-like abnormal nuclear structures in normal human fibroblasts, being more frequent in the elderly, suggesting that lamin A may be involved in the regulation of photoageing. The objective of this study was to elucidate the sensitivity to cell damage induced by oxidative stress or UVA in fibroblasts from APS/AWS patient. Using immunofluorescence staining and flow cytometry analysis, the amount of early apoptotic cells and degree of intra-cellular reactive oxygen species (ROS) generation were higher in H2 02 - or UVA-treated APS/AWS fibroblasts than in normal fibroblasts, suggesting that repeated UV exposure may induce premature ageing of the skin in APS/AWS patients and that protecting against sunlight is possibly important for delaying the emergence of APS/AWS symptoms. In addition, we demonstrated that H2 O2 -, or UVA-induced apoptosis and necrosis in normal and APS/AWS fibroblasts were enhanced by farnesyltransferase inhibitor (FTI) treatment, indicating that FTI might not be useful for treating our APS/AWS patient. PMID:27539898
Psychiatrists and medical historians Werner Leibbrand (1896 - 1974) and Annemarie Wettley (1913 - 1996) are amongst the most striking figures in the field of history of medicine. Leibbrand was appointed director of the "Heil- und Pflegeanstalt" in Erlangen shortly after the war. Fuelled by his own experiences of suppression and persecution during the Nazi era he promised to unearth the crimes and atrocities which had happened under watch of the Nazi regime. He was joined by Annemarie Wettley, who worked as a physician at the hospital and had developed an increasing interest in the history of medicine. In 1946 they published "Um die Menschenrechte der Geisteskranken" ("Human Rights of the Mentally Ill") about the "euthanasia" campaign of the Nazi regime. Although a number of substantial works followed, Leibbrand and Wettley failed to inform in more depth on crimes and atrocities, for instance killings of patients and forced malnutrition. Doubts and charges against Wettley regarding her role in dietary programmes at the Erlangen hospital and against Leibbrand regarding special expert's reports--both had a short-term arrest warrant--might have contributed to stagnation in their efforts. In 1953 Leibbrand accepted the offer of a chair at the University in Munich, Wettley followed and habilitated in history of medicine; in the year 1962 they married. Contacts and exchange amongst medico-historical experts shed light on developments during the post-war era; still, a critical and fundamental review of the crimes within the medical system of the Nazi regime did not take place during this time. PMID:25980306
In the quest for new catalysts that can deliver single enantiomer pharmaceuticals and agricultural chemicals, chemists have extensively mined the “chiral pool”, with little in the way of inexpensive, readily available building blocks now remaining. It is found that Werner complexes based upon the D3 symmetric chiral trication [Co(en)3]3+ (en = 1,2-ethylenediamine), which features an earth abundant metal and cheap ligand type, and was among the first inorganic compounds resolved into enantiomers 103 years ago, catalyze a valuable carbon–carbon bond forming reaction, the Michael addition of malonate esters to nitroalkenes, in high enantioselectivities and without requiring inert atmosphere conditions. The title catalysts, [Co((S,S)-dpen)3]3+ ((S,S)-33+) 3X–, employ a commercially available chiral ligand, (S,S)-1,2-diphenylethylenediamine. The rates and ee values are functions of the configuration of the cobalt center (Λ/Δ) and the counteranions, which must be lipophilic to solubilize the trication in nonaqueous media. The highest enantioselectivities are obtained with Λ and 2Cl–BArf–, 2BF4–BArf–, or 3BF4– salts (BArf– = B(3,5-C6H3(CF3)2)4–). The substrates are not activated by metal coordination, but rather by second coordination sphere hydrogen bonding involving the ligating NH2 groups. Crystal structures and NMR data indicate enthalpically stronger interactions with the NH moieties related by the C3 symmetry axis, as opposed to those related by the C2 symmetry axes; rate trends and other observations suggest this to be the catalytically active site. Both Λ- and Δ-(S,S)-33+ 2Cl–BArf– are effective catalysts for additions of β-ketoesters to RO2CN=NCO2R species (99–86% yields, 81–76% ee), which provide carbon–nitrogen bonds and valuable precursors to α-amino acids. PMID:27162946
In the quest for new catalysts that can deliver single enantiomer pharmaceuticals and agricultural chemicals, chemists have extensively mined the "chiral pool", with little in the way of inexpensive, readily available building blocks now remaining. It is found that Werner complexes based upon the D3 symmetric chiral trication [Co(en)3](3+) (en = 1,2-ethylenediamine), which features an earth abundant metal and cheap ligand type, and was among the first inorganic compounds resolved into enantiomers 103 years ago, catalyze a valuable carbon-carbon bond forming reaction, the Michael addition of malonate esters to nitroalkenes, in high enantioselectivities and without requiring inert atmosphere conditions. The title catalysts, [Co((S,S)-dpen)3](3+) ((S,S)-3 (3+)) 3X(-), employ a commercially available chiral ligand, (S,S)-1,2-diphenylethylenediamine. The rates and ee values are functions of the configuration of the cobalt center (Λ/Δ) and the counteranions, which must be lipophilic to solubilize the trication in nonaqueous media. The highest enantioselectivities are obtained with Λ and 2Cl(-)BArf (-), 2BF4 (-)BArf (-), or 3BF4 (-) salts (BArf (-) = B(3,5-C6H3(CF3)2)4 (-)). The substrates are not activated by metal coordination, but rather by second coordination sphere hydrogen bonding involving the ligating NH2 groups. Crystal structures and NMR data indicate enthalpically stronger interactions with the NH moieties related by the C3 symmetry axis, as opposed to those related by the C2 symmetry axes; rate trends and other observations suggest this to be the catalytically active site. Both Λ- and Δ-(S,S)-3 (3+) 2Cl(-)BArf (-) are effective catalysts for additions of β-ketoesters to RO2CN=NCO2R species (99-86% yields, 81-76% ee), which provide carbon-nitrogen bonds and valuable precursors to α-amino acids. PMID:27162946
Using ab initio potential curves and dipole transition moments, cross-section calculations were performed for the direct continuum photodissociation of H{sub 2} through the B{sup 1}{Sigma}{sup +}{sub u} Werner) transitions. Partial cross-sections were obtained for wavelengths from 100 A to the dissociation threshold between the upper electronic state and each of the 301 bound rovibrational levels v''J'' within the ground electronic state. The resulting cross-sections are incorporated into three representative classes of interstellar gas models: diffuse clouds, photon-dominated regions, and X-ray-dominated regions (XDRs). The models, which used the CLOUDY plasma/molecular spectra simulation code, demonstrate that direct photodissociation is comparable to fluorescent dissociation (or spontaneous radiative dissociation, the Solomon process) as an H{sub 2} destruction mechanism in intense far-ultraviolet or X-ray-irradiated gas. In particular, changes in H{sub 2} rotational column densities are found to be as large as 20% in the XDR model with the inclusion of direct photodissociation. The photodestruction rate from some high-lying rovibrational levels can be enhanced by pumping from H Ly{beta} due to a wavelength coincidence with cross-section resonances resulting from quasi-bound levels of the upper electronic states. Given the relatively large size of the photodissociation data set, a strategy is described to create truncated, but reliable, cross-section data consistent with the wavelength resolving power of typical observations.
The praying mantis genus Majangella Giglio-Tos, 1915 is taxonomically treated with a re-description of the genus and the two included species, M. moultoni Giglio-Tos, 1915 and M. carli Giglio-Tos, 1915. The genus Ephippiomantis Werner, 1922 is newly determined to be the junior synonym of Majangella Giglio-Tos, 1915 based on morphology. The species for which the genus name Ephippiomantis was erected, E. ophirensis Werner, 1922, is re-described and now included within Majangella. This synonymy was determined herein as the direct result of erroneous higher-level placement of Majangella within the Majanginae by Giglio-Tos and was not recognized even after the genus was moved to within Liturgusidae. Action is now taken to move Majangella from within Liturgusidae to within the Hymenopodidae subfamily of Acromantinae, which is supported by morphological and molecular data. A key to the three species is provided along with habitus images, images of the head, pronotum, and foreleg, and illustrations of the male genitalia. Species distributions are presented and locality coordinates are provided in print as well as being available for download as a KML file viewable in Google Earth. PMID:24870860
... diabetes , diminished fertility, severe hardening of the arteries ( atherosclerosis ), thinning of the bones ( osteoporosis ), and some types ... most common causes of death are cancer and atherosclerosis. Related Information What does it mean if a ...
The purpose of this article is the analyses of discussion between Albert Einstein and Werner Heisenberg in the period 1925-1927. Their disputes, relating to the sources of scientific knowledge, its methods and the value of knowledge acquired in this way, are part of the characteristic for the European science discourse between rationalism and empirism. On the basis of some sources and literature on the subject, the epistemological positions of both scholars in the period were reconstructed. This episode, yet poorly known, is a unique example of scientific disputes, whose range covers a broad spectrum of methodological problems associated with the historical development of science. The conducted analysis sheds some light on the source of popularity of logical empirism in the first half of the 20th century. A particular emphasis is placed on the impact of the neopositivist ideas which reflect Heisenberg's research program, being the starting point for the Copenhagen interpretation of quantum mechanics. The main assumption of logical empirism, concerning acquisition of scientific knowledge only by means of empirical procedures and logical analysis of the language of science, in view of the voiced by Einstein arguments, bears little relationship with actual testing practices in the historical aspect of the development of science. The criticism of Heisenberg's program, carried out by Einstein, provided arguments for the main critics of the neopositivist ideal and contributed to the bankruptcy of the idea of logical empirism, thereby starting a period of critical rationalism prosperity, arising from criticism of neopositivism and alluding to Einstein's ideas. PMID:25675728
A 49-year-old man was first seen in our department for the evaluation of scleroderma-like skin changes and a nonhealing ulcer on his leg from years before referral. His medical history was of long duration. His growth was stunted at the age of 12. At 21 years of age, the patient noted graying of the scalp hair, most prominent on his temples, and the process was progressively completed by the age of 23. At the same age, atrophy and thinning of the skin and loss of subcutaneous fat resulted in a tense, shining, and adherent appearance of his skin, most obvious on his face and extremities. Soon after, he developed a high-pitched, hoarse voice. He had undergone bilateral cataract surgery at the age of 30. Around the age of 46, he developed a unilateral nonhealing chronic leg ulcer (Figure 1). He had separated from his wife because of infertility. He was the first offspring of his second-degree healthy relative parents. The other 3 siblings had similar signs and symptoms. Our patient gave the history of premature graying of the hair of his younger brother at the age of 18 and his 2 younger sisters at the age of 12 and 16. His brother had recently received diagnoses of bilateral cataract and diabetes mellitus. All of the siblings had ceased growth from early adolescence. On physical examination, our patient's weight was 48 kg and his height was 150 cm. He had normal intelligence. He was speaking with a high-pitched and childish voice. He had a bird-like appearance with a beak-shaped nose. Mottled and diffuse pigmentation and poikiloderma appearance was conspicuous on his neck (Figure 2). The entire skin was smooth, shiny, and scleroderma-like, and a marked decrease in the subcutaneous fat was noted over the extremities. A deep cutaneous ulcer was evident on his slimmed leg. Digital ulcers were not found, and radial and dorsalis pedis pulses were palpable. Clinodactyly of the toes were conspicuous. His nails were dystrophic and he had used dentures from the age of 20. On examination of the external genitalia, his testes were smaller than normal. In the biopsy taken from the leg ulcer, there were no signs of malignancy. There were no signs ofosteomyelitis on x-ray. Biopsy of the normal skin revealed atrophic epidermis and thick dermis with hyalinization of the collagen fibers and absence of pilosebaceous structures (Figure 3). The patient's scalp hair was thin and sparse and there were few axillary and pubic hairs. His fasting plasma glucose level was normal. PMID:21137629
Propagation of a gel/glass transition boundary in a polymer is considered in the context of drug release. Drug molecules are assumed to undergo subdiffusive motion in the gel and be quiescent in the glass region. Exact self-similar solutions for the drug concentration are constructed, and the amount of released drug is determined as a function of time.
Where does Hawking radiation originate? A common picture is that it arises from excitations very near or at the horizon, and this viewpoint has supported the "firewall" argument and arguments for a key role for the UV-dependent entanglement entropy in describing the quantum mechanics of black holes. However, closer investigation of both the total emission rate and the stress tensor of Hawking radiation supports the statement that its source is a near-horizon quantum region, or "atmosphere," whose radial extent is set by the horizon radius scale. This is potentially important, since Hawking radiation needs to be modified to restore unitarity, and a natural assumption is that the scales relevant to such modifications are comparable to those governing the Hawking radiation. Moreover, related discussion suggests a resolution to questions regarding extra energy flux in "nonviolent" scenarios, that does not spoil black hole thermodynamics as governed by the Bekenstein-Hawking entropy.
Notes that creating focus which leads to formulating a thesis is a task with which many writers have trouble. Describes a process model of conceptual development that helps students gain confidence in abstracting, conceptualizing, and formulating a thesis. (NH)
The exploding use of electricity in homes and industry in the second half of the 19th century was accompanied by many injuries and fatalities from electric currents. Their study by my father was the serendipitous outcome of his early work on possible blood pressure changes from electric currents in a career that started in internal medicine. It became his limited field of electro-pathology which embraced first aid, the care of the injured, histopathology and accident prevention. He was an enthusiastic teacher and collector of specimens, from tree trunks struck by lightning down to the microscopy of accidental and experimental electric lesions. PMID:24944049
This workshop is one of an annual series covering penetration phenomena of charged particles in matter. This specific workshop includes electron scattering, ion and atom scattering, stopping powers, and cluster ion impacts on solids. Abstracts were prepared for individual items in the proceedings for inclusion in the data base. (GHT)
Background Atlantolacerta andreanskyi is an enigmatic lacertid lizard that, according to the most recent molecular analyses, belongs to the tribe Eremiadini, family Lacertidae. It is a mountain specialist, restricted to areas above 2400 m of the High Atlas Mountains of Morocco with apparently no connection between the different populations. In order to investigate its phylogeography, 92 specimens of A. andreanskyi were analyzed from eight different populations across the distribution range of the species for up to 1108 base pairs of mitochondrial DNA (12S, ND4 and flanking tRNA-His) and 2585 base pairs of nuclear DNA including five loci (PDC, ACM4, C-MOS, RAG1, MC1R). Results The results obtained with both concatenated and coalescent approaches and clustering methods, clearly show that all the populations analyzed present a very high level of genetic differentiation for the mitochondrial markers used and are also generally differentiated at the nuclear level. Conclusions These results indicate that A. andreanskyi is an additional example of a montane species complex. PMID:22946997
This paper examines the process of self-translation undertaken by German exile writers who translated their own works, written in English, the language of their host country, back into their mother tongue, German. It postulates that the necessary precondition for self-translation is not just bilinguality but also biculturality and that it is this…
Researchers from the University of Queensland of New South Wales provided guidance to designers regarding the hydraulic performance of embankment dam stepped spillways. Their research compares a number of high-quality physical model data sets from multiple laboratories, emphasizing the variability ...
WRN belongs to the RecQ family of DNA helicases and it plays a role in recombination, replication, telomere maintenance and long-patch base excision repair. Here, we demonstrate that WRN efficiently unwinds DNA substrates containing a 1-nucleotide gap in the translocating DNA strand, but when the gap size is increased to 3-nucleotides unwinding activity significantly declines. In contrast, E. coli UvrD (3'-->5' helicase), which recognizes nicks in DNA to initiate unwinding, does not unwind past a 1-nucleotide gap. This unique ability of WRN to bypass gaps supports its involvement in DNA replication and LP-BER where such gaps can be produced by glycosylases and the apurinic/apyrimidinic endonuclease 1 (APE1). Furthermore, we tested telomere repeat binding factor 2 (TRF2), both variants 1 and 2 of protector of telomeres 1 (POT1v1 and POT1v2) and RPA on telomeric DNA substrates containing much bigger gaps than 3-nucleotides in order to determine whether unwinding could be facilitated through WRN-protein interaction. Interestingly, POT1v1 and RPA are capable of stimulating WRN helicase on gapped DNA and 5'-overhang substrates, respectively. PMID:19262689
Presented is an insight into man's idea about physics and being a physicist in the days when Heisenberg, P. A. M. Dirac, Louis de Broglic and other famous physicists were young men. Heisenberg is compared to Newton, inventing new math as he needed it. Emphasis is placed on the fact that he was not a Nazi sympathizer. (EB)
Optimized procedures for the previously reported conversions of 1,3-diiodobenzene and perfluorohexyliodide (Rf6I; copper, DMSO, 140 °C) to 1,3-C6H4(Rf6)2 (3; 86-70%) and 3 to Br(3,5-C6H3(Rf6)2 (2; NBS, H2SO4/CF3CO2H; 88-75%) are described. The latter is converted (t-BuLi, BCl3) to the "fluorous BArf" salt NaB(3,5-C6H3(Rf6)2)4 (1 or NaBArf6; 77-70%), as given earlier. When orange aqueous solutions of [Co(en)3]Cl3 (en = ethylenediamine) are treated with perfluoro(methylcyclohexane) (PFMC) solutions of 1 (1:3 mol ratio), the aqueous phase decolorizes and [Co(en)3](BArf6)3 can be isolated from the fluorous phase (96%). Similar reactions with the trans-1,2-cyclohexanediamine analogue [Co(R,R-chxn)3]Cl3 and [Ru(bipy)3]Cl2 give [Co-(R,R-chxn)3](BArf6)3 (92%) and [Ru(bipy)3](BArf6)2 (95%). All of these salts are isolated as hydrates and exhibit toluene/PFMC partition coefficients of ≤1:≥99, establishing that the anion BArf6(-) can efficiently transport polar polycations into highly nonpolar fluorous phases. When equal volumes of CH2Cl2 and PFMC are charged with the "nonfluorous" BArf (B(3,5-C6H3-(CF3)2)4) salt [Co(en)3](BArf)3 and 3.0 equiv of the fluorous salt NaBArf6, the cobalt trication partitions predominantly into the fluorous phase (64:36). The arene 2 crystallizes in a polar space group (tetragonal, I4, Z = 8) with fluorous and nonfluorous domains and all eight bromine atoms located essentially on one face of the unit cell. PMID:23895404
Single crystals of the title Co(II) complex, [Co(stpy) 4(NCS) 2] [stpy= trans-4-styrylpyridine] are prepared and characterized by elemental analysis, IR, and UV-visible spectroscopy and X-ray crystal structure determination. The complex crystallizes in the orthorhombic space group Pna2 1 with unit-cell parameters, a=32.058(3), b=15.362(5), c=9.818(5) Å, and Z=4. The structure consists of discrete monomeric units of [Co(stpy) 4(NCS) 2]. The equatorial positions of the Co(II) polyhedron are occupied by nitrogen atoms of the four stpy ligands and the axial positions are occupied by the nitrogen atoms of the two thiocyanate ions. The unit cell packing reveals interpenetration of styryl groups owing to conformational flexibility of phenyl and pyridyl rings in stpy ligands. Thus, it leads to efficient packing of the crystal lattice leaving no space available for guest inclusion. IR spectra reveal nitrogen coordination from stpy and terminal -NCS coordination of the thiocyanate group. The optical reflectance bands 475, 540 (shoulder) and 1022 nm suggest octahedral geometry in accordance with the X-ray data. However, the optical spectrum of acetonitrile solution shows an intense band at 615 nm and a weak shoulder at 570 nm suggesting participation of the solvent molecules in the coordination sphere. These bands indicate the presence of both tetrahedral and octahedral species in solution.
Fifty eight Chaunus ictericus and 42 C. schneideri specimens were collected on São Cristóvão district, Três Barras, SC for helminthological studies. Fourteen helminth species were diagnosed, from which only five species were found on both hosts. Chaunus ictericus showed higher values of species richness (2,8448+/-1,1516) and diversity (H = 1,374), with mild dominance (1-D = 0,642, J = 0,5528), in comparison with C. schneideri (0,6428+/-1,007; H = 1,165; 1-D = 0,5822 e J = 0,5985). Also, descriptors of helminthic infection were superior in the former host. Little number of shared species between the analyzed toad species suggests parasitic host-specificity. PMID:20059839
In their paper Gross et al., 2011 present an excellent description of a series of outcrops from the Eirunepe region in western Amazonia (Brazil). The authors interpret these sediments as relics of a Late Miocene anastomosing fluvial system and conclude that the paleogeography of the entire western Amazon region must have been characterized by this environmental setting. They also imply that therefore a long-lived lake system - or megawetland - never existed. We contend this assumption for some reasons, amongst them, the most important are: (1) this is an inconsistent overgeneralized conclusion; (2) The authors make references to previous scientific works we published which we consider incorrect, and therefore can mislead their readers.
Glutathione (GSH) is present as the most abundant low molecular weight thiol (LMWT) in virtually all mitochondria-bearing eucaryotic cells, often at millimolar concentrations (Meister, 1988). Functions of GSH include roles in DNA and protein synthesis, maintenance of cell membra...
Farmers are commonly regarded as stewards of the land. Farmers have, however, become cynical toward nature (Meister, Hest, & Burnett, 2009) and distrustful of the government (Cantrill, 2003). This study examines whether or not that cynicism and distrust is reflected in U.S. farmers' opinions of and future participation in conservation buffer…
Discussed is a technique used by Alfred Werner to resolve inorganic coordination compounds. The materials, procedures and analysis necessary for undergraduates to repeat this procedure are described. (CW)
Stefan Bengtsson's commentary about policy hegemony discusses the alternative discourses of socialism, nationalism, and globalism. However, Stefan does not adequately demonstrate how these discourses can overcome the Dominant Western Worldview (DWW), which is imbued with anthropocentrism. It will be argued here that most policy choices promoting…
Examines Martha Muchow's work from the perspective of Heinz Werner's organismic-developmental theory, in terms of its stress on the environment as perceived and experienced by the child and its relevance to Werner's concept of differing "spheres of reality." (Author/SO)
This paper examines how Piaget, Werner, and Gardner differ regarding the roles of cognition, intelligence, and learning in the developmental process. Piaget believes in the predominance of genetic factors. Werner stresses the influence of biological factors, while Gardner proposes that the environment plays a greater influence in how intelligence…
Bounds on the effective elastic moduli of randomly oriented aggregates of hexagonal, trigonal, and tetragonal crystals are derived using the variational principles of Hashin and Shtrikman. The bounds are considerably narrower than the widely used Voigt and Reuss bounds. The Voigt-Reuss-Hill average lies within the Hashin-Shtrikman bounds in nearly all cases. Previous bounds of Peselnick and Meister are shown to be special cases of the present results.
This article presents results of solid-liquid phase change, the Stefan Problem, where melting is driven internal heat generation, in a cylindrical geometry. The comparison between a quasi-static analytical solution for Stefan numbers less than one and numerical solutions shows good agreement. The computational results of phase change with internal heat generation show how convection cells form in the liquid region. A scale analysis of the same problem shows four distinct regions of the melting process.
Presents the author's recollections of the emergence of the new quantum theory and his associations with such men as Oskar Klein, Niels Bohr, Frederick Hund, Werner Heisenberg, J. J. Thomson, and others. (GS)
Werner Heisenberg's work is the foundation for many topics of present research. This is also true for the search for extra gauge bosons. The prospects of future colliders in this search are shortly mentioned.
Thirty-five Werner H. Kirsten student interns toured the National Library of Medicine and the National Institutes of Health Clinical Center in Bethesda in August to learn about the services and opportunities available.
This chart describes the Skylab student experiment In-Vitro Immunology, proposed by Todd A. Meister of Jackson Heights, New York. He suggested an in-vitro observation of the effects of zero-gravity on a presipitin-type antigen-antibody reaction, as compared with the same reaction carried out in an Earth-based laboratory. In March 1972, NASA and the National Science Teachers Association selected 25 experiment proposals for flight on Skylab. Science advisors from the Marshall Space Flight Center aided and assisted the students in developing the proposals for flight on Skylab.
The achievements of the Jesuits from the Austrian and Bohemian provinces, who have published books on chemistry are focused. Their links with the area of today's Slovenia are particularly exposed. The guidelines which have enabled prompt victories of the ideas about the structure of matter of Jesuit Ru|er Bokovi are indicated. Inconceivable fast spread of Bošković's adherents in the Hapsburg monarchy is compared with a similar rapid introduction of the kinetic theories of atoms of Slovene Jožef Stefan and Ludwig Boltzmann in the same geographical area. Boltzmann was not only Stefan's best student, but he also married a half Slovenian maid. PMID:27333568
ABSTRACT The present paper examines the Eckhartian motives in Derrida's critique of Levinas’ concept of the “Other”. The focus is put on the Husserlian concept of alter ego that is at the core of the debate between Levinas and Derrida. Against Levinas, Derrida argues that alter is not an epithet that expresses a mere accidental modification of the ego, but an indicator of radical exteriority. Interestingly enough, this position is virtually identical with Meister Eckhart's interpretation of the famous proposition from Exodus 3:14 “I am who I am”. Eckhart claims that the pronoun ego denotes the absolutely simple substance of the uncreated intellect, which can, by definition, never receive any accidental determination whatsoever. The reduplication of the “I am” is by no means tautological, but expresses the intra-divine dynamic of the Father who engenders the Son as his perfect equal and alter ego. This transcendental conception of egoity also governs the relationships between human beings: the ethical encounter with the “Other” requires that we consider them not primarily in their empirical, contingent existence but in the transcendental purity of their indeclinable ego, which is identical with the incessant act in which God knows himself in the Son as his absolutely Other. Thus, Meister Eckhart's approach proves, against Levinas, that it is possible to develop an “egological” philosophy that avoids the pitfalls of a naturalistic and potentially violent ontology of the subject. PMID:27152029
A technique of dynamically defined measures is developed and its relation to the theory of equilibrium states is shown. The technique uses Carathéodory's method and the outer measure introduced in a previous work by I. Werner [Math. Proc. Camb. Phil. Soc. 140(2), 333-347 (2006), 10.1017/S0305004105009072]. As an application, equilibrium states for contractive Markov systems [I. Werner, J. London Math. Soc. 71(1), 236-258 (2005), 10.1112/S0024610704006088] are obtained.
The interrelationship between the various forms of the Planck radiation equation is discussed. A differential equation that gives intensity or energy density of radiation per unit wavelength or per unit frequency is emphasized. The Stefan-Boltzmann Law and the change in the glow of a hot body with temperature are also discussed. (KR)
We report on the physics around an incandescent lamp. Using a consumer-grade digital camera, we combine electrical and optical measurements to explore Planck's law of black-body radiation. This simple teaching experiment is successfully used to measure both Stefan's and Planck's constants. Our measurements lead to a strikingly accurate value for…
The 2014 Nobel Prize in Chemistry awarded to Eric Betzig, Stefan W. Hell, and William E. Moerner "for the development of superresolved fluorescence microscopy" can be seen as a combined prize for single-molecule detection and superresolution imaging. Neurons, arguably the most morphologically complex cell type, are the subject of choice for this application, now generically called "nanoscopy." PMID:25521373
When physicists at Trinity College Dublin began looking after an antique funnel full of pitch, they had no idea their humble experiment would spawn one of 2013's most “viral” news stories. Shane D Bergin, Stefan Hutzler and Denis Weaire reflect on the value of “slow science” to a hyper-connected, social-media world.
Today many authors and artists adapt works of classic literature into a medium more "user friendly" to the increasingly visual student population. Stefan Petrucha and Kody Chamberlain's version of "Beowulf" is one example. The graphic novel captures the entire epic in arresting images and contrasts the darkness of the setting and characters with…
This month’s column reviews the theory and current applications of pulsed electric field (PEF) processing for fruits and vegetables to improve their safety and quality. This month’s column coauthor, Stefan Toepfl, is advanced research manager at the German Institute of Food Technologies and professo...
In this essay Stefan Neubert argues that John Dewey was a philosopher of reconstruction and that the best use we can make of him today is to reconstruct his work in and for our own contexts. Neubert distinguishes three necessary and equally important components of the overall project of reconstructing Deweyan pragmatism: first, to make strong and…
Why is John Dewey still such an important philosopher today? Writing from the perspective of the Cologne Program of Interactive Constructivism, Stefan Neubert tries in what follows to give one possible answer to this question. Neubert notes that Cologne constructivism considers Dewey in many respects as one of the most important predecessors of…
Based on Snyder's idea of quantized space-time, we derive a new generalized uncertainty principle and new modified density of states. Accordingly, we discuss the influence of the modified generalized uncertainty principle on the black hole entropy and the influence of the modified density of states on the Stefan-Boltzman law.
In this chapter, Stefan LoBuglio discusses the politics and practices of educational programs for adults in correctional facilities. To begin, LoBuglio provides an overview of the field of corrections, including various types of facilities and correctional programs, as well as demographic and educational data on the U.S. incarcerated population…
In his 2001 article "Teaching to Lie and Obey: Nietzsche on Education", Stefan Ramaekers defends Nietzsche's concept of perspectivism against the charge that it is relativistic. He argues that perspectivism is not relativistic because it denies the dichotomy between the "true" world and the "seeming" world, a dichotomy central to claims to…
A mathematical model of fibrin polymerization is described. The problem of the propagation of phase transition wave is reduced to a nonlinear Stefan problem. A one-dimensional discontinuity fitting difference scheme is described, and the results of one-dimensional computations are presented.
Most humanities courses rarely require students to create the kinds of work they are studying. Sean Gouglas, Stefan Sinclair, Olaf Ellefson, and Scott Sharplin outline the value of this rare experience by describing an assignment in their graduate humanities computing course in which students examined hypermedia narratives by authoring a…
This article explores why some universities may be "invisible" to adults in their local communities. It suggests that funding changes in UK higher education, particularly those initiated by the Browne Review in 2010, may reinforce such a divide. The article draws on Stefan Collini's critiques of government policy, particularly in relation to the…
Numerical investigations have been carried out to examine the characteristics of unsteady freezing heat transfer in water-saturated porous media. Also, the effects of Stefan number and of the ratio if cooling to heating temperature are discussed for the unsteady freezing heat transfer.
In a previous article in this journal, we reported on a laboratory activity in which students used a derivation from the Stefan-Boltzmann law to calculate planetary temperatures and compare them to measured values from various (mostly online) sources. The calculated temperatures matched observed values very well with the exceptions of Venus and…
The different responses, interpretations, and consequent critiques of Stefan Lars Bengtsson's "Hegemony and the Politics of Policy Making for Education for Sustainable Development" highlight how the various critical outlooks are framed by, seemingly, incommensurable positions, or figures of reasoning, that inform their thinking.…
Stefan Ramaekers and Joris Vlieghe's "Infants, childhood and language in Agamben and Cavell: education as transformation" is an insightful discussion of an important facet of educational experience. In the article, they consider a Fred Astaire dance sequence from the 1953 Vincente Minnelli film, "The Band Wagon," in combination…
The peculiarities of pulsed laser melting and evaporation of the superconducting ceramics are analyzed by means of numerical simulation. The appearance of the overheated metastable states in solid and liquid phases is shown as a result of the phase front dynamics and volume nature of laser energy release. A method of dynamic adaptation for the multifront Stefan problem is proposed.
This collection of papers presents essays by German scholars and practitioners writing from within the German Didaktik tradition and interpretive essays by U.S. scholars. After an introduction, "Starting a Dialogue: A Beginning Conversation between Didaktik and the Curriculum Traditions" (Stefan Hopmann and Kurt Riquarts), there are 18 chapters in…
In this essay Luc Van den Berge and Stefan Ramaekers take the idea(l) of "scientific parenting" as an example of ambiguities that are typical of our late-modern condition. On the one hand, parenting seems like a natural thing to do, which makes "scientific parenting" sound like an oxymoron; on the other hand, a disengaged…
This response problematizes Stefan Bengtsson's (2016) defense of education for sustainable development. He argues that sustainable development and education for sustainable development are not globalizing and hegemonic discourses, as some have claimed, and uses case-study analysis of Vietnamese policy documents to support his claims. He observes…
In this article we propose an activity aimed at introductory students to help them understand the Stefan-Boltzmann and Wien's displacement laws. It only requires simple materials that are available at any school: an incandescent lamp, a variable dc energy supply, and a computer to run an interactive simulation of the blackbody spectrum.…
It is from historical perspectives on more than 40 years of environment related education theories, practices, and policies that we revisit what might otherwise become a tired conversation about environmental education and sustainable development. Our contemporary critical analysis of Stefan Bengtsson's research about policy making leads us to…
The report gives results of a laboratory pilot-scale evaluation of a Flux Force/Condensation (FF/C) scrubber for collecting fine particles, those smaller than 2 micrometers in diameter. FF/C scrubbing includes the effects of diffusiophoresis, thermophoresis, Stefan flow, and part...
In response to Stefan Bengtsson's search for alternatives to Education for Sustainable Development practices outside the mainstream of the state and its policy formulations, this response outlines how our journey, experiences, and approaches reflect a de-professionalizing encounter with autonomous places of learning emerging from indigenous…
Two lectures on the development of Berlin's adult education centers after World War II are included. The lecture by Werner Korthaase begins by describing the situation prior to 1920, when Berlin was divided into independent districts, each with its own administrative authorities. It then describes the reestablishment of the local adult education…
This paper advances the hypothesis that young children use narrative play and stories to construct two types of fiction, the worlds of "what is" and "what if." Heinz Werner's conceptualization of children's spheres of reality, in which actions, symbols, and events are constructed in particular ways, is used as a theoretical framework for…
Introduces the 1983 SRCD symposium on Martha Muchow, the German child psychologist and associate of William Stern and Heinz Werner at the University of Hamburg. Her work integrates developmental and ecological approaches to the study of children's knowledge of and interaction with their physical surroundings. (Author/SO)
We propose a natural generalization of bipartite Werner and isotropic states to multipartite systems consisting of an arbitrary even number of d-dimensional subsystems (qudits). These generalized states are invariant under the action of local unitary operations. We study basic properties of multipartite invariant states and present necessary and sufficient separability criteria.
In 1955, the first longitudinal study of resilience began on the island of Kauai. This research continues to the present. This article presents an interview with Emmy Werner, the principal investigator. In a series of five books published over a period of thirty years, she demonstrated the remarkable ability of children from difficult backgrounds…
The field of college developmental reading does not have a unified, agreed-upon approach to creating effective and efficient readers at the college level, as Reynolds and Werner (2003) have pointed out. For example, Keefe and Meyer (1991) assert the appropriateness of a holistic, whole-language approach for adult readers, while Bohr (2003)…
This theme issue focuses on skills and qualifications in future world markets in general and in the Single Market within the European Community (EC). The first two articles are "Anthropocentric Production Systems: Advanced Manufacturing is Based on Skilled People" (Werner Wobbe) and "New Skills or a New Concept of 'the Job'"? (Enrique Retuerto de…
2Max-Planck-Institut für Physik (Werner-Heisenberg-Institut) Föhringer Ring 6, D-80805 MünchenAbstract. We have asked how the Heisenberg relations of space and time change if we replace the Lorentz group by a q-deformed Lorentz group (Lorek et al. 1997).
The play Copenhagen has attracted the attention of a large audience in several countries. The hypothetical discussion between two of the giants in physics, Niels Bohr and Werner Heisenberg, has inspired us to start a theoretical and experimental exploration of quantum physics. This theme has been used in Stockholm Science Laboratory for audiences…
The play Copenhagen has attracted the attention of a large audience in several countries. The hypothetical discussion in Copenhagen between two of the giants in physics, Niels Bohr and Werner Heisenberg, has inspired us to start a theoretical and experimental exploration of quantum physics. This theme has been used in Stockholm Science Laboratory for audiences of both students and the general public.
An elementary treatment of the critical mass used in nuclear weapons is presented and applied to an analysis of the wartime activities of the German nuclear program. In particular, the work of Werner Heisenberg based on both wartime and postwar documents is discussed.
The recent release of draft letters from Niels Bohr to Werner Heisenberg provides new insights into German fission research during World War II and into the reasons for its relative failure. I refute claims of deliberate failure and briefly summarize other contributing factors.
The book Physics in Mind: a Quantum View of the Brain certainly aims high. Written by the eminent biophysicist Werner Loewenstein, its goal is nothing less than a theory that explains our sense of conscious existence, built from the bottom up.
All four of the most important figures in the early twentieth-century development of quantum physics--Niels Bohr, Erwin Schroedinger, Werner Heisenberg and Wolfgang Pauli--had strong interests in the traditional mind--brain, or "hard," problem. This paper reviews their approach to this problem, showing the influence of Bohr's complementarity…
Based on the seminal work of Emmy Werner (1990), practitioners have recognized the powerful role protective and risk factors play in the development of children's emotional and behavioral adjustment. Researchers have concluded that differences in children's reactions to difficult events are influenced by the type and level of protective factors in…
Discusses two widely practiced principles of management (protecting the rear and knowing the limits of a job) as they relate to the philosophy of education. The article examines Werner Jaeger's definition of education in his 1939 book, "Paideia," as well as other definitions that have helped shape current educational management. (SM)
This article represents an amazing reversal of linguistic analysis. Usually Montessori language is translated into "state" terminology. In this case, Sarah Werner Andrews puts state quality assessment terms into Montessori language. For example, domains for school readiness include 1) physical wellbeing and motor development, 2) social…
Purpose: This study examined the empirical evidence for using the Structured Photographic Expressive Language Test: Third Edition (SPELT-3; Dawson, Stout, & Eyer, 2003) to diagnose language impairment in preschool children. The SPELT-3 is a revision of the SPELT-II (Werner & Kresheck, 1983), which has been proven in the past to have high levels of…
Physical education is a prime content area for interdisciplinary learning. The movement components of physical education can be used as a medium through which children are provided with opportunities to practice and strengthen language skills. Cone, Werner, Cone, and Woods (1998, p. 4) agree: "interdisciplinary learning is an educational process…
Reported here are the results of an open controlled study on the use of GM1 in cases of ischemic strokes in its acute phase. A statistically significant improvement was observed in cases treated with GM1 for neurological deficits (assessed by Mathew's rating scale, modified by Fritz-Werner) at 21, 60 and 120 days and for disability at 120 days. PMID:2206015
Previous research indicates that adults who live on cul-de-sac streets are more likely to have positive experiences with neighbors than residents of other street types (Brown and Werner, 1985; Hochschild Jr, 2011; Mayo Jr, 1979; Willmott, 1963). The present research ascertains whether street design has an impact on children's neighborhood…
The program of the 130th meeting of the Association of Research Libraries (ARL) explored the leadership challenges posed by the juxtapositions of cooperation and competing priorities in a consortial environment. Following an opening and welcome (Gloria Werner, ARL Presiding President), and a Keynote Address, "Defining Successful Leadership" (David…
In early 1948, less than three years after the end of the Second World War in Europe, Werner Heisenberg - the Nobel laureate and physicist leader of the failed German atomic bomb project - was invited to the UK as part of an attempt to repair relations between British and German physicists.
... addressed in the EIS/LEIS. This public scoping process starts with the publication of this Notice of Intent.... Werner, Lieutenant Commander, Office of the Judge Advocate General, U.S. Navy, Alternate Federal Register... research, development, test and evaluation (RDT&E) and training missions at NAWSCL, in addition to...
This book takes stock of the existing socioeconomic knowledge about a range of the core social issues of the information society. Chapter 1, "Information Infrastructures or Societies?" (Ken Ducatel, Juliet Webster, Werner Herrmann), is an introduction. Part 1, "Space, Economy, and the Global Information Society" looks at the processes of economic…
The goal of this paper is to contribute to the revival of Heinz Werner's organismic-developmental theory by considering some of its key claims in relation to contemporary developmental theory and research. The organismic-developmental definition of development in terms of differentiation and integration is first discussed in relation to…
Background. Associations between positive behaviour, emotion understanding and verbal ability have been reported in studies of preschoolers (Cassidy, Werner, Rourke, Zubernis, & Balaraman, 2003), but have yet to be investigated in younger children. Methods. In this study the performance of 36 toddlers (17 boys and 19 girls; mean age = 29 months,…
Schools are natural environments for helping all children cultivate the resilience that resides within them. Research shows that schools are filled with the conditions that promote resilience (Werner, 2003). These include caring, encouraging relationships, role models, and mentors (Theron & Engelbrecht, 2012; Thomsen, 2002; Walsh, 2012); clear…
The relation between short-term and long-term change (also known as learning and development) has been of great interest throughout the history of developmental psychology. Werner and Vygotsky believed that the two involved basically similar progressions of qualitatively distinct knowledge states; behaviorists such as Kendler and Kendler believed…
Three Werner H. Kirsten student interns claimed awards at the 35th Annual Frederick County Science and Engineering Fair—and got a shot at the national competition—for imaginative projects that reached out to the rings of Saturn and down to the details of advanced cancer diagnostics.
Available from UMI in association with The British Library. Requires signed TDF. After giving a description of the basic physical phenomena to be modelled, we begin by formulating a sharp -interface free-boundary model for the destruction of superconductivity by an applied magnetic field, under isothermal and anisothermal conditions, which takes the form of a vectorial Stefan model similar to the classical scalar Stefan model of solid/liquid phase transitions and identical in certain two-dimensional situations. This model is found sometimes to have instabilities similar to those of the classical Stefan model. We then describe the Ginzburg-Landau theory of superconductivity, in which the sharp interface is 'smoothed out' by the introduction of an order parameter, representing the number density of superconducting electrons. By performing a formal asymptotic analysis of this model as various parameters in it tend to zero we find that the leading order solution does indeed satisfy the vectorial Stefan model. However, at the next order we find the emergence of terms analogous to those of 'surface tension' and 'kinetic undercooling' in the scalar Stefan model. Moreover, the 'surface energy' of a normal/superconducting interface is found to take both positive and negative values, defining Type I and Type II superconductors respectively. We discuss the response of superconductors to external influences by considering the nucleation of superconductivity with decreasing magnetic field and with decreasing temperature respectively, and find there to be a pitchfork bifurcation to a superconducting state which is subcritical for Type I superconductors and supercritical for Type II superconductors. We also examine the effects of boundaries on the nucleation field, and describe in more detail the nature of the superconducting solution in Type II superconductors--the so-called 'mixed state'. Finally, we present some open questions concerning both the modelling and analysis of
We undertook a panbiogeographic analysis of 23 species of the Epicauta maculata group of America-Epicauta abeona Pinto, Epicauta adspersa (Klug), Epicauta andersoni Werner, Epicauta atomaria (Germar), Epicauta apache Pinto, Epicauta cavernosa (Courbon), Epicauta dilatipennis Pic, Epicauta fulvicornis (Burmeister), Epicauta horni Champion, Epicauta jeffersi Pinto, Epicauta koheleri Denier, Epicauta lizeri Denier, E. maculata (Say), Epicauta magnomaculata Martin, Epicauta minutepunctata Borchmann, Epicauta nigropunctata (Blanchard), Epicauta normalis Werner, Epicauta ocellata (Dugès), Epicauta pardalis LeConte, picauta phoenix Werner, Epicauta pluvialis Borchmann, Epicauta proscripta Werner, Epicauta rubella Denier, and Epicauta ventralis Werner-with the purpose of analyzing the distributional data for taxa, to establish patterns of distribution of an ancestral biota and areas where these groups have interacted. Based on the overlap of 20 individual tracks, four generalized tracks constituted by different numbers of species were identified; two of them are located in the Nearctic region and the Mexican transition zone (tracks "A" and "B"), and the other two are distributed in the Neotropical region and the South America transition zone ("C", "D"). Six nodes were recognized: Two of them are included in the Nearctic Region, node 'I' located in northern USA and node 'II' located in southwestern USA, both at the intersection of the tracks "A" and "B". The other four are included in the Neotropical Region at the intersection of the tracks "C" and "D": Node 'III' is located in Chaco province; node 'IV' is located in Parana Forest province; node 'V' is located in the northwest of Argentina in Puna province, and node 'VI' is located in Monte province. PMID:26174956
The picture showing the little Joseph Meister being treated against rabies under Louis Pasteur's eyes, on July 6, 1885, has quickly become a symbol of the triumphant progress of medicine, even though diseases with high mortality like tuberculosis or diphtheria could still not be healed with efficient therapeutic means. But before the discoveries of Pasteur, what was actually, in daily practice, the kind of response an ordinary doctor could give to human rabies? A Swiss physician, Charles-Hector Guisan, developed a therapy based on the use of sodium arsenate, which he published in the columns of the Gazette des Hôpitaux civils et militaires in 1854. This arsenic therapy was to be put into practice on a larger scale in the canton of Fribourg by Dr Jean-Louis Schaller (1816-1880), who meticulously wrote observations in a notebook on the cases of 13 persons wounded by a rabid dog in 1855. PMID:11810985
In order to obtain formulas providing estimates for elastic constants of random polycrystals of laminates, some known rigorous bounds of Peselnick, Meister, and Watt are first simplified. Then, some new self-consistent estimates are formulated based on the resulting analytical structure of these bounds. A numerical study is made, assuming first that the internal structure (i.e., the laminated grain structure) is not known, and then that it is known. The purpose of this aspect of the study is to attempt to quantify the differences in the predictions of properties of the same system being modeled when such internal structure of the composite medium and spatial correlation information is and is not available.
This report serves as a resource for policymakers who wish to learn more about levelized cost of energy (LCOE) calculations, including cost-based incentives. The report identifies key renewable energy cost modeling options, highlights the policy implications of choosing one approach over the other, and presents recommendations on the optimal characteristics of a model to calculate rates for cost-based incentives, FITs, or similar policies. These recommendations shaped the design of NREL's Cost of Renewable Energy Spreadsheet Tool (CREST), which is used by state policymakers, regulators, utilities, developers, and other stakeholders to assist with analyses of policy and renewable energy incentive payment structures. Authored by Jason S. Gifford and Robert C. Grace of Sustainable Energy Advantage LLC and Wilson H. Rickerson of Meister Consultants Group, Inc.
Fluid seepage of reduced organic compounds such as methane impacts the geology and biology of the seabed by inducing complex, microbially mediated biogeochemical processes. Authigenic carbonates serve as one of the few permanent records of these of dynamic biogeochemical interactions that involve methanogenesis, methanotrophy, sulfate reduction and carbonate precipitation. Meister et al. (2007) investigated deep-sea dolomite formation at Sites 1227-1229 on the Peru margin, where dolomite precipitation occurs in association with organic carbon-rich continental margin sediments. Geochemical and petrographic studies indicated episodic dolomite precipitation at a dynamic sulfate methane transition zone (SMTZ). Variations in δ13C values of these dolomites between +15‰ and -15‰ were attributed to non-steady state conditions as a result of the upward and downward migration of the SMTZ. Our study aims to better understand the biogeochemical processes associated with authigenic carbonate precipitation in this dynamic deep-sea setting. We focused our efforts on IODP Site 1230, which is a gas-hydrate-bearing site that shows sulphate consumption within the uppermost 10 m below the seafloor as well as high methane production. Using a multi proxy approach, we combined X-ray diffraction, stable isotope geochemistry, and trace metal analysis of authigenic carbonates to elucidate conditions for authigenic carbonate formation. Results from Site 1230 are compared to Sites 1227 and 1229, which lacks gas hydrates and is characterized by high pore water sulfate and low methane concentrations. This study contributes to a more comprehensive understanding of authigenic carbonate formation and associated biogeochemical processes in continental margin sediments. Meister, P., Mckenzie, J. A., Vasconcelos, C., Bernasconi, S., Frank, M., Gutjhar, M. and SCHRAG, D. P. (2007), Dolomite formation in the dynamic deep biosphere: results from the Peru Margin. Sedimentology, 54: 1007-1032.
Damages from noise and vibration are increasing every year, and most of which are noises between floors in deteriorated building caused by floor impact sound. In this study, the floor vibration of the deteriorated buildings constructed with the concrete slabs of thickness no more than 150 mm was evaluated by the vibration impact sound. This highly reliable study was conducted to assess floor vibration according with the serviceability evaluation standard of Reiher / Meister and Koch and vibration evaluation standard of ISO and AIJ. Designed pressure for the concrete slab sample of floor vibration assessment was 24MPa, and the sample was manufactured pursuant to KS F 2865 and JIS A 1440-2 with size of 3200 mm × 3200 mm × 140 mm. Tests were conducted twice with accelerometers, and Fast Fourier Transform was performed for comparative analysis by the vibration assessment criteria. The peak displacement from Test 1 was in the range of 0.00869 - 0.02540 mm; the value of peak frequency ranged from 18 to 27 Hz, and the average value was 22Hz. The peak acceleration value from Test 2 was in the range of 0.47 - 1.07 % g; the value of peak frequency was 18.5 - 22.57 Hz, and the average was 21Hz. The vibration was apparently recognizable in most cases according to the Reiher/Meister standard. In case of Koch graph for the damage assessment of the structure, the vibration was at the medium level and causes no damage to the building structure. The measured vibration results did not exceed the damage limit or serviceability limit of building according to the vibration assessment criteria of ISO and residential assessment guidelines provided by Architectural Institute of Japan (AIJ).
We show that when entropy variations are included and special relativity is imposed, the thermodynamics of a perfect fluid leads to two distinct families of equations of state whose relativistic compressible Euler equations are of Nishida type. (In the non-relativistic case there is only one.) The first corresponds exactly to the Stefan-Boltzmann radiation law, and the other, emerges most naturally in the ultra-relativistic limit of a γ-law gas, the limit in which the temperature is very high or the rest mass very small. We clarify how these two relativistic equations of state emerge physically, and provide a unified analysis of entropy variations to prove global existence in one space dimension for the two distinct 3 × 3 relativistic Nishida-type systems. In particular, as far as we know, this provides the first large data global existence result for a relativistic perfect fluid constrained by the Stefan-Boltzmann radiation law.
The distribution of the alleles and haplotypes for blood groups A1A2B0, MNSs, RHESUS, P1, KELL-CELLANO and biochemical markers of the alleles of loci AMY2, HPA, GC, C3, TF, BF, CP, PI (including subtypes) were studied in 125 Moldavian individuals from Karahasani settlement, Stefan-Voda District, Republic of Moldavia. The results show that the gene pool of Moldavians is similar to those of Southeastern European populations. PMID:16623088
The blackbody theory is revisited in the case of thermal electromagnetic fields inside uniaxial anisotropic media in thermal equilibrium with a heat bath. When these media are hyperbolic, we show that the spectral energy density of these fields radically differs from that predicted by Planck's blackbody theory and that the maximum of the spectral energy density determined by Wien's law is redshifted. Finally, we derive the Stefan-Boltzmann law for hyperbolic media which becomes a quadratic function of the heat bath temperature.
An infrared artificial thermochromic material composed of a metamaterial emitter and a bimaterial micro-electro-mechanical system is investigated. A differential emissivity of over 30% is achieved between 623 K and room temperature. The passive metamaterial device demonstrates the ability to independently control the peak wavelength and temperature dependence of the emissivity, and achieves thermal emission following a super Stefan-Boltzmann power curve. PMID:26619382
A numerical method for solving phase change problems involving a moving heat source is presented and illustrated by a two-dimensional example. The method uses a fixed grid and does not require the implementation of the Stefan condition at the solid-liquid interface; the procedure can thus be easily implemented using existing fixed grid codes. The problem considered as an example involves natural convection flow in the molten metal during tungsten inert gas welding.
Calculated triple differential cross sections are presented for the ionization of the 3a1 orbital of water by electron impact. The cross sections are determined for symmetric coplanar and non-coplanar geometrical arrangements. The obtained results show reasonable agreement with experimental data for both geometries. Contribution to the Topical Issue "Elementary Processes with Atoms and Molecules in Isolated and Aggregated States", edited by Friedrich Aumayr, Bratislav Marinkovic, Stefan Matejcik, John Tanis and Kurt H. Becker.
Using a scale analysis approach, we model phase change (melting) for pure materials which generate internal heat for small Stefan numbers (approximately one). The analysis considers conduction in the solid phase and natural convection, driven by internal heat generation, in the liquid regime. The model is applied for a constant surface temperature boundary condition where the melting temperature is greater than the surface temperature in a cylindrical geometry. We show the time scales in which conduction and convection heat transfer dominate.
This is a report on the joint work with François Gieres, Stefan Hohenegger, Olivier Piguet and Manfred Schweda. We consider a non-commutative U(1) gauge theory with an extension which was originally proposed by A. A. Slavnov [3, 4] in order to get rid of UV/IR mixing problems. Here we show, that the improved IR behaviour of this model is mainly due to the appearence of a linear vector supersymmetry.
The optimal control of solidification in metal casting is considered. The underlying mathematical model is based on a three-dimensional two-phase initial-boundary value problem of the Stefan type. The study is focused on choosing a cost functional in the optimal control of solidification and choosing a difference scheme for solving the direct problem. The results of the study are described and analyzed.
We identify optimal measurement strategies for phase estimation in different scenarios in which the interferometer acts on two-mode symmetric states. For pure states of a single qubit, we show that optimal measurements form a broad set parametrized with a continuous variable. When the state is mixed, this set reduces to merely two possible measurements. For two-qubit symmetric Werner state, we find the optimal measurement and show that estimation from the population imbalance is optimal only if the state is pure. We also determine the optimal measurements for a wide class of symmetric N-qubit Werner-like states. Finally, for a pure symmetric state of N qubits, we find under which conditions the estimation from the full N-body correlation and from the population imbalance is optimal.
By Nathalie Walker, Guest Writer Editor’s note: This article is the second in a series describing one student’s perspective on her experiences as a Werner H. Kirsten student intern. “The future depends on what you do today.” Those wise words were spoken by Mahatma Gandhi. Before I started my Werner H. Kirsten (WHK) student internship, I did not know what I know now. I only knew what each of Gandhi’s words meant individually. I now understand the full meaning of the phrase. To me, Gandhi’s words mean that nothing in life is handed to you. You have to work hard today to get the results you want tomorrow.
Mullerian malformations result from defective fusion of the Mullerian ducts during development of the female reproductive system and have an incidence of 2-3%. The American Fertility Society classification of Mullerian anomalies is the most commonly utilized standardized classification. The least common form of these malformations is Herlyn-Werner-Wunderlich syndrome characterized by obstructed hemivagina and ipsilateral renal anomaly (OHVIRA). This syndrome has been described with case reports since 1922. Early diagnosis and surgery that include drainage of fluid and resection of the vaginal septum is necessary for OHVIRA to prevent late complications (i.e. pyocolpos, chronic cryptomenorrhea). Here in we report a case of Herlyn-Werner-Wunderlich syndrome that hymen has been preserved during the operation of non-fenestrated transverse vaginal septum resection with hysteroscopy. PMID:26676254
Mullerian malformations result from defective fusion of the Mullerian ducts during development of the female reproductive system and have an incidence of 2-3%. The American Fertility Society classification of Mullerian anomalies is the most commonly utilized standardized classification. The least common form of these malformations is Herlyn-Werner-Wunderlich syndrome characterized by obstructed hemivagina and ipsilateral renal anomaly (OHVIRA). This syndrome has been described with case reports since 1922. Early diagnosis and surgery that include drainage of fluid and resection of the vaginal septum is necessary for OHVIRA to prevent late complications (i.e. pyocolpos, chronic cryptomenorrhea). Here in we report a case of Herlyn-Werner-Wunderlich syndrome that hymen has been preserved during the operation of non-fenestrated transverse vaginal septum resection with hysteroscopy. PMID:26676254
This report covers the activity of the traveler participating in a workshop entitled The 13th Werner Brandt Workshop on the Interaction of Charged Particles with Solids and conducting collaborative research with two physicists at Tokyo University. The Werner Brandt Workshops are organized by members of the traveler's group, led by Dr. R. H. Ritchie, with advice from an international committee. The traveler participated in planning for the next in the series of workshops, which will be held in or near the traveler's home base. Oak Ridge, Tennessee, in early 1992. He interacted with scientists from Japan, Spain, USSR, Israel, and other countries, initiated plans for a new collaboration with a Japanese scientist, and renewed existing collaborations, At Tokyo University, the traveler performed collaborative research with Professors Y. Yamazaki and K. Komaki on two topics of importance to the traveler's programs with the Department of Energy (DOE).
Modeling of ionic diffusion in warm dense plasma mixtures has been of longstanding interest in astrophysics and in Inertial Confinement Fusion. In this work we employ classical Molecular Dynamics (MD) to calculate diffusion coefficients in mixed plasmas. In the MD study we make use of the Yukawa potential as an effective ion-ion interaction potential that accounts for the screening effects of the electrons. We focus in binary asymmetric mixtures between Deuterium and Argon at Temperatures from 10-100eV and ion densities from 1023-1025 ion/cc. In uniform mixed systems we use Green-Kubo techniques to calculate self-diffusivities and Maxwell-Stefan diffusivities over a range of conditions. The new results from this study show that a simple linear relations between Maxwell-Stefan diffusivity and self-diffusivities is not always valid. The interdiffusivity that enters in Fickian equation can be related to the Maxwell-Stefan diffusivities through the thermodynamic factor. The latter requires knowledge of the equation of state of the mixture. We compare these results with classical kinetic theories that assume binary collisions. To test these Green-Kubo approaches and to estimate the activity contribution we have also employed large-scale non-equilibrium, non-uniform mixed, MD. This work was performed under the auspices of the US Dept. of Energy by Lawrence Livermore National Security, LLC under Contract DE-AC52-07NA27344.
The accuracy and complexity of solving multicomponent gaseous diffusion using the detailed multicomponent equations, the Stefan-Maxwell equations, and two commonly used approximate equations have been examined in a two part study. Part I examined the equations in a basic study with specified inputs in which the results are applicable for many applications. Part II addressed the application of the equations in the Langley Aerothermodynamic Upwind Relaxation Algorithm (LAURA) computational code for high-speed entries in Earth's atmosphere. The results showed that the presented iterative scheme for solving the Stefan-Maxwell equations is an accurate and effective method as compared with solutions of the detailed equations. In general, good accuracy with the approximate equations cannot be guaranteed for a species or all species in a multi-component mixture. 'Corrected' forms of the approximate equations that ensured the diffusion mass fluxes sum to zero, as required, were more accurate than the uncorrected forms. Good accuracy, as compared with the Stefan- Maxwell results, were obtained with the 'corrected' approximate equations in defining the heating rates for the three Earth entries considered in Part II.
I propose a novel mechanism for the brain cancer tissue treatment: nonlinear interaction of ultrashort pulses of beat-photon, (ω1 -- ω2) , or double-photon, (ω1 +ω2) , beams with the cancer tissue. The multiphoton scattering is described via photon diffusion equation. The open-scull cerebral tissue can be irradiated with the beat-modulated photon pulses with the laser irradiances in the range of a few mW/cm2 , and repetition rate of a few 100s Hz generated in the beat-wave driven free electron laser. V. Stefan, B. I. Cohen, and C. Joshi, Nonlinear Mixing of Electromagnetic Waves in PlasmasScience 27 January 1989: V. Alexander Stefan, Genomic Medical Physics: A New Physics in the Making, (S-U-Press, 2008).} This highly accurate cancer tissue ablation removal may prove to be an efficient method for the treatment of brain cancer. Work supported in part by Nikola Tesla Laboratories (Stefan University), La Jolla, CA.
Understanding mass transport in liquids by mutual diffusion is an important topic for many applications in chemical engineering. The reason for this is that diffusion is often the rate limiting step in chemical reactors and separators. In multicomponent liquid mixtures, transport diffusion can be described by both generalized Fick's law and the Maxwell-Stefan theory. The Maxwell-Stefan and Fick approaches in an n-component system are related by the so-called thermodynamic factor [R. Taylor and H.A. Kooijman, Chem. Eng. Commun, 102, 87 (1991)]. As Fick diffusivities can be measured in experiments and Maxwell-Stefan diffusivities can be obtained from molecular simulations/theory, the thermodynamic factors bridge the gap between experiments and molecular simulations/theory. It is therefore desirable to be able to compute thermodynamic factors from molecular simulations. Unfortunately, presently used simulation techniques for computing thermodynamic factors are inefficient and often require numerical differentiation of simulation results. In this work, we propose a modified version of the Widom test-particle method to compute thermodynamic factors from a single simulation. This method is found to be more efficient than the conventional Widom test particle insertion method combined with numerical differentiation of simulation results. The approach is tested for binary systems consisting of Lennard-Jones particles. The thermodynamic factors computed from the simulation and from numerically differentiating the activity coefficients obtained from the conventional Widom test particle insertion method are in excellent agreement.
Mathematical model of a contact bouncing takes into account elastic-plastic and electrodynamic forces, phase transformations during interaction of electrical arc with the contact surface as a result of increasing temperature. It is based on the integro-differential equations for the contact motion and Stefan problem for the temperature field. These equations describe four consecutive stages of the contact vibration from the impact at contact closing up to opening after bouncing including effects of penetration and restitution. The new method for the solution of the Stefan problem is elaborated, which enables us to get the information about dynamics of zones of elasticity, plasticity and phase transformations during contact vibration. It is shown that the decrement of damping depends on the coefficient of plasticity and the moment of inertia only, while the frequency of vibration depends also on the hardness of contact, its temperature, properties of contact spring, and geometry of rotational mechanism. It is found also from the solution of Stefan problem that the relationship between dynamical zones of plasticity and melting explains the decrease of current density and contact welding. The results of calculations are compared with the experimental data.
Recently, I have proposed a novel heuristic method for the deconfinement of quarks.footnotetextM. Gell-Mann. The Quark and the Jaguar: Adventures in the Simple and the Complex (New York, NY: W.H. Freeman and Co., 1994) [cf. M. Gell-Mann, The Garden of Live Flowers in: V. Stefan (Editor), Physics and Society. Essays Honoring Victor Frederick Weisskopf (Springer, 1998), pp. 109-121]. It proceeds in two phases.footnotetextV. Alexander Stefan, On a Heuristic Point of View About Inertial Deconfinement of Quarks, American Physical Society, 2009 APS April Meeting, May 2-5, 2009, abstract #E1.038. Firstly, a frozen hydrogen pellet is inertially confined by the ultra-intense lasers up to a solid state density. Secondly, a solid state nano-pellet is ``punched'' by the photon beam created in the beat wave driven free electron laser (BW-FEL), leading to the ``rapture'' (in a ``karate chop'' model) of the ``MIT Bag''footnotetextJ. I. Friedman and H. Kendall, Viki, in: V. Stefan (Editor), Physics and Society. (Springer, 1998), pp. 103-108]. before the asymptotically free quarks move apart. Hereby, I propose TeV, a few 100s attosecond, photon beams in interaction with the nano-pellet. The threshold ``rapture force'' of the TeV attosecond photon is 10^7 N. )
The Building 549 auditorium is often packed with high school interns eager to hear a scientific lecture. On April 22, however, the room swelled with interns spanning a wider age range. At the 25th Werner H. Kirsten Student Intern Program (WHK SIP) Anniversary Symposium, incoming, current, and former interns gathered to celebrate the program, which has provided biomedical research experience for local high school seniors.
The Heisenberg uncertainty principle shows that no one can specify the values of the non-commuting canonically conjugated variables simultaneously. However, the uncertainty relation is usually applied to two incompatible measurements. We present tighter bounds on both entropic uncertainty relation and information exclusion relation for multiple measurements in the presence of quantum memory. As applications, three incompatible measurements on Werner state and Horodecki’s bound entangled state are investigated in details.
The Max-Planck-Institut für Astrophysik, now located in the town of Garching north of Munich in Germany, is one of the more than 70 autonomous research institutes of the Max-Planck-Gesellschaft. It was founded in 1958 under the direction of Ludwig Biermann as part of the Max-Planck-Institut für Physik und Astrophysik, directed at that time by Werner Heisenberg. In 1979, when the headquarters of t...
In his book Niels Bohr's Times, the physicist Abraham Pais captures a paradox in his subject's legacy by quoting three conflicting assessments. Pais cites Max Born, of the first generation of quantum physics, and Werner Heisenberg, of the second, as saying that Bohr had a greater influence on physics and physicists than any other scientist. Yet Pais also reports a distinguished younger colleague asking with puzzlement and scepticism "What did Bohr really do?".
We give a tour of Munich and some outlying sites that focuses on the lives and work of the most prominent physicists who lived in the city, Count Rumford, Joseph Fraunhofer, Georg Simon Ohm, Max Planck, Ludwig Boltzmann, Albert Einstein, Wilhelm Conrad Röntgen, Wilhelm Wien, Arnold Sommerfeld, Max von Laue, and Werner Heisenberg. We close with a self-guided tour that describes how to reach these sites in Munich.
In 1956, three men were awarded the Nobel Prize in Physiology or Medicine, in particular 'for their discoveries concerning heart catheterisation and pathological changes in the circulatory system'. Their names in alphabetical order: André F. Cournand, Werner Forssmann and Dickinson W. Richards. Forssmann's experiment dated from 1929, while Cournand and Richards started their work in 1941. The order in which they presented their Nobel lectures on 11 December 1956 was Forssmann, Richards, Cournand. ImagesFigure 1Figure 2 PMID:25696475
A development of quantum theory that was initiated in the 1920s by Werner Heisenberg (1901-76) and Erwin Schrödinger (1887-1961). The theory drew on a proposal made in 1925 Prince Louis de Broglie (1892-1987), that particles have wavelike properties (the wave-particle duality) and that an electron, for example, could in some respects be regarded as a wave with a wavelength that depended on its mo...
Too often, students don't feel engaged in their research projects. The problem begins as early as the topic-creation stage, when students may choose from a list of teacher-selected topics that don't interest them or struggle to select a single fruitful topic on their own. Nanci Werner-Burke describes how two students in an English…
To mark the occasion of the 75th anniversary of Bruno Bloch's appointment to the Chair of Dermatology in Zurich, a commemorative lecture was established. The speaker paid tribute to his professional achievements and to the careers of some of his followers (Wilhelm Lutz, Basel; Marion B. Sulzberger, New York; Edwin Ramel, Lausanne; Hubert Jäger, Lausanne; Werner Jadassohn, Geneva; Guido Miescher, Zurich). PMID:8320121
The Heisenberg uncertainty principle shows that no one can specify the values of the non-commuting canonically conjugated variables simultaneously. However, the uncertainty relation is usually applied to two incompatible measurements. We present tighter bounds on both entropic uncertainty relation and information exclusion relation for multiple measurements in the presence of quantum memory. As applications, three incompatible measurements on Werner state and Horodecki's bound entangled state are investigated in details. PMID:26118488
At a key time in his scientific development, Pauli was undergoing analysis by Jung. What can we learn about Pauli's discoveries of the exclusion principle and the CPT theorem, as well as his thoughts on non-conservation of parity, and his quest with Heisenberg for a unified field theory of elementary particles from Jung?s analysis of his dreams? A very different Pauli emerges, one at odds with esteemed colleagues such as Niels Bohr and Werner Heisenberg.
WHAG-TV (Hagerstown, Md.) visited Fort Detrick to highlight the 2015 Spring Research Festival (SRF), sponsored by the National Interagency Confederation for Biological Research (NICBR). Visit the WHAG-TV website to see the video broadcast, which aired May 6. The video was produced by WHAG Reporter Mallory Sofastaii. The video featured Linganore High School senior Rebecca Matthews, a Werner H. Kirsten student intern in the Human Retrovirus Pathogenesis Section, Vaccine Branch, NCI Center for Cancer Research; Lanessa Hill, public affairs specialist,
The Heisenberg uncertainty principle shows that no one can specify the values of the non-commuting canonically conjugated variables simultaneously. However, the uncertainty relation is usually applied to two incompatible measurements. We present tighter bounds on both entropic uncertainty relation and information exclusion relation for multiple measurements in the presence of quantum memory. As applications, three incompatible measurements on Werner state and Horodecki’s bound entangled state are investigated in details. PMID:26118488
Quantum mechanics is interpreted, in the spirit of Niels Bohr and Werner Heisenberg, as about physical objects in so far as these are revealed by and within the local, social, and historical process of measurement. An analysis of the hermeneutical aspect of quantum mechanical measurement reveals close analogues with the hermeneutical social/historical sciences. The hermeneutical analysis of science requires the move from the epistemological attitude to an ontological one.
Using a new geometrical approach introduced by Gibbons and Werner we study the deflection angle by Reissner-Nordström black holes in the background spacetimes with a global monopole and a cosmic string. By calculating the corresponding optical Gaussian curvature and applying the Gauss-Bonnet theorem to the optical metric we find the leading terms of the deflection angle in the weak limit approximation. We find that the deflection angle increases due to the presence of topological defects.
At a key time in his scientific development, Pauli was undergoing analysis by Jung. What can we learn about Pauli's discoveries of the exclusion principle and the CPT theorem, as well as his thoughts on non-conservation of parity, and his quest with Heisenberg for a unified field theory of elementary particles from Jung’s analysis of his dreams? A very different Pauli emerges, one at odds with esteemed colleagues such as Niels Bohr and Werner Heisenberg.
We show that the gravitational modification of the phase of a neutron beam [the Colella-Overhauser-Werner (COW) experiment] has a classical origin, being due to the time delay that classical particles experience in traversing a background gravitational field. Similarly, we show that classical light waves also undergo a phase shift in traversing a gravitational field. We show that the COW experiment respects the equivalence principle even in the presence of quantum mechanics. {copyright} {ital 1998} {ital The American Physical Society}
By Nancy Parrish, Staff Writer The Werner H. Kirsten Student Internship Program (WHK SIP) has enrolled the largest class ever for the 2013–2014 academic year, with 66 students and 50 mentors. This enrollment reflects a 53 percent increase in students and a 56 percent increase in mentors, compared to 2012–2013 (43 students and 32 mentors), according to Julie Hartman, WHK SIP director.
By Ashley DeVine, Staff Writer Werner H. Kirstin (WHK) student intern Ben Freed was one of 40 finalists to compete in the Intel Science Talent Search (STS) in Washington, DC, in March. “It was seven intense days of interacting with amazing judges and incredibly smart and interesting students. We met President Obama, and then the MIT astronomy lab named minor planets after each of us,” Freed said of the competition.
By Nancy Parrish, Staff Writer The competitors in the cellular and molecular biology category of the Frederick County Science and Engineering Fair on March 22–23 didn’t stand a chance against the Werner H. Kirsten student interns at the National Cancer Institute at Frederick. These interns swept the entire category, with Madelyne Xiao, a rising intern, winning first place; Maria Hamscher, second place; Ashley Babyak and Dahlia Kronfli tying for third place; and Maham Ahmed receiving an honorable mention.
Werner Heisenberg is an important historical subject within the physics community partly because his actions as a human being are discussed nearly as often as his work as a physicist. But does the scientific community establish it's historical ideas with the same methods and standards as it's scientific conclusions? I interviewed Heisenberg's son, Jochen Heisenberg, a professor of physics at UNH. Despite a great amount of literature on Werner Heisenberg, only one historian has interviewed Jochen about his father and few have interviewed Werner's wife. Nature is mysterious and unpredictable, but it doesn't lie or distort like humans, and we believe it can give ``honest'' results. But are we keeping the same standards with history that we do with science? Are we holding historians to these standards and if not, is it up to scientists to not only be keepers of scientific understanding, but historical understanding as well? Shouldn't we record history by using the scientific method, by weighing the best sources of data differently than the less reliable, and are we right to be as stubborn about changing our views on history as we are about changing our views on nature?
The aim of this research is to explore the influence of sensor characteristics and interactions with vegetation and terrain properties on the estimation of vegetation parameters from LiDAR waveforms. This is carried out using waveform simulations produced by the FLIGHT radiative transfer model which is based on Monte Carlo simulation of photon transport (North, 1996; North et al., 2010). The opportunities for vegetation analysis that are offered by LiDAR modelling are also demonstrated by other authors e.g. Sun and Ranson, 2000; Ni-Meister et al., 2001. Simulations from the FLIGHT model were driven using reflectance and transmittance properties collected from the Howland Research Forest, Maine, USA in 2003 together with a tree list for a 200m x 150m area. This was generated using field measurements of location, species and diameter at breast height. Tree height and crown dimensions of individual trees were calculated using relationships established with a competition index determined for this site. Waveforms obtained by the Laser Vegetation Imaging Sensor (LVIS) were used as validation of simulations. This provided a base from which factors such as slope, laser incidence angle and pulse width could be varied. This has enabled the effect of instrument design and laser interactions with different surface characteristics to be tested. As such, waveform simulation is relevant for the development of future satellite LiDAR sensors, such as NASA’s forthcoming DESDynI mission (NASA, 2010), which aim to improve capabilities of vegetation parameter estimation. ACKNOWLEDGMENTS We would like to thank scientists at the Biospheric Sciences Branch of NASA Goddard Space Flight Center, in particular to Jon Ranson and Bryan Blair. This work forms part of research funded by the NASA DESDynI project and the UK Natural Environment Research Council (NE/F021437/1). REFERENCES NASA, 2010, DESDynI: Deformation, Ecosystem Structure and Dynamics of Ice. http
The present work was developed in the frame of a collaboration between CNR/Istituto Ricerche Combustione, University of Parma and ENEA. It was aimed at exploiting and recovering the thermal energy from liquid effluents and solid wastes derived from typical Italian manufacturing of agro-industrial companies. This paper focuses on an organic sludge that is obtained as a residue during steam concentration of waste water from alcohol production in distilleries. This sludge has a very low calorific value and cannot be directly used in a combustion process. The first objective was to turn the sludge into a coal/waste/water mixture, easy to prepare and to burn on site in a bubbling fluidized combustor. To do so, some preliminary runs were carried out on a significant experimental scale by employing the 2100 kW{sub t} FBC-370 pre-pilot facility and by feeding underbed a South African coal/dry residue/water mixture with a maximum particle size of 1 mm. Very satisfactory values of co-combustion efficiency (i.e., larger than 98%), were attained as a function of the dispersing air velocity. It was proven that the mechanism of combustion passes through the formation of carbon-sand aggregates and tiny carbon deposits on bed sand particles. Another outcome was that pumping the mixture directly into the bed without any atomization is feasible and favorable from the point of view of co-combustion efficiency. Therefore, a second objective was to investigate aggregate formation as a result of mixture injection into the hot bed. This has been pursued through a review of the fundamental aspects underlying the behavior of a liquid issuing from an orifice. Two simple approaches, one based on Scheele and Meister`s (1968) results and the other one based on a balance of force moments, were followed. These two approaches provided two different equations to predict the diameter of a drop that detaches from the injection nozzle. Furthermore, aggregate formation was investigated through the set
The effect of soil property uncertainties on permafrost thaw projections are studied using a three-phase subsurface thermal hydrology model and calibration-constrained uncertainty analysis. The Null-Space Monte Carlo method is used to identify soil hydrothermal parameter combinations that are consistent with borehole temperature measurements at the study site, the Barrow Environmental Observatory. Each parameter combination is then used in a forward projection of permafrost conditions for the 21st century (from calendar year 2006 to 2100) using atmospheric forcings from the Community Earth System Model (CESM) in the Representative Concentration Pathway (RCP) 8.5 greenhouse gas concentration trajectory. A 100-year projection allows for the evaluation of intra-annual uncertainty due to soil properties and the inter-annual variability due to year to year differences in CESM climate forcings. After calibrating to borehole temperature data at this well-characterized site, soil property uncertainties are still significant and result in significant intra-annual uncertainties in projected active layer thickness and annual thaw depth-duration even with a specified future climate. Intra-annual uncertainties in projected soil moisture content and Stefan number are small. A volume and time integrated Stefan number decreases significantly in the future climate, indicating that latent heat of phase change becomes more important than heat conduction in future climates. Out of 10 soil parameters, ALT, annual thaw depth-duration, and Stefan number are highly dependent on mineral soil porosity, while annual mean liquid saturation of the active layer is highly dependent on the mineral soil residual saturation and moderately dependent on peat residual saturation. By comparing the ensemble statistics to the spread of projected permafrost metrics using different climate models, we show that the effect of calibration-constrained uncertainty in soil properties, although significant, is
The effect of soil property uncertainties on permafrost thaw projections are studied using a three-phase subsurface thermal hydrology model and calibration-constrained uncertainty analysis. The Null-Space Monte Carlo method is used to identify soil hydrothermal parameter combinations that are consistent with borehole temperature measurements at the study site, the Barrow Environmental Observatory. Each parameter combination is then used in a forward projection of permafrost conditions for the 21$^{st}$ century (from calendar year 2006 to 2100) using atmospheric forcings from the Community Earth System Model (CESM) in the Representative Concentration Pathway (RCP) 8.5 greenhouse gas concentration trajectory. A 100-year projection allows for the evaluation of intra-annual uncertainty due to soil properties and the inter-annual variability due to year to year differences in CESM climate forcings. After calibrating to borehole temperature data at this well-characterized site, soil property uncertainties are still significant and result in significant intra-annual uncertainties in projected active layer thickness and annual thaw depth-duration even with a specified future climate. Intra-annual uncertainties in projected soil moisture content and Stefan number are small. A volume and time integrated Stefan number decreases significantly in the future climate, indicating that latent heat of phase change becomes more important than heat conduction in future climates. Out of 10 soil parameters, ALT, annual thaw depth-duration, and Stefan number are highly dependent on mineral soil porosity, while annual mean liquid saturation of the active layer is highly dependent on the mineral soil residual saturation and moderately dependent on peat residual saturation. By comparing the ensemble statistics to the spread of projected permafrost metrics using different climate models, we show that the effect of calibration-constrained uncertainty in soil properties, although significant
The effect of soil property uncertainties on permafrost thaw projections are studied using a three-phase subsurface thermal hydrology model and calibration-constrained uncertainty analysis. The Null-Space Monte Carlo method is used to identify soil hydrothermal parameter combinations that are consistent with borehole temperature measurements at the study site, the Barrow Environmental Observatory. Each parameter combination is then used in a forward projection of permafrost conditions for the 21st century (from calendar year 2006 to 2100) using atmospheric forcings from the Community Earth System Model (CESM) in the Representative Concentration Pathway (RCP) 8.5 greenhouse gas concentration trajectory. A 100-year projection allows for the evaluation of intra-annual uncertainty due to soil properties and the inter-annual variability due to year to year differences in CESM climate forcings. After calibrating to borehole temperature data at this well-characterized site, soil property uncertainties are still significant and result in significant intra-annual uncertainties in projected active layer thickness and annual thaw depth-duration even with a specified future climate. Intra-annual uncertainties in projected soil moisture content and Stefan number are small. A volume and time integrated Stefan number decreases significantly in the future climate, indicating that latent heat of phase change becomes more important than heat conduction in future climates. Out of 10 soil parameters, ALT, annual thaw depth-duration, and Stefan number are highly dependent on mineral soil porosity, while annual mean liquid saturation of the active layer is highly dependent on the mineral soil residual saturation and moderately dependent on peat residual saturation. By comparing the ensemble statistics to the spread of projected permafrost metrics using different climate models, we show that the effect of calibration-constrained uncertainty in soil properties, although significant, is
Here, the effect of soil property uncertainties on permafrost thaw projections are studied using a three-phase subsurface thermal hydrology model and calibration-constrained uncertainty analysis. The Null-Space Monte Carlo method is used to identify soil hydrothermal parameter combinations that are consistent with borehole temperature measurements at the study site, the Barrow Environmental Observatory. Each parameter combination is then used in a forward projection of permafrost conditions for the 21more » $$^{st}$$ century (from calendar year 2006 to 2100) using atmospheric forcings from the Community Earth System Model (CESM) in the Representative Concentration Pathway (RCP) 8.5 greenhouse gas concentration trajectory. A 100-year projection allows for the evaluation of intra-annual uncertainty due to soil properties and the inter-annual variability due to year to year differences in CESM climate forcings. After calibrating to borehole temperature data at this well-characterized site, soil property uncertainties are still significant and result in significant intra-annual uncertainties in projected active layer thickness and annual thaw depth-duration even with a specified future climate. Intra-annual uncertainties in projected soil moisture content and Stefan number are small. A volume and time integrated Stefan number decreases significantly in the future climate, indicating that latent heat of phase change becomes more important than heat conduction in future climates. Out of 10 soil parameters, ALT, annual thaw depth-duration, and Stefan number are highly dependent on mineral soil porosity, while annual mean liquid saturation of the active layer is highly dependent on the mineral soil residual saturation and moderately dependent on peat residual saturation. By comparing the ensemble statistics to the spread of projected permafrost metrics using different climate models, we show that the effect of calibration-constrained uncertainty in soil properties
The effect of soil property uncertainties on permafrost thaw projections are studied using a three-phase subsurface thermal hydrology model and calibration-constrained uncertainty analysis. The Null-Space Monte Carlo method is used to identify soil hydrothermal parameter combinations that are consistent with borehole temperature measurements at the study site, the Barrow Environmental Observatory. Each parameter combination is then used in a forward projection of permafrost conditions for the 21st century (from calendar year 2006 to 2100) using atmospheric forcings from the Community Earth System Model (CESM) in the Representative Concentration Pathway (RCP) 8.5 greenhouse gas concentration trajectory. A 100-year projection allows formore » the evaluation of intra-annual uncertainty due to soil properties and the inter-annual variability due to year to year differences in CESM climate forcings. After calibrating to borehole temperature data at this well-characterized site, soil property uncertainties are still significant and result in significant intra-annual uncertainties in projected active layer thickness and annual thaw depth-duration even with a specified future climate. Intra-annual uncertainties in projected soil moisture content and Stefan number are small. A volume and time integrated Stefan number decreases significantly in the future climate, indicating that latent heat of phase change becomes more important than heat conduction in future climates. Out of 10 soil parameters, ALT, annual thaw depth-duration, and Stefan number are highly dependent on mineral soil porosity, while annual mean liquid saturation of the active layer is highly dependent on the mineral soil residual saturation and moderately dependent on peat residual saturation. By comparing the ensemble statistics to the spread of projected permafrost metrics using different climate models, we show that the effect of calibration-constrained uncertainty in soil properties, although
The problem of controlling the phase boundary evolution in the course of solidification of metals with different thermodynamic properties is studied. The underlying mathematical model of the process is based on a three-dimensional nonstationary two-phase initial-boundary value problem of the Stefan type. The control functions are determined by optimal control problems, which are solved numerically with the help of gradient optimization methods. The gradient of the cost function is exactly computed by applying the fast automatic differentiation technique. The research results are described and analyzed. Some of them are illustrated.
The radiative heating or cooling of a body placed in an environment, whose temperature is considered constant is described by Stefan's law. In this paper, an analysis is made of how a time-dependent environmental temperature influences the heating/cooling process. We compare experimental results for a resistor first heated by the Joule effect inside a glass vacuum tube and then cooled under two different conditions: in a bath at a constant temperature and in air. We also discuss a model that describes how the time-dependent tube temperature influences the radiative resistor cooling by identifying the properties of the environment that make the resistor cooling rate linear.
We study properties of the baryon number distribution in QGP phase. We first point out that a Gaussian type of the canonical partition function with regard to the baryon number means the Roberge-Weiss phase transition. The canonical partition function of QCD at high temperatures is studied both analytically and numerically. We find that the canonical partition function obtained in lattice QCD simulation agrees with that obtained for Stefan-Boltzmann limit for T higher than Tc, and is the Gaussian function of the baryon number.
Detailed models of UO2+x at very high temperatures incorporating the effects of non-congruent melting have been developed to support the design and analysis of experimental work related to nuclear safety. Models based on both the Stefan formulation and phase field approach are implemented using recently published material properties. Simulations compare well with laser flash experiments performed on UO2+x. This work has application in modelling centreline melting of defective fuel which may occur due to the reduced thermal conductivity and lower incipient melting temperature associated with fuel oxidation.
Transport phenomena in an ion-exchange membrane containing both H+ and K+ are described using multicomponent diffusion equations (Stefan-Maxwell). A model is developed for transport through a Nafion 112 membrane in a hydrogen-pump setup. The model results are analyzed to quantify the impact of cation contamination on cell potential. It is shown that limiting current densities can result due to a decrease in proton concentration caused by the build-up of contaminant ions. An average cation concentration of 30 to 40 percent is required for appreciable effects to be noticed under typical steady-state operating conditions.
In this Letter we propose the use of whispering gallery mode resonance tracking as a label-free optical means to monitor diffusion kinetics in glassy polymer microspheres. Approximate solutions to the governing diffusion equations are derived for the case of slow relaxation and small Stefan number. Transduction of physical changes in the polymer, including formation of a rubbery layer, swelling, and dissolution, into detectable resonance shifts are described using a perturbative approach. Concrete examples of poly(methyl methacrylate) and polystyrene spheres in water are considered. PMID:25839311
The tackiness of various tablet coating solutions was determined using a parallel plate technique with a tensile testing machine in conjunction with an oscilloscope where the separation force was displayed as a function of time. Measurements were made at various rates of separation on liquid films of constant thickness. Results showed that the force required to split a liquid film increases with an increase in rate of separation, and that tackiness increases with an increase in viscosity. The relation between tack and viscosity was not linear, and a modified Stefan equation was proposed. PMID:7120095
The blackbody theory is revisited in the case of thermal electromagnetic fields inside uniaxial anisotropic media in thermal equilibrium with a heat bath. When these media are hyperbolic, we show that the spectral energy density of these fields radically differs from that predicted by Planck's blackbody theory and that the maximum of the spectral energy density determined by Wien's law is redshifted. Finally, we derive the Stefan-Boltzmann law for hyperbolic media which becomes a quadratic function of the heat bath temperature. PMID:26551116
In this article we propose an activity aimed at introductory students to help them understand the Stefan-Boltzmann and Wien's displacement laws. It only requires simple materials that are available at any school: an incandescent lamp, a variable dc energy supply, and a computer to run an interactive simulation of the blackbody spectrum. Essentially, the activity consists of calculating the filament's temperature for different values of electric power and comparing the color and brightness of the lamp's light, as seen by the eye, with the correspondent (simulated) black-body spectrum. Although the comparison is only qualitative, we find that the activity provides a tangible introduction to blackbody radiation.
A novel method for the possible prevention of epileptic seizures is proposed, based on the multi-ultraviolet-photon beam interaction with the epilepsy topion, (nonlinear coupling of an ultra high frequency mode to the brain beta phonons). It is hypothesized that epilepsy is a chaotic-dynamics phenomenon: small electrical changes in the epilepsy-topion lead, (within the 10s of milliseconds), to the onset of chaos, (seizure--excessive electrical discharge), and subsequent cascading into adjacent areas. The ultraviolet photons may control the imbalance of sodium and potassium ions and, consequently, may prove to be efficient in the prevention of epileptic seizures. Supported by Nikola Tesla Labs, Stefan University.
In recent years the Jožef Stefan Institute participated in numerous intercomparison exercises for determination of natural and man-made radionuclides. The reported values were mostly in good agreement with the resulting reference values. This paper describes an analysis of the measurement results obtained in intercomparison exercises for determination of actinides in the period from 2009 to 2011, organised by the National Physical Laboratory and the Bundesamt für Strahlenschutz. The review covers neptunium, plutonium and americium radioisotopes over this period. PMID:23566808
Using a scale/analytical analysis approach, we model phase change (melting) for pure materials which generate constant internal heat generation for small Stefan numbers (approximately one). The analysis considers conduction in the solid phase and natural convection, driven by internal heat generation, in the liquid regime. The model is applied for a constant surface temperature boundary condition where the melting temperature is greater than the surface temperature in a cylindrical geometry. The analysis also consider constant heat flux (in a cylindrical geometry).We show the time scales in which conduction and convection heat transfer dominate.
The buoyancy effect of a growing isolated dendrite on the solidification process in the undercooling liquid material was investigated by developing an analytic solution to the growth/convection problem in powers of a buoyancy parameter G. The solution depends on the Prandtl number P and the Stefan number S (undercooling) for the local velocity and thermal fields and also the buoyant alteration of the interface shape. Results suggest that buoyancy effect for metals (low P) may be qualitatively different from that for organics (high P).
A novel method for the treatment of Parkinson's disease is proposed. Pluripotent stem cells are laser cultured, using ultrashort wavelength, (around 0.1 micron-ultraviolet radiation-with intensities of a few mW/cm2) , multiple laser beams.[2] The multiple-energy laser photons[3] interact with the neuron DNA molecules to be cloned. The laser created dopaminergic substantia nigra neurons can be, (theoretically), laser transplanted, (a higher focusing precision as compared to a syringe method), into the striatum or substantia nigra regions of the brain, or both. Supported by Nikola Tesla Labs, Stefan University.
A novel method for the treatment of the neurological diseases is proposed. The multiple-energy laser photons (the blue scanning photons and ultraviolet focusing photons) interact with the specific DNA molecules within the topion (such as Parkinson's and Alzheimer's brain topion) via the matching of laser frequency with the oscillation eigen-frequency of a particular molecule within the DNA. In this way, the corrupt molecules (the structure of molecules) can be manipulated so as to treat (eliminate) the neurological disease. Supported by Nikola Tesla Labs, Stefan University.
The proton beam generation and focusing in fast ignition inertial confinement fusion is studied. The spatial and energy spread of the proton beam generated in a laser-solid interaction is increased due to the synergy of Weibel and Rayleigh-Taylor instabilities. The focal spot radius can reach 100 μm, which is nearly an order of magnitude larger than the optimal value. The energy spread decreases the beam deposition energy in the focal spot. Under these conditions, ignition of a precompressed DT fuel is achieved with the beam powers much higher than the values presently in consideration. Work supported in part by NIKOLA TESLA Laboratories (Stefan University), La Jolla, CA.
The fast ignition fusion pellet gain can be enhanced by a laser generated B-field shell. The B-field shell, (similar to Earth's B-field, but with the alternating B-poles), follows the pellet compression in a frozen-in B-field regime. A properly designed laser-pellet coupling can lead to the generation of a B-field shell, (up to 100 MG), which inhibits electron thermal transport and confines the alpha-particles. In principle, a pellet gain of few-100s can be achieved in this manner. Supported in part by Nikola Tesla Labs, Stefan University, 1010 Pearl, La Jolla, CA 92038-1007.
In cryosurgery operations, tumoural cells are killed by means of a freezing procedure realised with the insertion of cryoprobes in the diseased tissue. Cryosurgery planning aims at establishing the best values for operation parameters like number and position of the probes or temperature and duration of the freezing process. Here, we present an application of ant colony optimisation (ACO) to cryosurgery planning, whereby the ACO cost function is computed by numerically solving several direct Stefan problems in biological tissues. The method is validated in the case of a 2D phantom of a prostate cross section. PMID:22224977
In this Letter we propose the use of whispering gallery mode resonance tracking as a label-free optical means to monitor diffusion kinetics in glassy polymer microspheres. Approximate solutions to the governing diffusion equations are derived for the case of slow relaxation and small Stefan number. Transduction of physical changes in the polymer, including formation of a rubbery layer, swelling, and dissolution, into detectable resonance shifts are described using a perturbative approach. Concrete examples of poly(methyl methacrylate) and polystyrene spheres in water are considered.
The fragmentation of a gas-phase tryptophan molecule by a low-energy (<70 eV) electron impact was studied both experimentally and theoretically. Various positively charged fragments were observed and analyzed. A special attention was paid to the energy characteristics of the ionic fragment yield. The geometrical parameters of the initial molecule rearrangement were also analyzed. The fragmentation observed was due to either a simple bond cleavage or more complex reactions involving molecular rearrangements. Contribution to the Topical Issue "Elementary Processes with Atoms and Molecules in Isolated and Aggregated States", edited by Friedrich Aumayr, Bratislav Marinkovic, Stefan Matejcik, John Tanis and Kurt H. Becker.
The elemental composition of iron gall inks in historical documents can be effectively studied using the non-destructive proton induced X-ray emission (PIXE) method. The in-air proton beam experimental set-up installed at the Microanalytical Centre of the Jožef Stefan Institute was used for this purpose. The aim of the present investigation was to model and evaluate the uncertainties in the analysis due to the incompletely known matrix composition and iron gall ink layer thickness. Estimation of these uncertainties helped in quantifying the accuracy of multi-elemental PIXE analysis of historical documents.
Irradiation of materials with energetic particles produces changes in the microstructure that affect mechanical properties. In previous work we studied the thermal aspects of the quenching of collision cascades that involve nanoscale phase transitions between the solid and the liquid states of the target. In this work we present a rigorous treatment of these phenomena, including a detailed description of the Stefan problem in three dimensions and diffusion in thermal gradients. This approach is oriented to give a quantitative description of the influence of the primary knock-on spectrum on the microstructure short after the quenching of the heat spike. 1997 Elsevier Science B.V.
This is one of the few books on the subject of mathematical materials science. It discusses the dynamics of two-phase systems within the framework of modern continuum thermodynamics, stressing fundamentals. Two general theories are discussed: a mechanical theory that leads to a generalization of the classical curve-shortening equation and a theory of heat conduction that broadly generalizes the classical Stefan theory. This original survey includes simple solutions that demonstrate the instabilities inherent in two-phase problems. The free-boundary problems that form the basis of the subject should be of great interest to mathematicians and physical scientists.
The article depicts major concepts present in the contemporary historiography of medicine (positivistic and social-cultural trends) and some of the concepts of modern methodology of the history of science, reviewing the possibilities of its use in the analysis of the process of modernizing the European medicine that was implemented between the 16th and the 19th century. The author advocates the social-cultural trend that dominates the contemporary historiography of medicine. She discusses and analyzes the concepts developed by Ludwik Fleck, Samuel Kuhn, Imre Lakatos, Kurt Godl, Stefan Amsterdamski in respect of their sue to a historian of modern medicine. PMID:11625427
A Slovenian laboratory from the Jožef Stefan Institute (JSI) and a Romanian laboratory from the National Research and Development Institute for Cryogenics and Isotopic Technologies (ICIT) performed bilateral intercomparisons of tritium determination in environmental samples. On the basis of the results, the measurement and analysis methods were compared. Comparability and traceability were confirmed with the results from international radioactivity proficiency test exercises organized by IAEA and NPL where both laboratories participated. New knowledge gained leads to harmonized, precise and traceable results of low level tritium environmental samples measurements. PMID:24332881
Seeing is believing. So goes the old adage and seen evidence is undoubtedly satisfying because it can be interpreted easily, though not always correctly. For centuries, humans have developed such instruments as telescopes that observe the heavens and microscopes that reveal bacteria and viruses. The 2014 Nobel Prize in Chemistry was awarded to Eric Betzig, Stefan Hell, and William Moerner for their foundational work on superresolution fluorescence microscopy in which they overcame the Abbe diffraction limit for the resolving power of conventional light microscopes. (See Physics Today, December 2014, page 18.) That breakthrough enabled discoveries in biological research and testifies to the importance of modern microscopy.
Seeing is believing. So goes the old adage and seen evidence is undoubtedly satisfying because it can be interpreted easily, though not always correctly. For centuries, humans have developed such instruments as telescopes that observe the heavens and microscopes that reveal bacteria and viruses. The 2014 Nobel Prize in Chemistry was awarded to Eric Betzig, Stefan Hell, and William Moerner for their foundational work on superresolution fluorescence microscopy in which they overcame the Abbe diffraction limit for the resolving power of conventional light microscopes. (See Physics Today, December 2014, page 18.) That breakthrough enabled discoveries in biological research and testifiesmore » to the importance of modern microscopy.« less
An asymptotic limit of a class of Cahn-Hilliard systems is investigated to obtain a general nonlinear diffusion equation. The target diffusion equation may reproduce a number of well-known model equations: Stefan problem, porous media equation, Hele-Shaw profile, nonlinear diffusion of singular logarithmic type, nonlinear diffusion of Penrose-Fife type, fast diffusion equation and so on. Namely, by setting the suitable potential of the Cahn-Hilliard systems, all these problems can be obtained as limits of the Cahn-Hilliard related problems. Convergence results and error estimates are proved.
This paper describes the water vapor desorption characteristics of honeycomb shape type sorbent element containing new organic sorbent of the bridged complex of sodium polyacrylate. The transient experiments in which the dry air was passed into the honeycomb type sorbent element sorbed water vapor were carried out under various conditions of air velocity, temperature, relative humidity and honeycomb length. The obtained data for desorption process were compared with those for sorption process. Finally, Sherwood number of mass transfer of the organic sorbent for desorption process was derived in terms of Reynolds number, modified Stefan number and non-dimensional honeycomb length.
V505 Ser (GSC 02038-00293) is a short-period eclipsing RS CVn system which was discovered by Bernhard and Frank (2006). It has been the subject of several recent studies which have established physical parameters and distribution of spots (cf. eg. Korhonen et al., 2010; Dal et al., 2012). The present paper gives an overview over recent results from the literature and presents new photometry of V505 Ser which gives further evidence to the existence of a 6-year spot cycle. Klaus Bernhard, Peter Frank and Stefan Huemmerich are member of the BAV.
The purpose of this study is to investigate the effectiveness of structural control using tuned mass damper (TMD) for suppressing excessive traffic induced vibration of high performance steel bridge. The study considered 1-span steel plate girder bridge and bridge-vehicle interaction using HS-24 truck model. A numerical model of steel plate girder, traffic load, and TMD is constructed and time history analysis is performed using commercial structural analysis program ABAQUS 6.10. Results from analyses show that high performance steel bridge has dynamic serviceability problem, compared to relatively low performance steel bridge. Therefore, the structural control using TMD is implemented in order to alleviate dynamic serviceability problems. TMD is applied to the bridge with high performance steel and then vertical vibration due to dynamic behavior is assessed again. In consequent, by using TMD, it is confirmed that the residual amplitude is appreciably reduced by 85% in steady-state vibration. Moreover, vibration serviceability assessment using 'Reiher-Meister Curve' is also remarkably improved. As a result, this paper provides the guideline for economical design of I-girder using high performance steel and evaluates the effectiveness of structural control using TMD, simultaneously.
This article describes a new diatom genus Moreneis from the Yellow Sea sand flats on the west coast of Korea. The new genus is characterized by a unique combination of morphological characteristics, including the shape of the plastids, which have not been previously observed in diatoms. The valve morphology resembles other genera belonging to Lyrellaceae, within which we place this genus. In terms of areolae structure, Moreneis resembles Petroneis and Placoneis; however, it differs from both genera with respect to the raphe system and plastid shape. Cells of Moreneis spp. have a single large plastid appressed to the girdle of the secondary side of the valve, with two lobes extended toward the primary side of the valve. Furthermore, the unique feature of Moreneis frustules is the raphe, which has both external central and apical endings bent in opposite directions. We differentiated four taxa, which we describe as new for science. However, based on our findings, several established species from Navicula should also be formally transferred to Moreneis, including N. alpha Cleve, N. besarensis Giffen, N. epsilon Cleve, N. menaiana Hendey, N. polae Heiden, and N. quadri-undulata F. Meister. Analysis of published data revealed that species belonging to Moreneis are numerous in tropical marine littoral waters, and in moderate climate zones, especially in the western Pacific, with only a few species occurring in the Mediterranean and Atlantic. PMID:27009663
The critical finding of our work showed that the major role of gamma-glutamyl transferase is to hydrolyze GSH and related gamma-glutamyl peptides to form free amino acids and cysteine-S-conjugates on the apical membranes of cells of various tissues and basolateral membranes of the kidney and that the resulting metabolites are transported into cells to synthesize GSH and mercapturic acids. We also showed that GSH and its S-conjugates of xenobiotics are actively secreted from cells into the circulation and/or lumenal space of the liver. The excretory transport and extracellular hydrolysis of GSH and its S-conjugates of various metabolites by gamma-glutamyl transferase and related peptidases followed by absorption of the hydrolyzed amino acids to synthesize GSH forms intra-organ and inter-organ cycles for GSH metabolism in the liver, kidney, pancreas, small intestine and other tissues that have gamma-glutamyl transferase. The series of our experiments with Helmut showed that gamma-glutamyl cycle proposed by Alton Meister does not function as the putative amino acid transporter but plays critical role in the regulation of redox metabolism of toxic free radicals and xenobiotics. PMID:27095217
A well-known result due to Hill provides an exact expression for the bulk modulus of any multicomponent elastic composite whenever the constituents are isotropic and the shear modulus is uniform throughout. Although no precise analog of Hill's result is available for the opposite case of uniform bulk modulus and varying shear modulus, it is shown here that some similar statements can be made for shear behavior of random polycrystals composed of laminates of isotropic materials. In particular, the Hashin-Shtrikman-type bounds of Peselnick, Meister, and Watt for random polycrystals composed of hexagonal (transversely isotropic) grains are applied to the problem of polycrystals of laminates. An exact product formula relating the Reuss estimate of bulk modulus and an effective shear modulus (of laminated grains composing the system) to products of the eigenvalues for quasi-compressional and quasi-uniaxial shear eigenvectors also plays an important role in the analysis of the overall shear behavior of the random polycrystal. When the bulk modulus is uniform in such a system, the equations are shown to reduce to a simple form that depends prominently on the uniaxial shear eigenvalue - as expected from physical arguments concerning the importance of uniaxial shear in these systems. One application of the analytical results presented here is for benchmarking numerical procedures used for estimating elastic behavior of complex composites.
In this study we used a coupled hydrophysical-biogeochemical O-N-S-P-Mn-Fe- model based on ROLM (Yakushev et al., 2007) and GOTM (Burchard et al., 2006). Processes of organic matter (OM) formation and decay, the reduction and oxidation of species of nitrogen, sulphur, manganese, iron, as well as transformation of phosphorus species are parameterized. The model considered phytoplankton, zooplankton and bacteria. The model allowed to simulate the main features of the vertically balanced biogeochemical structure of the redox interfaces (i.e observed in the Black Sea, Gotland Deep, Oslo Fjord). Numerical experiments allowed to demonstrate how the changes in vertical mixing (from Kz=10-6 m2s-1 to Kz=10-4 m2s-1) affect the distributions of the considered parameters and the rates of their transformation. The received estimates allowed to analyze the influence of the water column redox interfaces on the fluxes of nutrients, in particular phosphate, in different conditions. Burchard, H., Bolding, K., Kuehn, W., Meister, A., Neumann, T., Umlauf, L. 2006. Description of a flexible and extendable physical-biogeochemical model system for the water column. J.of Mar.Sys., 61: 180-211. Yakushev E.V., Pollehne F., Jost G. et al. 2007. Analysis of the water column oxic/anoxic interface in the Black and Baltic seas with a Redox-Layer Model. Mar. Chem., 107: 388-410.
Extremely sandy soils and poorly distributed high annual rainfall in the state of Florida contribute to significant leaching losses of nutrients from routine fertilization practices. A leaching column experiment was conducted to evaluate the leaching losses of nutrients when using currently available N, P, K blend fertilizers for young citrus tree fertilization. Fertilizer blends included NH4NO3, Ca(NO3)2, IBDU, IBDU plus Escote, Nutralene, Osmocote, and Meister. Following leaching of 1000 ml of water through soil columns, which simulates leaching conditions with 26 cm of rainfall, the amount of NO3 and NH4 recovered in the leachate from soil columns amended with an NH4NO3 blend accounted for 37% and 88% of the respective nutrients contained in the quantity of blend per column. The corresponding values for soil columns amended with a Ca(NO3)2 blend were 48% and 100%. Leraching losses of both NO3 (<3%) and NH4 (<4%) were drastically decreased when using controlled-release fertilizers. The recoveries of P and K in 1000 ml of leachate were 1.3% and 8%, respectively, of the nutrients added as Osmocote, which contained coated P and K sources. In the case of the rest of fertilizer blends, the recoveries of P and K in 1000 ml of leachate were as high as 52%-100% and 28%-100%, respectively. Therefore, controlled-release technology offers an important capability for minimizing leaching losses of nutrients.
In this dissertation we study the role of the F spin-orbit excited state (F*) in the F + H2 and F + HD reactions using quantum mechanical calculations. The calculations involve multiple potential energy surfaces (the Alexander-Stark-Werner, or ASW, PESs), and include an accurate treatment of the couplings (non-adiabatic, spin-orbit, and Coriolis) among all three electronic states. For the F + H2 reaction, we calculate the center-of-mass differential cross sections and laboratory-frame angular distributions at the four different combinations of collision energies and hydrogen isotopomer investigated in the experiments of Neumark et al. [J. Chem. Phys., 82, 3045 (1985)]. Comparisons with the calculations on the Stark-Werner (SW) and Hartke-Stark-Werner (HSW) PESs, which are limited to the lowest electronically adiabatic state, show that non-adiabatic couplings greatly reduce backward scattering. Surprisingly, we find the shapes of both the CM DCSs and LAB ADs are insensitive to the fraction of F* presented in the F beam. For the F + HD reaction, we calculate the excitation functions and product translational energy distribution functions to study the reactivity of F*. Comparisons with the experiment by Liu and co-workers [J. Chem. Phys., 113, 3633 (2000)] confirm the relatively low reactivity of spin-orbit excited state (F*) atoms. Excellent agreement with the experiment is obtained under the assumption that the F*:F concentration ratio equals 0.16:0.84 in the molecular beam, which corresponds to a thermal equilibrium of the two spin-orbit states at the experimental temperature (600K). From the accurate calculation of the F* reactivity and its relatively small contribution to the overall reactivity of the reaction, we attribute discrepancies between calculation and experiment to an inadequacy in the simulation of the reactivity of the F ground state, likely a result of the residual errors in the ground electronic potential energy surface.
Reconstructions of the late-Holocene climate rely heavily upon proxies that are assumed to be accurately dated by layer counting. All of these proxies, such as measurements of tree rings, ice cores, and varved lake sediments do carry some inherent dating uncertainty that is not always fully accounted for. Considerable advances could be achieved if time uncertainties were recognized and correctly modeled, also for proxies commonly treated as free of age model errors. Current approaches for accounting for time uncertainty are generally limited to repeating the reconstruction using each one of an ensemble of age models, thereby inflating the final estimated uncertainty - in effect, each possible age model is given equal weighting. Uncertainties can be reduced by exploiting the inferred space-time covariance structure of the climate to re-weight the possible age models. Werner and Tingley (2015) demonstrated how Bayesian hierarchical climate reconstruction models can be augmented to account for time-uncertain proxies. In their method, probabilities associated with the age models are formally updated within the Bayesian framework, thereby reducing uncertainties. Numerical experiments (Werner and Tingley 2015) show that updating the age model probabilities decreases uncertainty in the resulting reconstructions, as compared with the current de facto standard of sampling over all age models, provided there is sufficient information from other data sources in the spatial region of the time-uncertain proxy. We show how this novel method can be applied to high resolution, sub-annually sampled lacustrine sediment records to constrain their respective age depth models. The results help to quantify the signal content and extract the regionally representative signal. The single time series can then be used as the basis for a reconstruction of glacial activity. van der Bilt et al. in prep. Werner, J.P. and Tingley, M.P. Clim. Past (2015)
Supermassive black holes (BHs) reside in the center of most local galaxies, but they also power active galactic nuclei and quasars, detected up to z = 7. These quasars put constraints on early BH growth and the mass of BH seeds. The scenario of "direct collapse" is appealing as it leads to the formation of large mass BH seeds, 10^4-10^6 {M_{⊙}}, which eases explaining how quasars at z = 6 - 7 are powered by BHs with masses >109 M⊙. Direct collapse, however, appears to be rare, as the conditions required by the scenario are that gas is metal-free, the presence of a strong photo-dissociating Lyman-Werner flux, and large inflows of gas at the center of the halo, sustained for 10 - 100 Myr. We performed several cosmological hydrodynamical simulations that cover a large range of box sizes and resolutions, thus allowing us to understand the impact of several physical processes on the distribution of direct collapse BHs. We identify halos where direct collapse can happen, and derive the number density of BHs. We also investigate the discrepancies between hydrodynamical simulations, direct or post-processed, and semi-analytical studies. Under optimistic assumptions, we find that for direct collapse to account for BHs in normal galaxies, the critical Lyman-Werner flux required for direct collapse must be about two orders of magnitude lower than predicted by 3D simulations that include detailed chemical models. However, when supernova feedback is relatively weak, enough direct collapse BHs to explain z = 6 - 7 quasars can be obtained for Lyman-Werner fluxes about one order of magnitude lower than found in 3D simulations.
Early human mummies examined recently by computed tomography demonstrated a high prevalence of vascular calcification, a pathognomonic sign of atherosclerosis, which was correlated with estimated age at death. Early populations had little exposure to modern-day metabolic risk factors: these observations thus suggest that humans have an inherent age-dependent predisposition to atherosclerosis. Premature aging syndromes are extremely rare genetic disorders that exhibit clinical phenotypes resembling accelerated aging, including severe atherosclerosis, but those phenotypes are usually segmental. Controversy persists, therefore, regarding the extent to which the molecular mechanisms underlying premature aging syndromes overlap with those of physiological aging. Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome are well-characterized premature aging syndromes. HGPS is caused by gain-of-function mutations in the LMNA gene, which result in the accumulation of a mutant nuclear protein, called "progerin," at the nuclear rim. In contrast, loss-of-function mutations in Werner syndrome ATP-dependent helicase (WRN) lead to Werner syndrome. Mesenchymal stem cells (MSCs), which can differentiate into vascular cells to maintain vascular homeostasis in response to injury, are severely affected in these syndromes. Mechanistically, either aberrant expression of progerin or loss of WRN protein in MSCs alters heterochromatin structure, resulting in premature senescence and exhaustion of functional MSCs in premature aging syndromes. Surprisingly, vascular cells and MSCs in elderly healthy individuals have shown progerin expression and decreased expression levels of WRN, respectively. Studying these rare genetic disorders could thus provide valuable insights into age-related vascular diseases that occur in the general population. PMID:26948039
By Nathalie Walker, Guest Writer, and Carolynne Keenan, Contributing Writer On July 31, NCI at Frederick hosted Student Poster Day, an annual event in which student interns can showcase the work they do in their various positions in NCI at Frederick labs and offices. Participating students are interns in the Student Internship Program, a program designed for undergraduate and graduate students during their summer breaks, as well as interns in the Werner H. Kirsten Student Internship Program (WHK SIP), a program for high school seniors. All the students have an opportunity to present their scientific posters.
Several families of states such as Werner states, Bell-diagonal states, and Dicke states are useful in understanding multipartite entanglement. Here we present a (2{sup N+1}-1)-parameter family of N-qubit ''X states'' that embraces all those families, generalizing previously defined states for two qubits. We also present the algebra of the operators that characterize the states and an iterative construction for this algebra, a subalgebra of su(2{sup N}). We show how a variety of entanglement witnesses can detect entanglement in such states. Connections are also made to structures in projective geometry.
Necessary conditions for separability are most easily expressed in the computational basis, while sufficient conditions are most conveniently expressed in the spin basis. We use the Hadamard matrix to define the relationship between these two bases and to emphasize its interpretation as a Fourier transform. We then prove a general sufficient condition for complete separability in terms of the spin coefficients and give necessary and sufficient conditions for the complete separability of a class of generalized Werner densities. As a further application of the theory, we give necessary and sufficient conditions for full separability for a particular set of n-qubit states whose densities all satisfy the Peres condition.
We give the explicit expressions of the pairwise quantum correlations present in superpositions of multipartite coherent states. A special attention is devoted to the evaluation of the geometric quantum discord. The dynamics of quantum correlations under a dephasing channel is analyzed. A comparison of geometric measure of quantum discord with that of concurrence shows that quantum discord in multipartite coherent states is more resilient to dissipative environments than is quantum entanglement. To illustrate our results, we consider some special superpositions of Weyl-Heisenberg, SU(2) and SU(1,1) coherent states which interpolate between Werner and Greenberger-Horne-Zeilinger states.
The names of his students read like a Who's Who of the pioneers in modern physics Peter Debye, Peter Paul Ewald, Wolfgang Pauli, Werner Heisenberg, Hans A. Bethe - to name only the most prominent. In retrospect, the success of Sommerfeld's school of modern theoretical physics tends to overshadow its less glorious beginnings. A century ago, theoretical physics was not yet considered as a distinct discipline. In this article I emphasize more the haphazard beginnings than the later achievements of Sommerfeld's school, which mirrored the state of theoretical physics before it became an independent discipline.
This paper investigates the entanglement dynamics of an anisotropic two-qubit Heisenberg spin chain in the presence of decoherence at finite temperature. The time evolution of the concurrence is studied for different initial Werner states. The influences of initial purity, finite temperature, spontaneous decay and Hamiltonian on the entanglement evolution are analyzed in detail. Our calculations show that the finite temperature restricts the evolution of the entanglement all the time when the Hamiltonian improves it and the spontaneous decay to the reservoirs can produce quantum entanglement with the anisotropy of spin-spin interaction. Finally, the steady-state concurrence which may remain non-zero for low temperature is also given.
In this paper, we study the entanglement dynamics of two-spin Heisenberg XYZ model with the Dzialoshinskii-Moriya (DM) interaction. The system is initially prepared in the Werner state. The effects of purity of the initial state and DM coupling parameter on the evolution of entanglement are investigated. The necessary and sufficient condition for the appearance of the entanglement sudden death (ESD) phenomenon has been deduced. The result shows that the ESD always occurs if the initial state is sufficiently impure for the given coupling parameter or the DM interaction is sufficiently strong for the given initial state. Moreover, the critical values of them are calculated.
Using the weak measurement (WM) and quantum measurement reversal (QMR) approach, robust state transfer and entanglement distribution can be realized in the spin-(1)/(2) Heisenberg chain. We find that the ultrahigh fidelity and long distance of quantum state transfer with certain success probability can be obtained using proper WM and QMR, i.e., the average fidelity of a general pure state from 80% to almost 100%, which is almost size independent. We also find that the distance and quality of entanglement distribution for the Bell state and the general Werner mixed state can be obviously improved by the WM and QMR approach.
Assuming a two-qubit system in Werner state which evolves in Heisenberg XY model with Dzyaloshinskii-Moriya (DM) interaction under the effect of different environments. We evaluate and compare quantum entanglement, quantum and classical correlation measures. It is shown that in the absence of decoherence effects, there is a critical value of DM interaction for which entanglement may vanish while quantum and classical correlations do not. In the presence of environment the behavior of correlations depends on the kind of system-environment interaction. Correlations can be sustained by manipulating Hamiltonian anisotropic-parameter in a dissipative environment. Quantum and classical correlations are more stable than entanglement generally.
We present the first detection of O VII lambda 1522 emission or absorption from archival IUE spectra in 14 planetary nebula nuclei and three PG 1159-type stars. The n = 5 approaching 6 transition of O VII was determined by Kruk & Werner and observed by them in the spectrum of the very hot PG 1159-type star H1504+65 from data obtained with the Hopkins Ultraviolet Telescope (HUT). Emission-line fluxes or absorption equivalent widths as well as radial velocities for the program stars are presented. The precise rest wavelength for the 5 approaching 6 transition requires further investigation.
Pure curiosity has been the driving force behind many groundbreaking experiments in physics. This is no better illustrated than in quantum mechanics, initially the physics of the extremely small. Since its beginnings in the 1920s and 1930s, researchers have wanted to observe the counterintuitive properties of quantum mechanics directly in the laboratory. However, because experimental technology was not sufficiently developed at the time, people like Niels Bohr, Albert Einstein, Werner Heisenberg and Erwin Schrödinger relied instead on "gedankenexperiments" (thought experiments) to investigate the quantum physics of individual particles, mainly electrons and photons.
Michelle Marcelino developed a strong interest in science as a child. The former Werner H. Kirsten student intern’s father was a physicist and often discussed with his daughters how the world works in terms of science. “I think my father instilled it in me from a very young age,” Marcelino said. “I remember being in elementary school and my father telling us colors are just wavelengths of light perceived by your eye. That’s my dad, explaining that concept in detail to a child.”
They came for a science lesson. They left with more. The new Werner H. Kirsten student interns filed into the auditorium in Building 549 to expand their knowledge of fundamental laboratory practices, as part of the Science Skills Boot Camp. A panel of presenters instructed the attendees on skills such as reading scientific papers effectively, practicing proper research ethics, and conducting professional presentations. Scientific Program Manager Ulrike Klenke, Ph.D., NIH Office of Intramural Training and Education, started the June event by welcoming her audience and encouraging the interns to break away from their familiar groups of classmates and to socialize with others from different schools and counties.
The nuclear lamina, a protein network located under the nuclear membrane, has during the past decade found increasing interest due to its significant involvement in a range of genetic diseases, including the segmental premature aging syndromes Hutchinson-Gilford progeria syndrome, restrictive dermopathy, and atypical Werner syndrome. In this review we examine these diseases, some caused by mutations in the LMNA gene, and their skin disease features. Advances within this area might also provide novel insights into the biology of skin aging, as recent data suggest that low levels of progerin are expressed in unaffected individuals and these levels increase with aging. PMID:26290387
For the first time we define a so-called Ket-Bra Entangled State (KBES) for two-qubits coupled with reservoirs by introduce an extra fictitious mode vector, and convert the corresponding master equation into Schrödinger-like equation by virtue of this state. Via this approach we concisely obtain the dynamic evolution of two uncoupled qubits each immersed in local thermal noise. Based on this, the decoherence evolution for the extended Werner-like states is derived and how purity and temperature influence the concurrence is analyzed. This KBES method may also be applied to tackling master equations of limited atomic level systems.
In this paper, we study comparatively the behaviors of Wigner function and quantum correlations for two quasi-Werner states formed with two general bipartite superposed coherent states. We show that the Wigner function can be used to detect and quantify the quantum correlations. However, we show that it is in fact not sensitive to all kinds of quantum correlations but only to entanglement. Then, we analyze the measure of non-classicality of quantum states based on the volume occupied by the negative part of the Wigner function.
We classify, up to local unitary equivalence, local unitary stabilizer Lie algebras for symmetric mixed states of n qubits into six classes. These include the stabilizer types of the Werner states, the Greenberger-Horne-Zeilinger state and its generalizations, and Dicke states. For all but the zero algebra, we classify entanglement types (local unitary equivalence classes) of symmetric mixed states that have those stabilizers. We make use of the identification of symmetric density matrices with polynomials in three variables with real coefficients and apply the representation theory of SO(3) on this space of polynomials.
We investigate an imbalance between the sensitivity of the common state measures - fidelity, trace distance, concurrence, tangle, von Neumann entropy, and linear entropy - when acted on by a depolarizing channel. Further, in this context we explore two classes of two-qubit entangled mixed states. Specifically, we illustrate a sensitivity imbalance between three of these measures for depolarized (i.e., Werner-state-like) nonmaximally entangled and maximally entangled mixed states, noting that the size of the imbalance depends on the state's tangle and linear entropy.
We propose a global measure for quantum correlations in multipartite systems, which is obtained by suitably recasting the quantum discord in terms of relative entropy and local von Neumann measurements. The measure is symmetric with respect to subsystem exchange and is shown to be nonnegative for an arbitrary state. As an illustration, we consider tripartite correlations in the Werner-GHZ (Greenberger-Horne-Zeilinger) state and multipartite correlations at quantum criticality. In particular, in contrast with the pairwise quantum discord, we show that the global quantum discord is able to characterize the infinite-order quantum phase transition in the Ashkin-Teller spin chain.
By Nathalie Walker, Guest Writer, and Carolynne Keenan, Contributing Writer On July 31, NCI at Frederick hosted Student Poster Day, an annual event in which student interns can showcase the work they do in their various positions in NCI at Frederick labs and offices. Participating students are interns in the Student Internship Program, a program designed for undergraduate and graduate students during their summer breaks, as well as interns in the Werner H. Kirsten Student Internship Program (WHK SIP), a program for high school seniors. All the students have an opportunity to present their scientific posters.
Most employees of NCI at Frederick have heard of the Werner H. Kirsten Student Intern Program (WHK SIP). The reason is simple—it has been wildly successful. And on Friday, April 22, the program will celebrate 25 years of mentoring and learning at the WHK SIP 25th Anniversary Symposium and Awards Ceremony. During the morning session, several former interns will talk about the impact that the WHK program has had on their lives. The afternoon session will begin with a panel of current and former mentors who will answer questions from students interested in the program and staff members interested in becoming mentors. Read more...
Students Share Their Research at Student Poster Day By Ashley DeVine, Staff Writer More than 50 Werner H. Kirsten student interns and college interns presented their research at Summer Student Poster Day on August 6 in the Building 549 lobby. Joseph Bergman, a high school intern in the Center for Cancer Research Nanobiology Laboratory, participated in the event “for the opportunity to present my summer research. It allowed me to meet people and get the experience of sharing and explaining my work.”
The growing diversity of heritable skin diseases, a practical challenge to clinicians and dermatonosologists alike, has nonetheless served as a rich source of insight into skin biology and disease mechanisms. I summarize below some key insights from the recent gene-driven phase of research on Werner syndrome, a heritable adult progeroid syndrome with prominent dermatologic features, constitutional genomic instability and an elevated risk of cancer. I also indicate how new insights into skin biology, disease and aging may come from unexpected sources. PMID:25810110
Helicases use the energy of ATP hydrolysis to separate double-stranded nucleic acids to facilitate essential processes such as replication, recombination, transcription and repair. This article focuses on the human RECQ helicase gene and protein family. Loss of function of three different members has been shown to cause Bloom syndrome (BS), Werner syndrome (WS) and Rothmund–Thomson syndrome (RTS). This article outlines clinical and cellular features of these cancer predisposition syndromes, and discusses their pathogenesis in light of our understanding of RECQ helicase biochemical activities and in vivo functions. I also discuss the emerging role for RECQ helicases as predictors of disease risk and the response to therapy. PMID:20934517
In October 2010, the initial deployment of the second ARM Mobile Facility (AMF2) took place at Steamboat Springs, Colorado, for the Storm Peak Laboratory Cloud Property Validation Experiment (STORMVEX). The objective of this field campaign was to obtain data about liquid and mixed-phase clouds using AMF2 instruments in conjunction with Storm Peak Laboratory (located at an elevation of 3220 meters on Mt. Werner), a cloud and aerosol research facility operated by the Desert Research Institute. STORMVEX datasets are freely available for viewing and download. Users are asked to register with the ARM Archive; the user's email address is used from that time forward as the login name.
The quantum correlation under weak measurements is studied via skew information. For 2 × d-dimensional states, it can be given by a closed form which linearly depends on the quantum correlation [EPL. 107 (2014) 10007] determined by the strength of the weak measurement. It is found that the quantum correlation under weak measurements only captures partial quantumness of the state. In particular, the extraction of the residual quantumness by the latter measurements will inevitably destroy too much quantumness. To demonstration, the Werner state is given as an example.
Cardiac catheterization has an illustrious history, originating in 1929 when Werner Forsmann, a surgical resident, performed a heart catheterization on himself. Transcatheter interventional procedures have been performed since the 1960s. The 1st intracardiac procedure to become standard therapy was a balloon atrial septostomy. Skeptics attacked this innovative procedure. However, the balloon septostomy procedure soon became the standard emergency procedure for certain congenital heart defects, and was the impetus for other investigators in the field of transcatheter intervention. We will discuss transcatheter treatment for congenital vascular stenoses and vascular occlusion. Images PMID:9456482
Open quantum system dynamics of random unitary type may in principle be fully undone. Closely following the scheme of environment-assisted error correction proposed by Gregoratti and Werner [J. Mod. Opt.10.1080/09500340308234541 50, 915 (2003)], we explicitly carry out all steps needed to invert a phase-damping error on a single qubit. Furthermore, we extend the scheme to a mixed-state environment. Surprisingly, we find cases for which the uncorrected state is closer to the desired state than any of the corrected ones.
Using a new geometrical method introduced by Werner, we find the deflection angle in the weak limit approximation by a spinning cosmic string in the context of the Einstein-Cartan (EC) theory of gravity. We begin by adopting the String-Randers optical metric, then we apply the Gauss-Bonnet theorem to the optical geometry and derive the leading terms of the deflection angle in the equatorial plane. Calculation shows that light deflection is affected by the intrinsic spin of the cosmic string and torsion.
All four of the most important figures in the early twentieth-century development of quantum physics-Niels Bohr, Erwin Schroedinger, Werner Heisenberg and Wolfgang Pauli-had strong interests in the traditional mind-brain, or 'hard,' problem. This paper reviews their approach to this problem, showing the influence of Bohr's complementarity thesis, the significance of Schroedinger's small book, 'What is life?,' the updated Platonism of Heisenberg and, perhaps most interesting of all, the interaction of Carl Jung and Wolfgang Pauli in the latter's search for a unification of mind and matter. PMID:16446022
Odoribacter splanchnicus (Werner et al. 1975) Hardham et al. 2008 is the type species of the genus Odoribacter, which belongs to the family Porphyromonadaceae in the order Bacteroidales . The species is of interest because members of the Odoribacter form an isolated cluster within the Porphyromonadaceae. This is the first completed genome sequence of a member of the genus Odoribacter and the fourth sequence from the family Porphyromonadaceae. The 4,392,288 bp long genome with its 3,672 protein-coding and 74 RNA genes and is a part of the Genomic Encyclopedia of Bacteria and Archaea project.
Class of 2014–2015 Werner H. Kirsten (WHK) student intern Rebecca “Natasha” Freed earned a fourth-place award in biochemistry at the 2015 Intel International Science and Engineering Fair (ISEF), the largest high school science research competition in the world, according to the Society for Science & the Public’s website. Freed described the event as “transformative experience,” where she was able to present her research to “experts, including Nobel laureates, as well as members of the general community and, of course, to [other students].”
Thermal striping is one of the possible initiator of pipe rupture. In this framework, thermal fluctuations in a heated periodic channel have been calculated using Large Eddy Simulation (LES). The fluid Prandtl number is set to 0.01 and the friction Reynolds number to 395. The Werner and Wengle Wall Function is used with the Navier-Stokes equations to reduce the computational cost. Satisfactory results can be noticed on the temperature fluctuations for low Prandtl number fluids. Several boundary conditions are considered, namely isothermal, isoflux, and conjugate heat transfer. The impacts of the wall properties on the temperature statistics for conjugated heat transfer boundary conditions are deeply analysed.
We study the non-Markovian effect on the dynamics of the quantum discord by exactly solving a model consisting of two independent qubits subject to two zero-temperature non-Markovian reservoirs, respectively. Considering the two qubits initially prepared in Bell-like or extended Werner-like states, we show that there is no occurrence of the sudden death, but only instantaneous disappearance of the quantum discord at some time points, in comparison to the entanglement sudden death in the same range of the parameters of interest. This implies that the quantum discord is more useful than the entanglement to describe the quantum correlation involved in quantum systems.
We study the dynamics of decoherence in an optical fiber for the case of entangled photons. Such a study will allow us to increase the physical length of fiber for transmission of entangled photon from the sources such as SPDC. We analytically derive the model for Decoherence of entangled state photons in a single-mode fiber. We also show that entanglement lifetime can be increased for Bell state and Werner state with open loop control technique called Dynamical decoupling. The authors would like to acknowledge support from the Air Force Office of Scientific Research, the Army Research Office, the National Science Foundation and the Northrop Grumman Corporation.
Are you looking forward to spring? Join Occupational Health Services (OHS) and the R&W Club Frederick for the next Take a Hike Day in April. At the fall event, about 30 employees walked or jogged the 1.3-mile course around the NCI at Frederick campus during their lunch hours. The event is designed to encourage employees to engage in physical activity, according to Sarah Hooper, manager of OHS. “It was so wonderful to see employees walking to wellness,” said Emily Burnett, a Werner H. Kirsten student intern in OHS who helped plan the fall event.
Uterus didelphys with obstructed hemivagina and ipsilateral renal agenesis (OHVIRA) or Herlyn-Werner-Wunderlich (HWW) syndrome is a rare congenital urogenital anomaly. A 13-year-old female presented with acute abdominal pain and dysmenorrhea. Ultrasonography and magnetic resonance imaging showed uterus didelphys, hematometrocolpos, obstructed hemivagina, and right renal agenesis. Hemivaginal septal resection and anastomosis between the obstructed hemivagina and the normal vagina was tried, but it was not possible. Unilateral hysterectomy was performed. HWW syndrome may present with acute abdomen and is usually treated with vaginal septum resection and drainage of the hematometrocolpos. PMID:24461469
We present here a case of an uncommon complex uterine anomaly - Obstructed HemiVagina with Ipsilateral Renal Agenesis (OHVIRA), also known as Herlyn-Werner-Wunderlich syndrome in a 14-year-old girl along with sonographic (trans-abdominal and trans labial), and MRI findings. The patient underwent surgery wherein imaging findings were confirmed. An MRI has proved to be of great help in correct diagnosis avoiding surgical interventions/ laparoscopy, which were needed in past to diagnose this rare anomaly. We also discuss the development of this anomaly with the help of a relatively new theory of uro-genital development by Acien and review the literature. PMID:22870020
Herlyn-Werner-Wunderlich syndrome (HWWS), characterized by uterus didelphys, obstructed hemivagina, and ipsilateral renal agenesis, is an uncommon combined Mullerian and mesonephric duct anomaly, and its presentation in adulthood is even rarer. We report here a 22-year-old female presenting with primary infertility where magnetic resonance imaging (MRI) suggested the diagnosis of HWWS with endometriosis. In a patient of infertility with endometriosis and unilateral renal agenesis, diagnosis of HWWS should be suspected and MRI is the investigation of choice for such anomalies. PMID:24347855
This paper is the first published report of vesicular dermatitis due to blister beetles of the family Meloidae in Panamá. A familial outbreak of bullous dermatitis caused by Epicauta flagellaria (Erichson) is described. All previous cases known in the Gorgas Memorial Laboratory were associated with E. isthmica Werner. Bullous lesions are produced when cantharidin, a vesicating toxin contained in the beetle's body, is released at the time the insect is crushed or rubbed upon the exposed skin. Rules for the treatment and prevention of this disease are indicated. PMID:2813877
A three-dimensional periodic table of the elements `Elementouch', useful in a wide variety of occasions of science education, is introduced. The element names are continuously arranged on three circular surfaces representing the electron orbits of an atom. In this way, the properties of each element in its typical ionic state can be seen more clearly than in the widely-used long period table, introduced in 1905 by Alfred Werner. The Elementouch can be readily made using the patterns downloaded from the following URL: http://www.ss.scphys.kyoto-u.ac.jp/elementouch/index-e.html .
By Ashley DeVine, Staff Writer Summer interns learned how to read a scientific paper, present a poster, maintain a laboratory notebook, and much more, at the Science Skills Boot Camp in June. “It was a great experience, and it was a great opportunity to meet some of the other interns also working on the campus,” said Alyssa Klein, a Werner H. Kirsten student intern in the Cellular Immunology Group, Laboratory of Molecular Immunoregulation. “The boot camp covered many topics essential to being a good scientist and science researcher.”
Class of 2014–2015 Werner H. Kirsten (WHK) student intern Rebecca “Natasha” Freed earned a fourth-place award in biochemistry at the 2015 Intel International Science and Engineering Fair (ISEF), the largest high school science research competition in the world, according to the Society for Science & the Public’s website. Freed described the event as “transformative experience,” where she was able to present her research to “experts, including Nobel laureates, as well as members of the general community and, of course, to [other students].”
By Carolynne Keenan, Contributing Writer When Amy Stull, a 2000 graduate of Walkersville High School, began working in a laboratory at the National Cancer Institute (NCI) at Frederick, she likely did not know the role NCI would play in her career. Stull started at NCI as a Werner H. Kirsten (WHK) student intern after her junior year of high school, working in a lab as she prepared for a career in chemical engineering. The student intern program pairs rising high school seniors with laboratory scientists to encourage the students to pursue careers in both science and health care fields.
We present here a case of an uncommon complex uterine anomaly – Obstructed HemiVagina with Ipsilateral Renal Agenesis (OHVIRA), also known as Herlyn-Werner-Wunderlich syndrome in a 14-year-old girl along with sonographic (trans-abdominal and trans labial), and MRI findings. The patient underwent surgery wherein imaging findings were confirmed. An MRI has proved to be of great help in correct diagnosis avoiding surgical interventions/ laparoscopy, which were needed in past to diagnose this rare anomaly. We also discuss the development of this anomaly with the help of a relatively new theory of uro-genital development by Acien and review the literature. PMID:22870020
We report experimental results on mixed-state generation by multiple scattering of polarization-entangled photon pairs created from parametric down-conversion. By using a large variety of scattering optical systems we have experimentally obtained entangled mixed states that lie upon and below the Werner curve in the linear entropy-tangle plane. We have also introduced a simple phenomenological model built on the analogy between classical polarization optics and quantum maps. Theoretical predictions from such a model are in full agreement with our experimental findings.
Three sessions at international conferences were held in 1997 to discuss the history of space and geophysics and its different disciplines. The first session was held during the Assembly of the German Geophysical Society in March in Potsdam, Germany. Topics included the theory of relativity and gravitation in geophysics; work by Albert Abraham Michelson, Leon Foucault, and Ernst Mach; work by Hermann von Helmholtz; and the physical application and geophysical evidence of Werner Heisenberg's research. Also included were discussions relevant to the history of geophysics, aeronomy, meteor astronomy, and geodetical research, including developments in instrumentation during the last few decades.
Werner Heisenberg (1901-1976) is one of the most controversial, most ambivalent and most important figures in the history of modern science. The debate surrounding him with respect to nuclear weapons and National Socialism appears unending. Even though Heisenberg's uncertainty principle of the quantum system and his involvement in the Nazi atomic bomb project have been thoroughly discussed in various journals over the past decades, no communication has ever been published at a holistic level of his greatest Nobel-prize winning achievement in theoretical physics. In order to fill up this hole, this piece explicitly communicates the Heisenberg's paradox at all levels of science. PMID:20105124
We employ classical molecular dynamics (MD) to investigate species diffusivity in binary Yukawa mixtures. The Yukawa potential is used to describe the screened Coulomb interaction between the ions, providing the basis for models of dense stellar materials, inertial confined plasmas, and colloidal particles in electrolytes. We use Green-Kubo techniques to calculate self-diffusivities and the Maxwell-Stefan diffusivities, and evaluate the validity of the Darken relation over a range of thermodynamic conditions of the mixture. The inter-diffusivity (or mutual diffusivity) can then be related to the Maxwell-Stefan diffusivities through the thermodynamic factor. The latter requires knowledge of the equation of state of the mixture. To test these Green-Kubo approaches and to estimate the activity contribution we have also employed large-scale non-equilibrium MD. In these simulations we can extract the inter-diffusivity value by calculating the rate of broadening of the interface in a diffusion couple. We also explore thermodynamic conditions for possible non-Fickian diffusivity. The main motivation in this work is to build a model that describes the transport coefficients in binary Yukawa mixtures over a broad range of thermodynamic conditions up to 1keV.
I propose a novel method for the modification of the corrupted human DNAootnotetextJ.D. Watson and F. H. C. Crick, Nature, 171, 737-738 (1953). code that causes particular genetic disease. The method is based on the nonlinear interaction between the DNA molecule and the ``modulation photons'' generated in beat wave driven free electron laser, BW-FEL.ootnotetextV. Alexander Stefan. Beat Wave Driven Free Electron Laser (S-U-Press, 2002, La Jolla, CA)[cf. V. Stefan, et al., Bull. Am. Phys. Soc. 32, No. 9, 1713 (1987)] The BW-FEL frequency is given by ν˜γ^2nφe (γ is the free electron beam relativistic factor, n is the harmonic number of the electron Bernstein plasma mode, and φe is the electron cyclotron frequency). The meV ``carrier photons'' are focused on the area of the brain, the source-center of a genetic disease. For the BW-FEL parameters: the free electron beam guiding d.c. magnetic field ˜ 1kG, γ˜10^3, and n=10, the keV ``modulation photons'' are generated, which are easily focused on the nucleotides. By modulating the frequency of the BW-FEL, the parametric resonance with the different DNA (sub-DNA) eigen molecular oscillation-modes are achieved, leading to the ``knock-on'' of the unwanted (corrupted) nucleotides.
This presentation concerns our continued research on adjoint--based optimization of viscous incompressible flows (the Navier--Stokes problem) coupled with heat conduction involving change of phase (the Stefan problem), and occurring in domains with variable boundaries. This problem is motivated by optimization of advanced welding techniques used in automotive manufacturing, where the goal is to determine an optimal heat input, so as to obtain a desired shape of the weld pool surface upon solidification. We argue that computation of sensitivities (gradients) in such free--boundary problems requires the use of the shape--differential calculus as a key ingredient. We also show that, with such tools available, the computational solution of the direct and inverse (optimization) problems can in fact be achieved in a similar manner and in a comparable computational time. Our presentation will address certain mathematical and computational aspects of the method. As an illustration we will consider the two--phase Stefan problem with contact point singularities where our approach allows us to obtain a thermodynamically consistent solution.
Inspired by recent works, we investigate how the thermodynamics parameters (entropy, temperature, number density, energy density, etc) of Bose-Einstein Condensate star scale with the structure of the star. Below the critical temperature in which the condensation starts to occur, we study how the entropy behaves with varying temperature till it reaches its own stability against gravitational collapse and singularity. Compared to photon gases (pressure is described by radiation) where the chemical potential, μ is zero, entropy of photon gases obeys the Stefan-Boltzmann Law for a small values of T while forming a spiral structure for a large values of T due to general relativity. The entropy density of Bose-Einstein Condensate is obtained following the similar sequence but limited under critical temperature condition. We adopt the scalar field equation of state in Thomas-Fermi limit to study the characteristics of relativistic Bose-Einstein condensate under varying temperature and entropy. Finally, we obtain the entropy density proportional to (σT{sup 3}-3T) which obeys the Stefan-Boltzmann Law in ultra-relativistic condition.
In this work, we examine the finite temperature properties of the CPT-even and Lorentz-invariance-violating (LIV) electrodynamics of the standard model extension, represented by the term W{sub {alpha}}{sub {nu}}{sub {rho}}{sub {phi}}F{sup {alpha}}{sup {nu}}F{sup {rho}}{sup {phi}}. We begin analyzing the Hamiltonian structure following the Dirac's procedure for constrained systems and construct a well-defined and gauge invariant partition function in the functional integral formalism. Next, we specialize for the nonbirefringent coefficients of the tensor W{sub {alpha}}{sub {nu}}{sub {rho}}{sub {phi}}. In the sequel, the partition function is explicitly carried out for the parity-even sector of the tensor W{sub {alpha}}{sub {nu}}{sub {rho}}{sub {phi}}. The modified partition function is a power of the Maxwell's partition function. It is observed that the LIV coefficients induce an anisotropy in the black body angular energy density distribution. The Planck's radiation law, however, retains its frequency dependence and the Stefan-Boltzmann law keeps the usual form, except for a change in the Stefan-Boltzmann constant by a factor containing the LIV contributions.
Solving balance equations is the essence of any fluid simulation of reactive, multicomponent plasmas. For plasmas in chemical non-equilibrium, balance equations are solved for all species of interest. When reactions are very fast with respect to transport time scales - and the plasma approaches chemical equilibrium - species abundances can be obtained from equilibrium relations. However, in many cases, balance equations still need to be solved for the elements, since the elemental composition can vary significantly in reactive multicomponent plasmas. Both in equilibrium and in non-equilibrium the species diffusive fluxes in these balance equations are governed by the Stefan-Maxwell equations. The use of Stefan-Maxwell diffusion leads to a coupled set of balance equations. Furthermore, this coupled set of equations is subject to charge and mass conservation constraints. Due to these complications the set of balance equations is often artificially decoupled to fit in the traditional finite volume discretization schemes and the constraints are explicitly applied. This approach can lead to very poor convergence behavior. We will present a new approach using a finite volume discretization scheme that takes into account the coupling and treats the constraints implicitly.
Elevation-dependent warming in high-elevation regions and Arctic amplification are of tremendous interest to many scientists who are engaged in studies in climate change. Here, using annual mean temperatures from 2781 global stations for the 1961-2010 period, we find that the warming for the world’s high-elevation stations (>500 m above sea level) is clearly stronger than their low-elevation counterparts; and the high-elevation amplification consists of not only an altitudinal amplification but also a latitudinal amplification. The warming for the high-elevation stations is linearly proportional to the temperature lapse rates along altitudinal and latitudinal gradients, as a result of the functional shape of Stefan-Boltzmann law in both vertical and latitudinal directions. In contrast, neither altitudinal amplification nor latitudinal amplification is found within the Arctic region despite its greater warming than lower latitudes. Further analysis shows that the Arctic amplification is an integrated part of the latitudinal amplification trend for the low-elevation stations (≤500 m above sea level) across the entire low- to high-latitude Northern Hemisphere, also a result of the mathematical shape of Stefan-Boltzmann law but only in latitudinal direction.
A review of the equations used to determine the 1-D vapor transport in the thermal diffusion cloud chamber (TDCC) is presented. These equations closely follow those of the classical Stefan tube problem in which there is transport of a volatile species through a noncondensible, carrier gas. In both cases, the very plausible assumption is made that the background gas is stagnant. Unfortunately, this assumption results in a convective flux which is inconsistent with the momentum and continuity equations for both systems. The approximation permits derivation of an analytical solution for the concentration profile in the Stefan tube, but there is no computational advantage in the case of the TDCC. Furthermore, the degree of supersaturation is a sensitive function of the concentration profile in the TD CC and the stagnant background gas approximation can make a dramatic difference in the calculated supersaturation. In this work, the equations typically used with a TDCC are compared with very general transport equations describing the 1-D diffusion of the volatile species. Whereas no pressure dependence is predicted with the typical equations, a strong pressure dependence is present with the more general equations given in this work. The predicted behavior is consistent with observations in diffusion cloud experiments. It appears that the new equations may account for much of the pressure dependence noted in TDCC experiments, but a comparison between the new equations and previously obtained experimental data are needed for verification.
The AURORA sensor slated for flight on the NPOESS satellites represents the culmination of over 20 years of experience at JHU/APL in the design, manufacture, flight, operation and analysis of compact, cost-effective far ultraviolet sensors for space weather data collection. The far ultraviolet covers the spectral range from about 115 to 185 nm. This region is ideal for observations of the upper atmosphere because, at these wavelengths, the lower atmosphere and Earth's surface are black. AURORA will observe the mid- and low-latitude F-region ionosphere, the auroral E-region ionosphere, the day thermosphere composition, auroral energy deposition and map ionospheric irregularities. AURORA implements the flight-proven design derived from SSUSI on the DMSP Block 5D spacecraft and GUVI on the NASA TIMED spacecraft. These instruments have provided the instrument and algorithm heritage for NPOESS/AURORA. In this talk the performance capabilities of the AURORA instrument will be summarized along with the design of the instrument and algorithms. Example products will be shown for each of the measurement regimes. We acknowldge support from DMSP and NASA and the collaboration with our science colleagues at the Aerospace Corporation (Paul Straus, Jim Hecht, Dave McKenzie, and Andy Christensen) and Computational Physics (Doug Strickland, Hal Knight, and Scott Evans) and Naval Research Laboratory (Robert Meier, Mike Picone, Stefan Thonnard, Pat Dandenault, and Andy Stefan) and our colleagues at APL (Michele Weiss, Doug Holland, Bill Wood, and Jim Eichert) among others.
A generalization of the Stefan-Skapski-Turnbull relation for the melt-crystal specific interfacial energy is developed in terms of the generalized Gibbs approach extending its standard formulation to thermodynamic non-equilibrium states. With respect to crystal nucleation, this relation is required in order to determine the parameters of the critical crystal clusters being a prerequisite for the computation of the work of critical cluster formation. As one of its consequences, a relation for the dependence of the specific surface energy of critical clusters on temperature and pressure is derived applicable for small and moderate deviations from liquid-crystal macroscopic equilibrium states. Employing the Stefan-Skapski-Turnbull relation, general expressions for the size and the work of formation of critical crystal clusters are formulated. The resulting expressions are much more complex as compared to the respective relations obtained via the classical Gibbs theory. Latter relations are retained as limiting cases of these more general expressions for moderate undercoolings. By this reason, the formulated, here, general relations for the specification of the critical cluster size and the work of critical cluster formation give a key for an appropriate interpretation of a variety of crystallization phenomena occurring at large undercoolings which cannot be understood in terms of the Gibbs' classical treatment.
Elevation-dependent warming in high-elevation regions and Arctic amplification are of tremendous interest to many scientists who are engaged in studies in climate change. Here, using annual mean temperatures from 2781 global stations for the 1961–2010 period, we find that the warming for the world’s high-elevation stations (>500 m above sea level) is clearly stronger than their low-elevation counterparts; and the high-elevation amplification consists of not only an altitudinal amplification but also a latitudinal amplification. The warming for the high-elevation stations is linearly proportional to the temperature lapse rates along altitudinal and latitudinal gradients, as a result of the functional shape of Stefan-Boltzmann law in both vertical and latitudinal directions. In contrast, neither altitudinal amplification nor latitudinal amplification is found within the Arctic region despite its greater warming than lower latitudes. Further analysis shows that the Arctic amplification is an integrated part of the latitudinal amplification trend for the low-elevation stations (≤500 m above sea level) across the entire low- to high-latitude Northern Hemisphere, also a result of the mathematical shape of Stefan-Boltzmann law but only in latitudinal direction. PMID:26753547
Universal exhaust gas oxygen sensors (UEGOs) are in widespread use in internal combustion engines where they are used to measure lambda (the non-dimensional air-fuel ratio) and oxygen concentration (X_{O_2 }). The sensors are used on production engines and for research and development. In a previous paper, a model of the UEGO sensor was presented, based on a solution of the Stefan-Maxwell equations for an axisymmetric geometry, and it was shown that for a known gas composition, predictions of the sensor response agreed well with experiment. In the present paper, the more ‘practical’ problem is addressed: how well can such a model predict λ and X_{O_2 } based on the sensor response? For IC engine applications, a chemistry model is required in order to predict λ, and such a model is also desirable for an accurate prediction of X_{O_2 }. A fast (matrix exponential) method of solving the Stefan-Maxwell equations is also introduced, which offers the possibility of a near real-time computation of λ and X_{O_2 }, with application, for example, to bench instruments. Extensive results are presented showing how the interpretation of the UEGO response may be compromised by uncertainties. These uncertainties may relate not only to the sensor itself, such as temperature, pressure and mean pore diameter, but also the chemistry model.
A phenomenological model was developed for multicomponent transport of charged species with simultaneous electrochemical reactions in concentrated solutions, and was applied to model processes in a thermal battery cell. A new general framework was formulated and implemented in GOMA (a multidimensional, multiphysics, finite-element computer code developed and being enhanced at Sandia) for modeling multidimensional, multicomponent transport of neutral and charged species in concentrated solutions. The new framework utilizes the Stefan-Maxwell equations that describe multicomponent diffusion of interacting species using composition-insensitive binary diffusion coefficients. The new GOMA capability for modeling multicomponent transport of neutral species was verified and validated using the model problem of ternary gaseous diffusion in a Stefan tube. The new GOMA-based thermal battery computer model was verified using an idealized battery cell in which concentration gradients are absent; the full model was verified by comparing with that of Bernardi and Newman (1987) and validated using limited thermal battery discharge-performance data from the open literature (Dunning 1981) and from Sandia (Guidotti 1996). Moreover, a new Liquid Chemkin Software Package was developed, which allows the user to handle manly aspects of liquid-phase kinetics, thermodynamics, and transport (particularly in terms of computing properties). Lastly, a Lattice-Boltzmann-based capability was developed for modeling pore- or micro-scale phenomena involving convection, diffusion, and simplified chemistry; this capability was demonstrated by modeling phenomena in the cathode region of a thermal battery cell.
Detailed numerical simulations of multicomponent plasmas require tractable expressions for species diffusion fluxes, which must be consistent with the given plasma current density J{sub q} to preserve local charge neutrality. The common situation in which J{sub q} = 0 is referred to as ambipolar diffusion. The use of formal kinetic theory in this context leads to results of formidable complexity. We derive simple tractable approximations for the diffusion fluxes in two-temperature multicomponent plasmas by means of a generalization of the hydrodynamical approach used by Maxwell, Stefan, Furry, and Williams. The resulting diffusion fluxes obey generalized Stefan-Maxwell equations that contain driving forces corresponding to ordinary, forced, pressure, and thermal diffusion. The ordinary diffusion fluxes are driven by gradients in pressure fractions rather than mole fractions. Simplifications due to the small electron mass are systematically exploited and lead to a general expression for the ambipolar electric field in the limit of infinite electrical conductivity. We present a self-consistent effective binary diffusion approximation for the diffusion fluxes. This approximation is well suited to numerical implementation and is currently in use in our LAVA computer code for simulating multicomponent thermal plasmas. Applications to date include a successful simulation of demixing effects in an argon-helium plasma jet, for which selected computational results are presented. Generalizations of the diffusion theory to finite electrical conductivity and nonzero magnetic field are currently in progress.
A method combining features of front-tracking methods and fixed-domain methods is presented to model dendritic solidification of pure materials. To explicitly track the interface growth and shape of the solidifying crystals, a fronttracking approach based on the level set method is implemented. To easily model the heat and momentum transport, a fixed-domain method is implemented assuming a diffused freezing front where the liquid fraction is defined in terms of the level set function. The fixed-domain approach, by avoiding the explicit application of essential boundary conditions on the freezing front, leads to an energy conserving methodology that is not sensitive to the mesh size. To compute the freezing front morphology, an extended Stefan condition is considered. Applications to several classical Stefan problems and two- and three-dimensional crystal growth of pure materials in an undercooled melt including the effects of melt flow are considered. The computed results agree very well with available analytical solutions as well as with results obtained using front-tracking techniques and the phase-field method.
Elevation-dependent warming in high-elevation regions and Arctic amplification are of tremendous interest to many scientists who are engaged in studies in climate change. Here, using annual mean temperatures from 2781 global stations for the 1961-2010 period, we find that the warming for the world's high-elevation stations (>500 m above sea level) is clearly stronger than their low-elevation counterparts; and the high-elevation amplification consists of not only an altitudinal amplification but also a latitudinal amplification. The warming for the high-elevation stations is linearly proportional to the temperature lapse rates along altitudinal and latitudinal gradients, as a result of the functional shape of Stefan-Boltzmann law in both vertical and latitudinal directions. In contrast, neither altitudinal amplification nor latitudinal amplification is found within the Arctic region despite its greater warming than lower latitudes. Further analysis shows that the Arctic amplification is an integrated part of the latitudinal amplification trend for the low-elevation stations (≤500 m above sea level) across the entire low- to high-latitude Northern Hemisphere, also a result of the mathematical shape of Stefan-Boltzmann law but only in latitudinal direction. PMID:26753547
The primary objective of the STS-99 mission was to complete high resolution mapping of large sections of the Earth's surface using the Shuttle Radar Topography Mission (SRTM), a specially modified radar system. This radar system produced unrivaled 3-D images of the Earth's Surface. This videotape shows a science press briefing. The panel members are Michael Kobrick, the SRTM Project Scientist at JPL; Thomas Henning, SRTM Program Manager at the National Imagery and Mapping Agency; Diane Evans, the Director of the Earth Sciences Program at NASA; and Marian Werner, XSAR Project Manager for the DLR, Deutschen Zentrum fur Luft- und Raumfahrt, Germany's National Aerospace Research Center. Michael Kobrick explained the mechanics of interferometric measurements of the Earth. He explained and demonstrated with a scale model the deployable mast's use. He also explained the importance of the attitude and orbit determination avionics. A brief animated video showing how four beams would give a 225 km wide swath of the Earth topography was viewed. Thomas Henning discussed some of the usage of the digital terrain elevation data for flood relief planning, cell phone station placement, military planning for command and control centers, and flight simulation. He explained that public access to the most precise data would be limited. Diane Evans described data usage in flood prediction, earthquake fault identification and archeology. Marian Werner described the German and Italian input to the project. The questions from the press concerned the time to process this data, and the reasons for the limited access to the more precise data.
In this paper, we present a class of maps for which the multiplicativity of the maximal output p-norm holds for p =2 and p ≥4. The class includes all positive trace-preserving maps from B(C3) to B(C2). In this sense, the result is a generalization of the corresponding result in the work of King and Koldan ["New multiplicativity results for qubit maps," J. Math. Phys. 47, 042106 (2006)], where the multiplicativity was proved for all positive trace-preserving maps from B(C2) to B(C2) with p =2 and p ≥4. Interestingly, by contrast, the multiplicativity of p-norm was investigated in the context of quantum information theory and shown not to hold, in general, for high dimensional quantum channels [Hayden, P. and Winter, A., "Counterexamples to the maximal p-norm multiplicativity conjecture for all p >1," Commun. Math. Phys. 284, 263 (2008)]. Moreover, the Werner-Holevo channel, which is a map from B(C3) to B(C3), is a counterexample for p >4.79 [Werner and Holevo, J. Math. Phys. 43, 4353 (2002).].
Highlights: Black-Right-Pointing-Pointer WRNIP1 accumulates in laser light irradiated sites very rapidly via UBZ domain. Black-Right-Pointing-Pointer The ATPase domain of WRNIP1 is dispensable for its accumulation. Black-Right-Pointing-Pointer The accumulation of WRNIP1 seems not to be dependent on the interaction with WRN. -- Abstract: WRNIP1 (Werner helicase-interacting protein 1) was originally identified as a protein that interacts with the Werner syndrome responsible gene product. WRNIP1 contains a ubiquitin-binding zinc-finger (UBZ) domain in the N-terminal region and two leucine zipper motifs in the C-terminal region. In addition, it possesses an ATPase domain in the middle of the molecule and the lysine residues serving as ubiquitin acceptors in the entire of the molecule. Here, we report that WRNIP1 accumulates in laser light irradiated sites very rapidly via its ubiquitin-binding zinc finger domain, which is known to bind polyubiquitin and to be involved in ubiquitination of WRNIP1 itself. The accumulation of WRNIP1 in laser light irradiated sites also required the C-terminal region containing two leucine zippers, which is reportedly involved in the oligomerization of WRNIP1. Mutated WRNIP1 with a deleted ATPase domain or with mutations in lysine residues, which serve as ubiquitin acceptors, accumulated in laser light irradiated sites, suggesting that the ATPase domain of WRNIP1 and ubiquitination of WRNIP1 are dispensable for the accumulation.
Highlights: {yields} In this study, we investigated the effect of a DNA secondary structure on the two WRN activities. {yields} We found that a DNA secondary structure of the displaced strand during unwinding stimulates WRN helicase without coordinate action of WRN exonuclease. {yields} These results imply that WRN helicase and exonuclease activities can act independently. -- Abstract: Werner syndrome (WS) is an autosomal recessive premature aging disorder characterized by aging-related phenotypes and genomic instability. WS is caused by mutations in a gene encoding a nuclear protein, Werner syndrome protein (WRN), a member of the RecQ helicase family, that interestingly possesses both helicase and exonuclease activities. Previous studies have shown that the two activities act in concert on a single substrate. We investigated the effect of a DNA secondary structure on the two WRN activities and found that a DNA secondary structure of the displaced strand during unwinding stimulates WRN helicase without coordinate action of WRN exonuclease. These results imply that WRN helicase and exonuclease activities can act independently, and we propose that the uncoordinated action may be relevant to the in vivo activity of WRN.
The Powder River Basin, and specifically the Gillette coal field, contains large quantities of economically extractable coal resources. These coal resources have low total sulfur content and ash yield, and most of the resources are subbituminous in rank. A recent U.S Geological Survey study of economically extractable coal in the Gillette coal field focused on five coal beds, the Wyodak rider, Upper Wyodak, Canyon, Lower Wyodak-Werner, and Gates/Kennedy. This report compares the coal quality of these economically extractable coal beds to coal in the Wyodak-Anderson coal zone in the Powder River Basin and in the Gillette coal field (Flores and others, 1999) and other produced coal in the Gillette coal field (Glass, 2000). The Upper Wyodak, Canyon, and Lower Wyodak/Werner beds are within the Wyodak-Anderson coal zone. Compared with all coal in the Wyodak-Anderson coal zone, both throughout the Powder River Basin and just within the Gillette coal field; the thick, persistent Upper Wyodak coal bed in the Gillette coal field has higher mean gross calorific value (8,569 Btu/lb), lower mean ash yield (5.8 percent), and lower mean total sulfur content (0.46 percent).
Ultraviolet spectra of the Jovian equatorial dayglow in the spectral range 830-1850 A were obtained at about 3 A resolution. The observed spectrum is dominated by electron impact excitation of the H2 Lyman and Werner band systems. Solar Lyman-beta induced fluorescence in the (6, nu-double prime) Lyman band progression is clearly identified in five distinct P(1) lines, and the contribution of solar fluorescence to the total 2.3 kR slit-averaged H2 emission rate is estimated to be 17-22 percent. The electron excitation spectrum is characterized by a relative weakness of the Werner band system and the absence of cascade contributions to the Lyman system and is very similar to that of the south polar aurora. The integrated H2 emission rate in the 900-1100 A band is a factor of two lower than that measured by the Voyager UVS. Based on model calculations, photoelectron excitation does not appear able to account for the amount of observed electron-excited H2 emission.
A spectrum of Pi Sco showing numerous atomic lines and 70 absorption features from the Lyman and Werner transitions of interstellar H2 in rotational level J from zero to five is presented. Their shapes of the composite column density profiles are very nearly Gaussian with a one-dimensional rms velocity dispersion of 3 km/s. The behavior of shifts in the inferred N(H2) as a function of velocity are consistent with the overall profiles being composed of nearly symmetrical, tightly paced assemblies of about seven unresolved components. The relative overall column densities in the higher J levels of H2 are consistent with a model where these states are populated by optical pumping through the Lyman and Werner transitions, powered by UV radiation from nearby stars. The slight narrowing of the high-J profiles may be due to small clumps of H2 at radial velocities some 5-8 km/s from the core of the profile are exposed to a pumping flux about 10 times lower than that for the material near the profile's center.
The results of a series of IUE observations of the north polar aurora obtained during a substantial fraction of one complete rotation of Jupiter are presented. From these data a spectrum of the aurora with high signal to noise ratio, and a resolution of about 8 A was obtained, making possible the identification of many H2 Lyman and Werner bands. The spectrum is of sufficient quality to provide reliable quantative data for a comparison with the model atmosphere calculations. The lack of an observable absorption signature makes it possible to set an upper limit on the column density of CH4 and C2H6 above the auroral emissions and hence an upper limit on the primary particle energies. A comparison of this spectrum with a laboratory spectrum of discharge excited H2 shows a remarkable similarity. The results of several IUE observations of the full disk of Saturn are also examined. The exposures were of approximately 2 hours each, and the H2 Lyman and Werner bands were observed near the north pole in two of them.
The genus Apteromantis Werner, 1931 comprises two species of wingless mantids, the Iberian A. aptera (Fuente, 1894) and the North African A. bolivari (Werner, 1929). Although A. aptera and A. bolivari have been traditionally considered as separate and valid species, their external appearance is quite similar and no comprehensive taxonomic study has analyzed their morphological and genetic characteristics. This taxonomic uncertainty has important implications for conservation because A. aptera is considered an Iberian endemic and the only praying mantis protected by international laws. In this study, we apply a comprehensive approach, including quantitative morphological and molecular analyses, to shed new light on the taxonomic and conservation status of the genus Apteromantis and the putative species. We have found that the Iberian and North African specimens analyzed herein significantly differ in female head shape, male genitalia morphology and several other traits related to body size. Molecular data suggest the presence of two main lineages, with sequence divergence rates of approximately 4 %, which are within the range reported for other well defined insect species. Overall, this study supports that A. aptera and A. bolivari are valid species despite their ecological and morphological similarity and highlights the importance of comprehensive approaches to resolve old taxonomic and conservation problems. PMID:24870858
Mount Erebus, a large intraplate stratovolcano dominating Ross Island, Antarctica, hosts the world's only active phonolite lava lakes. The main manifestation of activity at Erebus volcano in December 2004 was as the presence of two convecting lava lakes within an inner crater. The long-lived Ray Lake, ~ 1400 m 2 in area, was the site of up to 10 small Strombolian eruptions per day. A new but short-lived, ~ 1000-1200 m 2 lake formed at Werner vent in December 2004 sourced by lava flowing from a crater formed in 1993 by a phreatic eruption. We measured the radiative heat flux from the two lakes in December 2004 using a compact infrared (IR) imaging camera. Daily thermal IR surveys from the Main Crater rim provide images of the lava lake surface temperatures and identify sites of upwelling and downwelling. The radiative heat outputs calculated for the Ray and Werner Lakes are 30-35 MW and 20 MW, respectively. We estimate that the magma flux needed to sustain the combined heat loss is ~ 250-710 kg s - 1 , that the minimum volume of the magma reservoir is 2 km 3, and that the radius of the conduit feeding the Ray lake is ~ 2 m.
Ultraviolet spectra of the Jovian equatorial dayglow in the spectral range 830-1850 A were obtained at about 3 A resolution. The observed spectrum is dominated by electron impact excitation of the H2 Lyman and Werner band systems. Solar Lyman-beta induced fluorescence in the (6, nu-double prime) Lyman band progression is clearly identified in five distinct P(1) lines, and the contribution of solar fluorescence to the total 2.3 kR slit-averaged H2 emission rate is estimated to be 17-22 percent. The electron excitation spectrum is characterized by a relative weakness of the Werner band system and the absence of cascade contributions to the Lyman system and is very similar to that of the south polar aurora. The integrated H2 emission rate in the 900-1100 A band is a factor of two lower than that measured by the Voyager UVS. Based on model calculations, photoelectron excitation does not appear able to account for the amount of observed electron-excited H2 emission.
OHVIRA (Obstructed hemivagina and ipsilateral renal anomaly) by acronym and abbreviations in English or Herlyn Werner Wunderlich syndrome is a rare congenital malformation caused by an alteration in the Mullerian ducts and Wolffian Ducts. Which is characterized by a triad: uterus didelphys, obstructed and ipsilateral renal agenesis hemivagina still uncertain etiology. Patients are usually asymptomatic until menarche where the most common clinical presentation is pelvic pain, followed by a vaginal or abdominal mass, normal menstrual periods, infertility, and vaginal discharge rarely appears. The case of a female patient of 15 years, nubile with chronic fetid vaginal discharge, initially diagnosed and treated as pelvic inflammatory disease occurs, however because it is an exceptional condition with the background of the patient, by complementary studies were conducted where pelvic ultrasound revealed pyocolpos and absence of left kidney, uterus didelphys, blind hemivagina by other imaging studies, where we could integrate Herlyn-Werner-Wunderlich syndrome. In conclusion, abnormalities in the development of the Miillerian ducts are difficult to diagnose early, so you must have the embryological knowledge, conduct thorough clinical assessment and detailed picture in whom the coridition is suspected to identify malformations coexisting urinary tract and vaginal defects with the importance of preserving reproductive success through appropriate planning of surgical approach, given that the fertility rate in these patients is comparable to the average. PMID:25510063
The dielectric model for waves in the Earth's ionosphere is further developed and applied to possible electro-magnetic phenomena in seismic regions. In doing so, in comparison to the well-known dielectric wave model by R.O. Dendy [Plasma dynamics, Oxford University Press, 1990] for homogeneous systems, the stratification of the atmosphere is taken into account. Moreover, within the frame of many-fluid magnetohydrodynamics also the momentum transfer between the charged and neutral particles is considered. Discussed are the excitation of Alfvén and magnetoacoustic waves, but also their variations by the neutral gas winds. Further, also other current driven waves like Farley-Buneman ones are studied. In the work, models of the altitudinal scales of the plasma parameters and the electromagnetic wave field are derived. In case of the electric wave field, a method is given to calculate the altitudinal scale based on the Poisson equation for the electric field and the magnetohydrodynamic description of the particles. Further, expressions are derived to estimate density, pressure, and temperatur changes in the E-layer because of the generation of the electromagnetic waves. Last not least, formulas are obtained to determine the dispersion and polarisation of the excited electromagnetic waves. These are applied to find quantitative results for the turbulent heating of the ionospheric E-layer. Concerning the calculation of the dispersion relation, in comparison to a former work by Meister et al. [Contr. Plasma Phys. 53 (4-5), 406-413, 2013], where a numerical double-iteration method was suggested to obtain results for the wave dispersion relations, now further analytical calculations are performed. In doing so, different polynomial dependencies of the wave frequencies from the wave vectors are treated. This helped to restrict the numerical calculations to only one iteration process.
This study is concerned with how information about the direction of visual motion is encoded by motion-sensitive neurons. Motion-sensitive neurons are usually studied using stimuli unchanging in speed and direction over several seconds. Recently, it has been suggested that neuronal responses to more naturalistic stimuli cannot be understood on the basis of experiments with constant-motion stimuli (de Ruyter van Steveninck et al., 1997). We measured the variability and information content of spike trains recorded from directional neurons in the nucleus of the optic tract (NOT) of the wallaby, Macropus eugenii, in response to constant and time-varying motion. While the NOT forms part of the mammalian optokinetic system, we have shown previously that the responses of its directional neurons resemble those of insect H1 in many respects (Ibbotson et al., 1994). We find that directional neurons in the wallaby NOT respond with lower variability and higher rates of information transmission to time-varying stimuli than to constant motion. The difference in response variability is predicted by an inhomogeneous Poisson model of neuronal spiking incorporating an absolute refractory period of 2 ms during which no subsequent spike can be fired. Refractoriness imposes structure on the spike train, reducing variability (de Ruyter van Steveninck & Bialek, 1988; Berry & Meister, 1998). A given refractory period has a greater impact when firing rates are high, as for the responses of NOT neurons to time-varying stimuli. It is in just these cases that variability in experimentally observed spike trains is lowest. Thus, differences in response variability do not necessarily imply that different models are required to predict neuronal responses to constant- and time-varying motion stimuli. PMID:10824675
This paper seeks to convey an insight into the interrelationships between body, soul and mind and to show how the concept of "soul" has evolved through the course of history. In German the word "soul" has a confusing array of meanings today. For most of us it comprises all of man's emotions, his awareness, constructive thought, drive, state of mind and spirit. The soul thus represents the essence of a person and his relationships to those closest to him. For many people the soul was and still is the principle of life, the breath of life and the force of life. The immortal soul escapes, leaves the body, is weighed and judged. At all times in history man has doggedly pursued the mysteries of self-awareness, the ultimate truth and the soul. What he found varied, depending on the age and the place. What the Hebrew Bible and the New Testament express in deep-seated metaphors, the Greek philosophers put into clear-cut words: their concept of soul was then largely integrated into Christian thought. Meister Eckhart describes the soul in mystically transfigured passion. C.G. Jung writes of the "animus and anima." Sigmund Freud uses the term "psyche." Radical materialism denies the existence and independence of the soul's processes. The questions where we come from and where we are going, why and what for, no longer find a common answer. Psychiatry, however, takes up the intellectual call of the time and replies to the challenges of the day. Thus, the search for the "soul", a search that occupies so many people, also always involves the search for the whole person. PMID:12503473
Objective. Accurate modeling of retinal information processing remains a major challenge in retinal physiology with applications in visual rehabilitation and prosthetics. Most of the current artificial retinas are fed with static frame-based information, losing thereby the fundamental asynchronous features of biological vision. The objective of this work is to reproduce the spatial and temporal properties of the majority of ganglion cell (GC) types in the mammalian retina. Approach. Here, we combined an asynchronous event-based light sensor with a model pulling nonlinear subunits to reproduce the parallel filtering and temporal coding occurring in the retina. We fitted our model to physiological data and were able to reconstruct the spatio-temporal responses of the majority of GC types previously described in the mammalian retina (Roska et al 2006 J. Neurophysiol. 95 3810-22). Main results. Fitting of the temporal and spatial components of the response was achieved with high coefficients of determination (median R(2) = 0.972 and R(2) = 0.903, respectively). Our model provides an accurate temporal precision with a reliability of only few milliseconds-peak of the distribution at 5 ms-similar to biological retinas (Berry et al 1997 Proc. Natl Acad. Sci. USA 94 5411-16; Gollisch and Meister 2008 Science 319 1108-11). The spiking statistics of the model also followed physiological measurements (Fano factor: 0.331). Significance. This new asynchronous retinal model therefore opens new perspectives in the development of artificial visual systems and visual prosthetic devices. PMID:23075696
Thermal radiation plays an increasingly important role in many emerging energy technologies, such as thermophotovoltaics, passive radiative cooling and wearable cooling clothes [1]. One of the fundamental constraints in thermal radiation is the Stefan-Boltzmann law, which limits the maximum power of far-field radiation to P0 = σT4S, where σ is the Boltzmann constant, S and T are the area and the temperature of the emitter, respectively (Fig. 1a). In order to overcome this limit, it has been shown that near-field radiations could have an energy density that is orders of magnitude greater than the Stefan-Boltzmann law [2-7]. Unfortunately, such near-field radiation transfer is spatially confined and cannot carry radiative heat to the far field. Recently, a new concept of thermal extraction was proposed [8] to enhance far-field thermal emission, which, conceptually, operates on a principle similar to oil immersion lenses and light extraction in light-emitting diodes using solid immersion lens to increase light output [62].Thermal extraction allows a blackbody to radiate more energy to the far field than the apparent limit of the Stefan-Boltzmann law without breaking the second law of thermodynamics. Thermal extraction works by using a specially designed thermal extractor to convert and guide the near-field energy to the far field, as shown in Fig. 1b. The same blackbody as shown in Fig. 1a is placed closely below the thermal extractor with a spacing smaller than the thermal wavelength. The near-field coupling transfers radiative energy with a density greater than σT4. The thermal extractor, made from transparent and high-index or structured materials, does not emit or absorb any radiation. It transforms the near-field energy and sends it toward the far field. As a result, the total amount of far-field radiative heat dissipated by the same blackbody is greatly enhanced above SσT4, where S is the area of the emitter. This paper will review the progress in thermal
The effects of soil property uncertainties on permafrost thaw projections are studied using a three-phase subsurface thermal hydrology model and calibration-constrained uncertainty analysis. The null-space Monte Carlo method is used to identify soil hydrothermal parameter combinations that are consistent with borehole temperature measurements at the study site, the Barrow Environmental Observatory. Each parameter combination is then used in a forward projection of permafrost conditions for the 21st century (from calendar year 2006 to 2100) using atmospheric forcings from the Community Earth System Model (CESM) in the Representative Concentration Pathway (RCP) 8.5 greenhouse gas concentration trajectory. A 100-year projection allows for the evaluation of predictive uncertainty (due to soil property (parametric) uncertainty) and the inter-annual climate variability due to year to year differences in CESM climate forcings. After calibrating to measured borehole temperature data at this well-characterized site, soil property uncertainties are still significant and result in significant predictive uncertainties in projected active layer thickness and annual thaw depth-duration even with a specified future climate. Inter-annual climate variability in projected soil moisture content and Stefan number are small. A volume- and time-integrated Stefan number decreases significantly, indicating a shift in subsurface energy utilization in the future climate (latent heat of phase change becomes more important than heat conduction). Out of 10 soil parameters, ALT, annual thaw depth-duration, and Stefan number are highly dependent on mineral soil porosity, while annual mean liquid saturation of the active layer is highly dependent on the mineral soil residual saturation and moderately dependent on peat residual saturation. By comparing the ensemble statistics to the spread of projected permafrost metrics using different climate models, we quantify the relative magnitude of soil
The International Workshop on Multi-Rate Processes and Hysteresis (MURPHYS) conference series focuses on multiple scale systems, singular perturbation problems, phase transitions and hysteresis phenomena occurring in physical, biological, chemical, economical, engineering and information systems. The 6th edition was hosted by Stefan cel Mare University in the city of Suceava located in the beautiful multicultural land of Bukovina, Romania, from May 21 to 24, 2012. This continued the series of biennial multidisciplinary conferences organized in Cork, Ireland from 2002 to 2008 and in Pécs, Hungary in 2010. The MURPHYS 2012 Workshop brought together more than 50 researchers in hysteresis and multi-scale phenomena from the United State of America, the United Kingdom, France, Germany, Italy, Ireland, Czech Republic, Hungary, Greece, Ukraine, and Romania. Participants shared and discussed new developments of analytical techniques and numerical methods along with a variety of their applications in various areas, including material sciences, electrical and electronics engineering, mechanical engineering and civil structures, biological and eco-systems, economics and finance. The Workshop was sponsored by the European Social Fund through Sectoral Operational Program Human Resources 2007-2013 (PRO-DOCT) and Stefan cel Mare University, Suceava. The Organizing Committee was co-chaired by Mihai Dimian from Stefan cel Mare University, Suceava (Romania), Amalia Ivanyi from the University of Pecs (Hungary), and Dmitrii Rachinskii from the University College Cork (Ireland). All papers published in this volume of Journal of Physics: Conference Series have been peer reviewed through processes administered by the Editors. Reviews were conducted by expert referees to the professional and scientific standards expected of a proceedings journal published by IOP Publishing. The Guest Editors wish to place on record their sincere gratitude to Miss Sarah Toms for the assistance she provided
Lungless salamanders (family Plethodontidae) are relatively sedentary and are presumed to have limited dispersal ability (Marsh et al. 2004. Ecology 85:3396–3405). Site fidelity in Plethodontidae is high, and individuals displaced 90 m return to home territories (Kleeberger and Werner 1982. Copeia 1982:409–415). Individuals defend territories (Jaeger et al. 1982. Anim. Behav. 30:490–496) and female home ranges have been estimated to be 24.34 m2 (Kleeberger and Werner 1982, op. cit.). Females may seek out suitable subsurface habitat to oviposit eggs, yet little is known about their maximum movement distances (Petranka 1998. Salamanders of the United States and Canada. Smithsonian Institution Press, Washington. 587 pp.).On 18 September 2014, a female P. cinereus (lead back morphotype; SVL = 44.68 mm; 0.89 g) was found under a coverboard during a standard sampling event and uniquely marked using visual implant elastomer at the S.O. Conte Anadromous Fish Research Center, Massachusetts, USA (42.59280°N, 72.58070°W, datum WGS84; elev. 74 m). This individual was subsequently recaptured at ~1500 h on 8 October 2014 under a coverboard within 3 m of the original capture location and then again ~1430 h on 16 October 2014 under a log, within the same forest patch, though in a 50 x 150 m area adjacent to the original study area. Because we found the marked salamander while collecting multiple individuals for a laboratory study, the exact recapture location of the marked individual is not known. However, the distance between the 8 October capture location and the nearest edge of the 16 October search area (i.e. 50 x 150 m) was 143 m, indicating a minimum movement distance. As far as we are aware, this is the longest recorded movement for P. cinereus by more than 53 m (Kleeberger and Werner 1982, op. cit.). This finding followed a rain event of 1.63 cm within 24 h and the second largest sustained rain event during October. The movement we observed may have been due to
In the early part of the 20th century, the pioneers of radioactivity research, led by Marie Curie, Ernest Rutherford and Stefan Meyer, formed a Commission internationale des étalons de radium. The Commission made arrangements for the preparation and intercomparisons of the international standards of radium, which were identified as the Paris standard and the Vienna standard. Otto Hönigschmid from Vienna prepared a first set of international secondary standards in 1912 and a second set in 1934. In both instances, these secondary standards were compared by gamma-ray measurements with the Paris and Vienna standards. The usage of these international standards of radium in the 20th century is described. PMID:11839059
The results of numerical simulation of heat and mass transfer in an ejection apparatus during condensation of vapor-gas mixture components on cold brine droplets are presented. The local parameters of working flows were determined by solving a system of differential heat transfer equations with account for the hydrodynamic pattern. Calculations were carried out on the assumption that the liquid spray is directed horizontally. The Stefan formula has been derived with reference to a spherical coordinate system. The results of calculation of heat and mass transfer rates with and without regard for steam condensation jointly with hydrocarbon vapors are compared and analyzed. Estimation of the effect exerted by the apparatus and drip pan walls on the general process of heat and mass transfer was carried out. The results of simulation made it possible to quantitatively estimate the influence of the adopted thickness of the diffusional boundary layer on the vapor-air mixture cooling effect.
River discharges with very high sediment loads have the potential to develop into plunging hyperpycnal flows that transition from a river jet to a turbidity current at some location basinward of the river mouth due to the density difference between the turbid river and the receiving water body. However, even if the bulk density of the turbid river is greater than that of the receiving lake or ocean, some distance is needed for the forward inertia of the river to dissipate so that the downward gravitational pull can cause the system to collapse into a subaqueous turbidity current. This collapsing at the plunge point has been found to occur when the densimetric Froude number decreases to a value between 0.3 < Frd < 0.7 (Fang and Stefan 2000, Parker and Toniolo 2007, Dai and Garcia 2010, Lamb et al. 2010). In 2D channel flow analysis at the plunge point, this has led to the concept of a two-fold criterion for plunging. The first is simply for the need of high enough suspended sediment concentration to overcome the density difference between the river fluid and the fluid of the receiving water. The second is the need for sufficiently deep water to reduce the densimetric Froude below the critical value for plunging, which leads to dependence of plunging on the receiving water basin topography (Lamb et al. 2010). In this analysis, we expand on past work by solving a system of ODE river jet equations to account for bottom friction, lateral entrainment of ambient fluid, and particle settling between the river mouth and the plunge location. Typical entrainment and bottom friction coefficients are used and the model is tested against the laboratory density current data of Fang and Stefan (1991). A suite of conditions is solved with variable river discharge velocity, aspect ratio, suspended sediment concentration, and particle size; a range of salinity values and bottom slopes are used for the receiving water body. The plunge location is then expressed as a function of the
A Multi-pixel Geiger-mode APD, often called a Silicon Photomultiplier (SiPM), is a new type of photon counting device made up of multiple APD pixels operated in the Geiger-mode, which started to replace the PMT in a certain parts of photodetection field. Stefan Meyer Institute in Vienna has been working on an evaluation of several kinds of SiPMs from different manufacturers with different sizes of cells, sensitive area. We operate SiPMs in combination with scintillating fiber and Cherenkov radiator to test its potential with special focus on its timing performance, compactness and low-cost. The detectors are going to be applied in experiments like FOPI, AMADEUS and PANDA.
Earth's climate sensitivity is often interpreted in terms of feedbacks that can alter the sensitivity from that of a no-feedback Stefan-Boltzmann radiator, with the feedback concept and algebra introduced by analogy to the use of this concept in the electronics literature. This analogy is quite valuable in interpreting the sensitivity of the climate system, but usage of this algebra and terminology in the climate literature is often inconsistent, with resultant potential for confusion and loss of physical insight. Here a simple and readily understood electrical resistance circuit is examined in terms of feedback theory to introduce and define the terminology that is used to quantify feedbacks. This formalism is applied to the feedbacks in an energy-balance model of Earth's climate and used to interpret the magnitude of feedback in the climate system that corresponds to present estimates of Earth's climate sensitivity.
This investigation concerns adjoint--based optimization of viscous incompressible flows (the Navier-Stokes problem) coupled with heat conduction involving change of phase (the Stefan problem) and occurring in domains with moving boundaries such as the free and solidification surfaces. This problem is motivated by optimization of advanced welding techniques used in automotive manufacturing. We characterize the sensitivity of a suitable cost functional defined for the system with respect to control (the heat input) using adjoint equations. Given that the shape of the domain is also a dependent variable, characterizing sensitivities necessitates the introduction of ``non-cylindrical'' calculus required to differentiate a cost functional defined on a variable domain. As a result, unlike the forward problem, the adjoint system is defined on a domain with a predetermined evolution in time and also involves ordinary differential equations defined on the domain boundary (``the adjoint transverse system''). We will discuss certain computational issues related to numerical solution of such adjoint problems.
This paper addresses the intrinsic uncertainty of k0 neutron activation analysis (NAA) by evaluating the partial uncertainties of the nuclear parameters and parameters given by the irradiation conditions. Uncertainty propagation factors are determined from the basic equations of the k0-NAA and the combined uncertainties are calculated using a software package specially developed for this purpose. The nuclear parameter values and respective uncertainties are taken from an IUPAC database. The uncertainties are calculated for specific conditions given at the TRIGA Mark II reactor of the Jožef Stefan Institute, for all reactions where data is available. On average, neutron reaction-specific values in the range of 1-2% were obtained for 44 elements. For 23 elements, some data are missing in the database, so the values should be obtained elsewhere. The developed approach is generally applicable to other neutron flux conditions.
Numerous cold regions water flow and energy transport models have emerged in recent years. Dissimilarities often exist in their mathematical formulations and/or numerical solution techniques, but few analytical solutions exist for benchmarking flow and energy transport models that include pore water phase change. This paper presents a detailed derivation of the Lunardini solution, an approximate analytical solution for predicting soil thawing subject to conduction, advection, and phase change. Fifteen thawing scenarios are examined by considering differences in porosity, surface temperature, Darcy velocity, and initial temperature. The accuracy of the Lunardini solution is shown to be proportional to the Stefan number. The analytical solution results obtained for soil thawing scenarios with water flow and advection are compared to those obtained from the finite element model SUTRA. Three problems, two involving the Lunardini solution and one involving the classic Neumann solution, are recommended as standard benchmarks for future model development and testing.
This work examines the finite temperature properties of the CPT-even and parity-odd electrodynamics of the standard model extension. The starting point is the partition function computed for an arbitrary and sufficiently small tensor (k{sub F}){sub {alpha}{nu}{rho}{phi}} [see R. Casana, M. M. Ferreira, Jr., J. S. Rodrigues, and M. R. O. Silva, Phys. Rev. D 80, 085026 (2009).]. After specializing the Lorentz-violating tensor (k{sub F}){sub {alpha}{nu}{rho}{phi}}for the leading-order-nonbirefringent and parity-odd coefficients, the partition function is explicitly carried out, showing that it is a power of the Maxwell partition function. Also, it is observed that the Lorentz invariance violation coefficients induce an anisotropy in the black-body angular energy density distribution. Planck's radiation law retains its usual frequency dependence and the Stefan-Boltzmann law keeps the same form, except for a global proportionality constant.
Two-dimensional solidification influenced by anisotropic heat conduction has been considered. The interfacial energy balance was derived to account for the heat transfer in one direction (x or y) depending on the temperature gradient in both the x and y directions. A parametric study was made to determine the effects of the Stefan number, aspect ratio, initial superheat, and thermal conductivity ratios on the solidification rate. Because of the imposed boundary conditions, the interface became skewed and sometimes was not a straight line between the interface position at the upper and lower adiabatic walls (spatially nonlinear along the height). This skewness depends on the thermal conductivity ratio k(yy)/k(yx). The nonlinearity of the interface is influenced by the solidification rate, aspect ratio, and k(yy/k(yx).
An explicit and unconditionally stable finite difference method for the solution of the transient inverse heat conduction problem in a semi-infinite or finite slab mediums subject to nonlinear radiation boundary conditions is presented. After measuring two interior temperature histories, the mollification method is used to determine the surface transient heat source if the energy radiation law is known. Alternatively, if the active surface is heated by a source at a rate proportional to a given function, the nonlinear surface radiation law is then recovered as a function of the interface temperature when the problem is feasible. Two typical examples corresponding to Newton cooling law and Stefan-Boltzmann radiation law respectively are illustrated. In all cases, the method predicts the surface conditions with an accuracy suitable for many practical purposes.
The design and properties of a new cryogenic set-up for laser–microwave–laser hyperfine structure spectroscopy of antiprotonic helium – an experiment performed at the CERN-Antiproton Decelerator (AD), Geneva, Switzerland – are described. Similar experiments for 4He have been performed at the AD for several years. Due to the usage of a liquid helium operated cryostat and therefore necessary refilling of coolants, a loss of up to 10% beamtime occurred. The decision was made to change the cooling system to a closed-circuit cryocooler. New hermetically sealed target cells with minimised 3He gas volume and different dimensions of the microwave resonator for measuring the 3He transitions were needed. A new set-up has been designed and tested at Stefan Meyer Institute in Vienna before being used for the 2009 and 2010 beamtimes at the AD. PMID:22267883
Almost all the analyses of tritium in Slovenia have been performed by the tritium laboratory at the Jozef Stefan Institute. Nearly 90 % of its measurements have been covered by two national programs, both approved by the Slovenian Nuclear Safety Administration: the radioactive monitoring program in the environs of Krsko Nuclear Power Plant (KNPP) and the program of global radioactive contamination monitoring in the environment. These programs include samples of groundwaters, surface waters, precipitation and drinking waters, as well as liquid and gaseous effluents from KNPP. Tritium was determined in some research projects and in hydrological studies of thermal waters, groundwater and coalmine waters. Tritium in the Karst region was mapped as well as the springs of entire territory of Slovenia. Around 5500 samples have been analyzed up to 2004.
A comprehensive investigation of heat transfer and induced fluid flow interactions during melting in a confined storage medium is reported in this paper. This study focuses on thermal characterization of a single constituent storage module rather than an entire storage system to precisely capture the energy exchange contributions of all fundamental heat transfer mechanisms during phase change process. Two-dimensional, axisymmetric, transient equations for mass, momentum and energy conservation were solved numerically by the finite volume scheme. Results report the influence of the Grashof, Stefan and Prandtl numbers on the melting dynamics of capsules with various diameters (20, 30, 40, and 50 mm). Also the effects of the shell material have been analyzed. Correlating equations for melt fraction and Nusselt number have been developed for possible general design applications. |
Teen, 14, shot to death; 2 gunmen on the run
HOUSTON - Local 2 has learned extra police officers were at a southwest Houston school campus Wednesday following the shooting death of a 14-year-old student.
Houston police say Javier Alejo was shot as he and another person sat outside of their apartment in the 8900 block of Beechnut on Tuesday night.
Alejo was taken to Ben Taub General Hospital in critical condition and later died.
Police haven't released a motive, but sources told Local 2 that investigators believe the shooting was gang related.
A spokesperson for HISD confirmed Alejo was a student at Sugar Grove Academy and said counselors and security support were on campus Wednesday. She referred all other questions to the Houston Police Department.
Letters were sent home with students Wednesday afternoon, notifying parents about Alejo's death. The letter also said even though the incident happened off campus, additional measures are being taken to ensure the safety of students.
"It's really sad. You become concerned about the safety of your children and the area where they are living," said a parent, who didn't want to be identified.
Several police vehicles could also be seen patrolling the area around the school after the school day ended. Local 2 has learned several fights have happened in the area recently, also possibly gang related.
The suspects in the shooting are described as two men. They were last seen in a white or silver 4-door sedan.
Anyone with information in this case is asked to call the HPD Homicide Division at 713-308-3600 or Crime Stoppers at 713-222-TIPS.
Copyright 2013 by Click2Houston.com. All rights reserved. This material may not be published, broadcast, rewritten or redistributed. |
The Blog
AirBnB property photography
An interior photo shoot for another AirBnB property in Brighton the other day. This one was right in town in the North Laine area, near pub The Pond.
There are three bedrooms in this holiday let house. This is one of the two doubles.
A small single bedroom in between.
Hard to take more meaningful photos of that one. The third one was spacious again, though.
You know what happened when I took this photo above? As I was trying to take the shot from as far away from the bed as possible so it wouldn’t look distorted by an extreme wide angle lens, my back touched a mirror on the wall and it crashed down and broke. Luckily the mirror itself didn’t break but only its frame, so I was able to put it back together and pretend nothing happened. ;-) Never believe what you see in a photo nowadays, because Photoshop can change reality in a couple of minutes!
Before editing… (I’m sure they have replaced the mirror since)
To be honest, I think I was cursed this day. After breaking the mirror frame in the previous room, I thought I’d take a photo of the corridor with the doors of the fabulous wardrobe closed, and then opened, so clients can see the hanging etc space at their disposal.
Only, I wasn’t able to close the door after I’d opened it! Thank goodness Emma was there at the property with me so she could sort everything out after me.
Which brings me to the kitchen. First general shots of the room.
…and the teas and coffee provided for guests…
Then Emma said: “Hey, maybe you could take a photo from the window, looking down onto the outdoor area?”
Well, the window didn’t open very smoothly and easily so I asked Emma to open it. I wasn’t going to risk breaking the sash window trying to open it, given my track record of the day so far!
Nice outdoors chill-out area, though, eh?
A couple of more photos of the living / dining room.
Bathroom.
For AirB&B and other holiday let properties, it’s good to show where everything is in relation to the other rooms and floors of the house. I showed the stairs in a couple of the photos.
There was no other way to show the first stairs when entering the house other than point the camera down, which I hate doing when photographing interiors. But this is just to demonstrate that there are steps to take as soon as you enter the property. I included a tiny bit of the kitchen chair for reference so guests get an idea where everything is located.
To finish the shoot, I took a photo of the pub opposite.
…and a couple of shots of the exterior of the building.
If you’d like your holiday let property – or any other kind of dwelling for that matter – photographed, do give me a call or send a quick email. I promise not to break anything! This was the one and only time I’ve ever caused anything to break on a shoot and I’m back to my normal calm and collected self again, so you will be fine! :D
Contact details are in the footer. I look forward to hearing from you! |
Q:
I need help on plotting surface through my list of data points
I have this data which you can access through pastebin,
http://pastebin.com/6VGiR4dc
I want to draw a cone like surface through these points, which would be hollow on the inside as you could visualize.
When I used ListPointPlot3D, it looks somewhat like this
However when I try to use PointPlot3D, it gives me this weird looking surface. I also tried ListSurfacePlot3D, but that gives me an even weirder looking thing. I asked this question Yesterday, and people suggested increasing Maxpoints for surfaceplot but that didn't work either. My previous question was put on hold because it didn't have enough data. So now i've attached all data. Please help me out, Im new to mathematica...
A:
PerhapsConvexHullMesh:
ch = ConvexHullMesh[pts];
RegionPlot3D[ch, PlotStyle -> Opacity[0.5], Background -> Black,
Boxed -> False]
Show[ListPointPlot3D[pts, PlotStyle -> {Red, PointSize[0.01]},
Background -> Black, Boxed -> False],
RegionPlot3D[ch, PlotStyle -> Opacity[0.5]], Axes -> False]
|
Effect of the TP5 analogue of thymopoietin on the rejection of male skin by aged and thymectomized female mice.
Although young adult C3H/HeJ (C3H) females do not reject C3H male skin grafts, C3H females older than 1 year commonly do so, as also do many thymectomized, young adult C3H females. Therapy with TP5, a synthetic pentapeptide analogue of thymopoietin which has biological properties of the parent molecule, substantially reduced the capacity of aged C3H females and of thymectomized, young C3H females to reject C3H male skin. |
Conventionally, there is known a toilet seat covering paper feeding apparatus for setting a seat covering paper on the toilet seat hygienically such as the one disclosed in Japanese Utility Model-Laid Open Publication No. 155399/1985.
This apparatus comprises a seat covering paper roll holder for storing continuous seat covering papers arranged in such a size and shape as to be capable of covering the upper surface of the toilet seat and being taken up in a sheet form or in a folded form, a seat covering paper feeding mechanism provided with a feed roller for feeding forward the seat covering paper a predetermined length onto the upper surface of the toilet seat, and a seat covering paper cutting mechanism provided with a sharp cutting blade for cutting the rear end of the seat covering paper thus fed.
In the conventional apparatus as described above, the feeding and cutting operations of the seat covering paper are carried out by turning on an operation switch to rotate the feed roller or to elevate the cutter.
In the above construction, the cutting of the seat covering paper is carried out by shearing, namely, by slidably moving a movable blade having a sharp cutting edge or ridge relative to a fixed blade also having a sharp cutting edge or ridge.
After cutting the seat covering paper with such blades, for example, thousands of times, the cutting edges of these blades become rounded thus deteriorating the cutting performance.
Furthermore, in spite of the fact that the movable blade and the fixed blade are disposed at the rear portion of the toilet seat which is subjected to the splashing water, the movable blade and the fixed blade are both made of metal such as carbon steel to obtain the sharp cutting edges. Therefore, the cutting edges of the movable blade and the fixed blade become corroded thus deteriorating the cutting or shearing performance from this point of view as well.
For maintaining favorable cutting or shearing performance, the cutting edges of the movable blade and the fixed blade must be ground periodically. This grinding operation, however, takes considerable time and effort making the maintenance operation considerably cumbersome.
Accordingly, it is an object of the present invention to provide a toilet seat structure capable of automatically feeding a seat covering paper onto a toilet seat which can overcome the above drawbacks of the conventional apparatus, wherein the seat covering paper is torn by pressure applied onto the seat covering paper by the pressing of a press plate but not by the conventional shearing force so that the sheet tearing mechanism virtually can be set free from the maintenance for many years.
It is another object of the present invention to provide a toilet seat structure capable of automatically feeding a seat covering paper on a toilet seat which can prevent dirty water such as splashed flushing water from entering into the functional casing which accommodates various mechanisms such as the seat covering feeding mechanism and seat cover tearing mechanism or the control unit so that damage or malfunction of the mechanisms or the control device in the functional casing can be effectively prevented.
It is still another object of the present invention to provide a toilet seat structure capable of automatically feeding a seat covering paper onto a toilet seat wherein the seat covering paper feeding mechanism is incapable of feeding the seat covering paper so long as the user sits on the seat body whereby the feeding of the paper by error or mischievously can be prevented and entanglement of the seat covering paper in the casing body can be prevented.
It is a further object of the present invention to provide a toilet seat structure capable of automatically feeding a seat covering paper onto a toilet seat wherein the seat covering paper is held clamped until the user stands up from the seat body after using the toilet so that displacement of the seat covering paper or sticking of the seat covering paper to the buttocks can be prevented.
It is a still further object of the present invention to provide a toilet seat structure capable of automatically feeding a seat covering paper onto a toilet seat wherein after the seat covering paper is torn, the rear end of the seat covering paper cut is held firmly so that falling of the seat covering paper from the seat body due to a breeze can be effectively prevented and the user uses the toilet without being bothered by the falling off of the seat covering paper.
It is a still further object of the present invention to provide a toilet seat structure capable of automatically feeding a seat covering paper onto a toilet seat wherein any problems with the seat covering paper such as clogging of the seat covering paper in the functional casing or using up of the seat covering paper are effectively solved, namely, the clogged paper can be readily removed from the functional casing and a new seat covering paper roll is readily set in the functional casing.
It is a still further object of the present invention to provide a toilet seat structure capable of automatically feeding a seat covering paper onto a toilet seat wherein in case the seat covering paper fed onto the seat body is twisted or becomes wet with, splashed water so that the paper is not usable, the clamping of the seat covering paper is readily released and the seat covering paper can be readily removed from the seat body and discarded into the toilet bowl so that a fresh seat covering paper can be fed onto the seat body to facilitate the usability of the toilet.
It is a still further object of the present invention to provide a toilet seat structure capable of automatically feeding a seat covering paper onto a toilet seat wherein when the seat covering paper roll cover is to be opened for replacement of the seat covering paper roll or for the removal of clogged seat covering paper, the power source is turned off so as to stop the operation of all the mechanisms in the functional casing, whereby the paper roll replacement operation or the removal of the clogged paper can be readily carried out.
In summary, the present invention discloses a toilet seat structure capable of automatically feeding a seat covering paper onto a toilet seat comprising (a) a seat covering paper roll in a seat covering paper roll protection cover disposed at the rear of a toilet seat body, (b) a seat covering paper feeding mechanism for feeding a seat covering paper from the seat covering paper roll to the upper surface of the seat body, (c) a seat covering paper tearing mechanism for tearing the seat covering paper after delivery, and (d) a control unit for controlling the seat covering paper tearing mechanism, wherein the improvement is characterized in that the toilet seat structure further comprises tension applying means for applying tension to the seat covering paper and the seat covering paper tearing mechanism comprises a press plate which is capable of applying pressure on the tensioned seat covering paper for tearing the seat covering paper.
In the above construction, for facilitating the tearing of the seat covering paper, the seat covering paper may preferably be provided with a plurality of breaking lines each of which is made of a multiplicity of small perforations formed continuously and transversely on the entire width of the seat covering paper.
Due to such construction, the present invention has the following advantages.
(1) Without using the shearing force exerted by the sliding movement of a movable blade relative to a fixed blade, the seat covering paper is torn by a pressure applied by the press plate on and along the breaking lines disposed at regular intervals on the seat covering paper.
Accordingly, the tearing edge of the press plate can be formed in a round shape so that the wear of the tearing edge which is generated through the tearing operation can be minimized whereby maintenance or repairing can be also minimized.
(2) Without using the shearing force exerted by sliding movement of a movable blade relative to a fixed blade, the seat covering paper is cut by pressure applied by the press plate on and along the breaking lines disposed at regular intervals on the seat covering paper.
Accordingly, the tearing edge of the press plate can be formed in a round shape and the press plate can be made of plastics or ceramics which do not corrode. Therefore, the prevention of the occurrence of wear of the tearing edge can be promoted whereby maintenance or repairing can be further minimized. |
Universidade Luterana do Brasil
The Universidade Luterana do Brasil (ULBRA or Ulbra; Lutheran University of Brazil) is a university which covers several states throughout Brazil.
History
The Lutheran University of Brazil (ULBRA) has its roots in the parish school of the St. Paul's Lutheran Church of Canoas (CELSP), in Canoas, Rio Grande do Sul, founded in 1911. The first impulse towards the University was the creation of the Cristo Redentor College, in 1969 under the direction of Reverend Ruben Eugen Becker.
In March 1972, in an effort to expand its education in higher education, the Evangelical Lutheran Community of São Paulo founded an Administration College with fifty vacancies. In 1974, the Federal Council of Education authorized the operation of the Canoas Colleges.
In January 1988, the President of Brazil, José Sarney, allowed the creation of the Lutheran University of Brazil.
Campuses
The university's headquarters is located in the city of Canoas, in the state of Rio Grande do Sul (the southernmost province of Brazil). Within this state, Ulbra also has campuses in the cities of Cachoeira do Sul, Carazinho, Gravataí, Guaíba, Porto Alegre, Santa Maria, São Jerônimo and Torres. Apart from these cities, the university also has campuses in the states of Amazonas (Manaus), Goiás (Itumbiara), Pará (Santarém), Rondônia (Ji-Paraná and Porto Velho), Tocantins (Palmas) and in the state of São Paulo.
Academics
Ulbra offers several majors, including medicine, which the university became entitled to offer after building its hospital, located within the university premises and currently serving the community of Canoas and neighbouring cities.
Athletics
The university has a football team that plays in the first division of the Campeonato Gaúcho, as well as having teams participate in many sports tournaments, including volleyball, basketball, Judo and Athletics. As of 2007, Sport Club Ulbra have contested the Campeonato Brasileiro Third Division for the fourth time in a row, but have not been successful in their attempts towards promotion.
Automobile museum
They also maintained one of the largest Museums of Technology, which had a collection of cars with more than 200 vehicles. From Ford T to 2000 Corvette, even an Indy car piloted by Emerson Fittipaldi when he won Indianapolis 500 and its pace car. In 2009, due to the university's financial problems, the museum was closed and had its collection auctioned by Justice. Currently, the Museum of Technology building houses the studios of Ulbra TV (a local educational TV station affiliated to TV Cultura), and Radio Mix FM 107.1.
External links
Official Website (in Portuguese)
Category:Lutheran universities and colleges
Category:Educational institutions established in 1972
Category:1972 establishments in Brazil
Category:Universities and colleges in Rio Grande do Sul
Category:Christian universities and colleges in Brazil
Category:Canoas |
Les Carabins de l’Université de Montréal commencent à avoir pas mal d’expérience dans les fins de match à la Hollywood. Et ils ont prouvé samedi qu’ils n’étaient pas encore à court de scénarios avec une conquête in extremis de la coupe Dunsmore, une deuxième de suite face au Rouge et Or de l’Université Laval.
Il aura fallu attendre le dernier jeu du match pour connaître le vainqueur. Avec à peine quelques secondes à écouler, le Rouge et Or pouvait l’emporter avec un placement. Mais Junior Luke a levé la main gauche et a réussi à bloquer le ballon. Du coup, il concrétisait la victoire des siens, au compte de 18-16, et anéantissait les espoirs d’une équipe entière et de plus de 12 000 spectateurs.
Les Carabins se dirigeront maintenant à Guelph pour y affronter les Gryphons à la Coupe Mitchell, samedi prochain.
C’est un véritable match rempli d’émotions que nous ont offert les deux meilleures équipes du football universitaire canadien.
«Je suis un amateur de montagnes russes, mais un peu moins au football! Je suis juste content qu’on ait fini en haut et non en bas», a dit le quart Gabriel Cousineau, ajoutant à la blague qu’avec toutes ces fins dramatiques, il allait avoir l’impression d’avoir 45 ans et non 25 à la fin de sa carrière.
Remontée des locaux
Le Rouge et Or, qui voulait venger sa défaite de l’an dernier, a réussi à effacer un déficit de 15 points en deuxième demie, grâce à deux touchés rapides et un converti de deux points, pour porter le score à 16-16.
Le vent avait semblé changer de bord. La foule était de retour dans le match et le quart Hugo Richard avait retrouvé sa confiance.
Mais du côté des Carabins, personne n’a cédé à la panique. Même quand le Rouge et Or a repris le ballon la ligne de 34 en zone après un mauvais botté de dégagement et une pénalité pour rudesse.
Il y avait du danger pour la troupe de Danny Maciocia, mais Maïko Zepeda a fait perdre le ballon à Maxime Boutin et les Carabins l’ont recouvré.
L’égalité a donc persisté jusqu’à la 10e minute du dernier quart. Les deux points qui ont fait la différence à la toute fin ont toutefois été obtenus sur des placements ratés de Louis-Philippe Simoneau. Ce dernier a encore fait preuve d’inconstance, avec trois réussites et autant de tentatives ratées.
Des occasions manquées
À la mi-temps, les Carabins menaient 9-1, mais leur avance aurait pu être bien plus grande s’ils n’avaient pas dû se contenter de placements à chaque fois qu’ils se sont retrouvés dans la zone payante.
Cousineau a bien failli marquer lui-même un touché, mais il a glissé à cinq verges de la ligne des buts après avoir été accroché par un adversaire.
Le botteur Louis-Philippe Simoneau, qui affichait un faible taux de réussite de 61,9% avant la rencontre a raté un 10e placement cette saison, alors que le ballon a donné contre le poteau gauche à sa première tentative de la journée.
Les «Bleus» auraient aussi pu profiter davantage des revirements créés par leur unité défensive. Ils n’ont entre autres rien fait après les deux interceptions réussies par Zackary Alexis.
Solide en défense
Les deux défenses ont réussi de gros jeux. Celle du Rouge et Or a été particulièrement agressive, avec cinq sacs du quart, dont quatre en première demie.
L’attaque des Carabins a même dû s’ajuster à mi-chemin dans le match, car le Rouge et Or a commencé à trouver des solutions pour contrer leur jeu aérien.
«On a réussi à lancer pas mal en première demie et ils se sont s’ajustés en deuxième. Les trous n’étaient plus là, mais ç’a ouvert le jeu au sol. La ligne à l’attaque a fait un boulot incroyable pour Sean [Thomas Erlignton] et Gabriel [Parent] qui ont réussi à faire les gros jeux», a noté Cousineau. |
Tag Archives: Walking
A regular walking routine can lower blood pressure, stave off diabetes, and prevent heart disease. Finding walking buddies, using a pedometer, and following a walking workout plan may help people stick to a program.
Walking is a low-impact, do-anywhere exercise that helps lower blood pressure and stave off diabetes. And two large, long-term Harvard studies suggest that walking for about 20 minutes a day may cut the risk of heart disease by as much as 30%, according to the December 2015 Harvard Heart Letter.
But many people need some added inspiration to start — and stick with — a walking program. One of the best ways is to find walking buddies, says Dr. Lauren Elson, physical medicine and rehabilitation instructor at Harvard Medical School. “I find that if I can get someone to walk with — a partner, a spouse, or a friend — that helps a lot.” Even better is getting several friends to walk together, because they all hold each other accountable. “They call each other up and say, ‘Where are you?’” Dr. Elson says.
Other people find motivation by using a pedometer to track their steps and distance, says Dr. Elson. One review of 26 studies found that people who used pedometers raised their physical activity levels by nearly 27%, adding about 2,500 steps a day. Most stores that sell exercise equipment have inexpensive pedometers. Other options include smartphone apps that track steps, such as Moves, Breeze, or Pedometer++.
For people who’ve had a heart attack or been diagnosed with heart disease, walking is an ideal exercise because it can be easily adapted based on a person’s fitness level. People with heart failure should ask their physician to recommend a cardiac rehabilitation program to safely reap the benefits of exercise. This type of supervised exercise is particularly helpful for people who haven’t been active for a while.
Read the full-length article: “Marching orders: How to start a walking program”
Also in the November 2015 issue of the Harvard Heart Letter:
* Cardiac rehabilitation: Best medicine for recovery
* Heart-friendly holiday eating
* When blood pressure dips too low
The Harvard Heart Letter is available from Harvard Health Publications, the publishing division of Harvard Medical School, for $20 per year. Subscribe at http://www.health.harvard.edu/heart or by calling 877-649-9457 (toll-free).
Getting out and about with your loved ones is certainly a fantastic experience. This is even more so when you plan on trekking through the wilderness for days on end, enjoying some of the finest sights that nature can provide. As well as experiencing some amazing vistas, you’ll also keep fit and active, bonding with your loved ones in a manner that brings everyone together. Of course, you’ll need to plan your journey in the right way, especially since you’ll have to take care of your family in remote locations away from standard facilities. Here, we’ll look at a few of the most important aspects to consider when preparing for your next walking holiday.
Is the Route Suitable?
Since you’ll want to make the upcoming trekking adventure as enjoyable as possible, you’ll also need to think about your family’s physical capabilities as well as the type of outdoor gear you own. In this regard, you’ll need to choose a route that matches their exercise level. When researching nearby trails, keep an eye on the following characteristics:
If you’re going on your first walking holiday, choose a path that’s relatively flat and that has a well-marked path. This will help remove most of the hurdles, giving you a simple holiday itinerary that each member of your family can enjoy regardless of their fitness ability.
Do You Have the Right Gear?
Now, you’ll need to prepare your loved ones for the forthcoming journey by supplying them with the necessary gear. If you’re spending a few nights in the wilderness, you’ll need a decent tent, some cooking supplies, and the right bathing necessities to make a comfortable journey in which everyone can enjoy themselves significantly. You’ll also need to think about the clothing that you bring along. Avoid purchasing anything too cheap as this won’t be durable enough for the expedition.
Is Your Family Prepared?
Now that you’ve got the right equipment, you’ll have to hone your loved one’s physical capabilities to get through the upcoming walking holiday with ease. After all, if you just spend your time in front of the television, going on a three-day trek with no fitness preparation is a recipe for disaster. This means that you should plan an exercise routine before you depart to build up your loved ones’ fitness levels. You can do this by putting on your walking gear and heading to the park every weekend. Start by trekking to the maximum limit possible and then build up the duration slowly each time that you and your family practise your walking after that.
What Belongings Do You Need?
Now, you’ll need to think about what you should take along with you on your next wilderness adventure. You’ve bought your clothing and accessories, but you should also think about other items as well. Some of the most important include:
Depending on where you’re going, you’ll need different items for your adventure. For example, those walking through villages might be able to stay in a local motel instead of a tent. Likewise, if you’re passing a river, lake or waterfall, you should bring along some swimming gear, towels and sunscreen so you and the family can cool down along the way.
– Danielle Steele represents Trekwear, a company based in the United Kingdom that offers clothing and merchandise for skiing, running, and cycling. Find out more of the products such as walking sandals available from Trekwear on their website.
• They spend larger than average amounts of time in sedentary situations such as sitting in aircraft, vehicles, restaurants, and bars;
• They are likely to suffer from more stress and poorer sleep owing to time zone changes and extended work hours;
• Their diets may suffer owing to the temptation to increase intake of comfort foods;
• They are deprived of many of their regular fitness generating activities, including their sports partners, sporting and social clubs, family members, and local team activities.
One of the few fitness fallbacks that travelers have is the hotel gym. However, the average hotel gym is not a particularly attractive place – often hot and stuffy, with less equipment than one would like, and not quite the right companions. Such factors typically cause hotel guests to spend less time in the gym than they really should to maintain fitness.
Some travel advisers advocate exercising in the hotel room but that idea is of little help. Any trainer will confirm that a good exercise session demands breaking a sweat, which is simply not practical in the hotel room. Any hotel room activity that approaches an adequate workout will unquestionably cause more of an annoyance to neighboring room guests than it provides benefit to the person exercising.
Why Not Just Run?
There is one activity that can keep a traveler fit, while increasing wellness generally – running (or jogging or athletic walking) outdoors. This activity is very efficient, requires carrying only a pair of running shoes, shirt, and shorts, is invigorating in fresh air and a new environment, can be done alone or with company, and is very inexpensive. In fact, there are so many good qualities one might wonder why more travelers do not systematically run outdoors in places they visit.
The resistance to running outdoors stems mainly from concerns about possible security risks, possible road traffic incursions, and other unknowns that might lead to some form of unpleasantness.
But all cities have some places where one can run with other runners around and without substantial concerns of the above type.
Plan Your Routes Wisely
A traveler needs solid, reliable information to help make an on-foot outing a truly enjoyable experience. This will motivate the traveler to actually venture out. Here are some general factors that combine to make an on-foot route irresistible:
• Good underfoot conditions;
• A “good” neighborhood; nasty surprises are unlikely;
• Not too many other people and not too few;
• Minimal disruptions from intersecting auto roads;
• Pretty scenery; interesting sites to pass along the way;
• Public transit to the start and finish points;
• A loop route is more enjoyable than an out-and-back route;
• A suitable place to wind down for a refreshing beverage or snack at the end.
Taking into account all the above requirements, plan your routes wisely. Ask your local hotel staff for route recommendations but treat their recommendations cautiously since many staff members have limited first-hand knowledge of running or walking conditions. More importantly, buy and consult a good local runners’ guidebook or map.
When in an unfamiliar city, get outdoors and run or walk as much as you can. Plan your routes well. You can find this activity enormously enjoyable, educational, and great for your fitness.
– Warwick Ford, a marathon runner, was a frequent business traveler before retiring as a corporate executive. He and his wife Nola have personally researched the top running and walking routes in many major US cities. Their book Fun on Foot in America’s Cities describes the running conditions and most visitor-friendly routes in 14 major US cities. They also have detailed running/walking guide books on the Boston, New York City, and Philadelphia regions. Their books and much other relevant information are available from their website www.funonfoot.com.
From Your Health Journal…..”A great article I wanted to share and plug today from the Green Bay Gazette written by Patti Zarling entitled Walking to school said to improve kids’ studies. In a day and age where many experts are worried that this generation of children could be the first to have a shorter life expectancy than their parents, it is refreshing to read an article that not only promotes physical activity, but improving cognitive skills. So many children have become sedentary in the technological era – where they play on the laptops or video games rather than play outside. The definition of play has truly changed over the last decade. So many children take a bus to school, whereas many years ago, so many children walked or biked to school. Times have certainly changed. But, effort needs to be made to make change in the daily routine of children, and bring back some of those ‘lost arts’ ‘ which include physical activity. Walking to school on a regular basis is one such change that can make a difference in a child’s life. Not only will it improve them physically, but also cognitively. Even if you live far from the school, possibly go for a morning walk with your child before the bus arrives. Please visit the Green Bay Gazette web site (link provided below) to read the complete article. It was well written and informative.”
From the article…..
Walking and biking to school can not only help prevent childhood obesity, but that physical activity also can help students do well in class, a local health advocate says.
The federal Centers for Disease Control and Prevention says kids should get at least 60 minutes of exercise a day. But surveys show 30 percent of high school-aged students in Wisconsin don’t get that, according to Melinda Morella, community engagement specialist for Live54218, a nonprofit that promotes healthy lifestyles in Brown County.
She noted that since the 1960s the number of kids who walk to school has decreased by about 50 percent.
“At the same time we’re seeing obesity rates go up,” Morella said. “This is something to be concerned about.”
According to the CDC, obesity has more than doubled in children and tripled in adolescents nationwide in the past 30 years.
The percentage of 6- to 11-year-olds in the U.S. who were obese increased from 7 percent in 1980 to nearly 18 percent in 2010, the most recent figures available. The percentage of adolescents who were obese increased from 5 percent to 18 percent in the same time period.
The federal agency found that more than one third of children and adolescents were overweight or obese in 2010.
Exercise can help combat that and young people who walk or bike to school automatically build physical activity into their day, Morella said.
From Your Health Journal…..”I found such a great article today online from ‘Wicked Local – Norton’ by Harry Chase, that I had to promote and share it here. I hope all of you visit the Wicked Local web site (link provided below) to read the complete story. Mr. Chase starts the article by discussing a change he has noticed over the years, where children do not walk to school anymore, rather – many are taking the bus or in the family car. Mr. Chase reminisces on how he used to walk miles to school every day, how nobody took a bus. Mr. Chase continues to discuss the amount of homework kids get these days – which reduces the play time outside. He points out how childhood obesity is on the rise, and many children suffer from heart disease, cancer, type 2 diabetes, weak bones, and low self-esteem. This article brought a smile to my face, as I found it very refreshing. I provided a short snip below, but please visit the Wicked Local site to read the complete article.”
From the article…..
The most obvious difference between schoolchildren in the present iPhone age and in the Neanderthal era when I attended classes is that I almost never see today’s kids walking to school.
As early as 6:45 a.m., while I’m doing my daily exercises, I see from my bedroom window the school buses rolling past, accumulating long lines of vehicles behind them as they stop every 200 yards to pick up pupils.
Some parents turn up their noses at buses and add to the traffic by chauffeuring their youngsters to school in the family car.
In my boyhood, when Mansfield had 10 schoolhouses and no buses, every child lived within 11/2-mile walking distance of an elementary school. Multiply that mileage by four, because we came home for dinner (as lunch was called).
Beginning at age 5, when I entered first grade, I hiked 20 miles weekly to and from Roland Green School on Dean Street. By second grade I ran it. I think this exercise has worked in my favor all the rest of my life.
It’s true that many if not most kids today don’t live within walking distance of their schools. And without question, buses are better than the old inefficient one-room one-teacher neighborhood schoolhouses.
Yet does anyone ever think that maybe – just maybe — the rate of childhood obesity, which in the U.S. has more than tripled in the last 30 years, might somehow be related to the fact that children no longer walk (or run) to school?
Another difference between school kids then and now is that these days even small fry await their buses loaded like Grand Canyon pack mules with knapsacks almost as big as themselves. I assume the packs carry homework. We had no homework until seventh grade and that usually consisted of one or two books easily toted in the hand. |
NEW YORK (CNNMoney.com) -- The Federal Reserve and Treasury Department on Tuesday unveiled a plan to pump $800 billion into the struggling U.S. economy in an attempt to jumpstart lending by banks to consumers and small businesses.
The government hopes that these initiatives will enable more money to flow to consumers in the form of loans than has occurred so far in previous bailout plans.
One program will make $200 billion available from the Federal Reserve Bank of New York to holders of securities backed by consumer debt, such as credit cards, car loans and student loans.
The Treasury Department will allocate $20 billion to back that lending in order to cover any losses that the New York Fed might suffer.
In addition, the Federal Reserve, announced it will purchase up to $500 billion in mortgage backed securities that have been backed by Fannie Mae (FNM, Fortune 500), Freddie Mac (FRE, Fortune 500) and Ginnie Mae, the three government-sponsored mortgage finance firms set up to promote home ownership. It will also buy another $100 billion in direct debt issued by those firms.
Together, the programs from the Federal Reserve and the New York Fed are more than Congress approved in October for a bailout of the nation's banks and Wall Street firms. The Fed said the money will come from an increase in its reserves -- in essence, it is creating new money.
The idea is that by making money available for investors who are interested in buying loans bundled together into securities, it will be easier and more profitable for banks to loan money to consumers and small businesses.
Before the current credit crisis, lenders got the money they needed to extend credit by selling the loans they had already made. But the Treasury Department said the issuance of those securities essentially came to a halt in October.
Still, previous efforts to pump money directly into financial institutions have done relatively little to expand credit available for consumers, and some economists said it was not immediately clear if this money would flow through to households as planned.
"It's certainly not directly going to go through to the consumers. I don't know if anyone can say how much will get through," said Keith Hembre, chief economist at First American Funds. "It certainly shouldn't hurt. We'll have to see how much it does help."
To that end, government officials said that they would not set up the $200 billion consumer lending program until February. So officials couldn't say if the mere announcement of the program would cause lenders to make more credit available to consumers in time for the holiday shopping season.
Paulson described the $200 billion consumer lending program as a first step, one that could be expanded later to include different kinds of debt, including assets backed by commercial real estate mortgages and business debt.
He said the fact that the Fed and Treasury had to work together to get an additional $800 billion into the system is not a sign that the $700 billion bailout of banks and Wall Street firms passed by Congress last month has been a failure. He said that, without that program, it is likely that the financial markets would be in even worse shape than they are today.
"I wish, and I know everybody wishes, that one piece of legislation, and then magically the credit markets would unfreeze," he said. "That's not the type of situation we're dealing with."
The fact that the New York Fed is taking the lead on the consumer lending program means that the man nominated by President-elect Obama to succeed Paulson, New York Fed President Timothy Geithner, played a central role in this new effort.
But Paulson said this is not a sign that the Bush administration is letting the new administration call the shots on further efforts to revive the economy.
How it may affect mortgages
The larger part of the new program is geared toward ending the mortgage crisis, which was the original intent of the bank bailout plan proposed in September and signed into law in October.
That plan, known as the Troubled Asset Relief Program, or TARP, was quickly dropped for one in which Treasury instead made direct capital investments in banks in return for the government receiving preferred shares in the institutions getting funds.
This new program is much closer to the planned bailout. But government officials stressed that this new plan is different from TARP in that only mortgage securities backed by Fannie, Freddie and Ginnie Mae will be in the new program.
The loans being backed by the new program, for the most part, are of better quality than many of the troubled assets that would have been purchased under the original TARP plan.
"This action is being taken to reduce the cost and increase the availability of credit for the purchase of houses, which in turn should support housing markets and foster improved conditions in financial markets more generally," the Fed said in a statement.
There is also limited additional risk for the federal government from the Fed buying that $600 billion in debt from the three firms, since the government is already on the hook for losses those firms suffer on the loans they back.
Despite that implicit government guarantee behind Fannie and Freddie's debt, there gap between rates for U.S. Treasurys and the rates for mortgage assets continues to widen.
But with the Fed buying such a large amount of mortgage assets directly, the hope is that this will narrow that gap and drive down mortgage rates.
The Treasury, which oversees the $700 billion in the TARP program, has been reluctant to expand the use of those funds beyond direct capital investments in banks, despite request to use the funds to help out insurance companies and even the nation's automakers.
The moves came as the Commerce Department announced that gross domestic product, the broadest measure of economic activity, fell at an annual rate of 0.5% in the third quarter.
That was the biggest drop in seven years and economists believe that the economy will decline further in the current quarter and into early next year. |
INTRODUCTION {#S1}
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Human pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), can be propagated almost indefinitely and can give rise to all cell types of the body ([@R29]; [@R30]; [@R34]; [@R42]). Because of these properties, human PSCs areanexcellent systemto study cellular differentiation in normal and diseased states, with potential far-reaching implications in regenerative medicine. Unlike mouse ESCs ([@R9]; [@R18]), which are isolated from the inner cell mass (ICM) of blastocysts and can be preserved in vitro in a naive ICM-like state, human ESCs and iPSCs are in a so-called "primed" pluripotent state that resembles the post-implantation epiblast ([@R22]). The derivation and characterization of human naive PSCs is of significant interest for the following reasons: (1) they are expected to have an elevated growth rate and efficient clonal growth from single cells, relative to human primed PSCs; (2) this higher ease of culture is anticipated to facilitate genome engineering using homologous recombination, transcription activator-like effector nucleases (TALENs), or clustered regularly interspaced short palindromic repeat (CRISPR) approaches ([@R14]); and (3) naive PSCs provide an opportunity to dissect the regulation of otherwise inaccessible stages of human embryology.
It has been suggested that the ability to maintain mouse cells in a naive state may be possible because mouse blastocysts can enter a dormant state called diapause, where development is suspended for days to weeks while the uterine environment is unfavorable ([@R23]). Given that human embryos do not undergo diapause, it remained unclear whether the transcriptional circuitry to sustain the naive state is present in human cells. However, as early as 2009, several groups reported conditions that allowed the derivation of human cells in alternative pluripotent states with some features of the mouse naive state, although the cells carried transgenes and could not be maintained long term ([@R3]; [@R13]; [@R16]). Subsequently, different panels of growth factors and small molecules that could promote maintenance of transgene-free human naive-like PSCs were described ([@R6]; [@R10]; [@R37]). These methods were often not straightforward to implement in different human PSCs, and subsequent studies questioned the extent to which the cells derived approached the naive state ([@R31]; [@R33]). [@R33] used a systematic approach to identify small molecules that support maintenance of naive-like human ESCs induced by overexpression of NANOG and KLF2. The authors successfully identified a combination that can induce and maintain OCT4 distal enhancer (DE) activity, a key criterion of mouse naive pluripotency, even in the absence of transgene induction. However, these transgene-free cells have a slow growth rate, and their long-term karyotypic stability was not assessed. [@R31] also used overexpression of NANOG and KLF2 to trigger the transcriptional circuitry of naive pluripotency in human cells, and they observed that optimal cell growth requires transgene induction. These recent studies lend encouragement to the notion that the naive pluripotent state may indeed be achieved in human cells, although it may be less stable than in mouse cells, and they pave the way for the identification of novel factors and culture conditions that may contribute to stabilization of human naive PSCs.
The Hippo pathway is emerging as a major regulator of stem cells and organ growth, and its dysfunction is common in several types of cancer ([@R20]). We previously found that Yes-associated protein (YAP), a signaling and transcriptional effector that is inhibited by the Hippo pathway, is upregulated in multiple mouse stem and progenitor cells, including ESCs ([@R28]). Recent studies from our lab in human iPSCs, including an analysis of Hippo signaling ([@R26]) and a genome-wide RNAi screen ([@R27]), revealed that the Hippo pathway is a barrier to reprogramming to pluripotency. The divergent roles of the Hippo pathway in mouse versus human PSCs suggested to us that YAP may regulate human naive pluripotency ([@R26]).
We report here that YAP overexpression in human ESCs and iPSCs promotes the generation of naive PSCs. YAP-induced naive PSCs (Yin-PSCs) are capable of rapid growth long term with a stable karyotype; have a transcriptional profile, heterochromatin levels, and the activity of the OCT4 DE typical of the naive state; and form teratomas containing tissues from all three germ layers. YAP overexpression can be mimicked by supplementing the culture medium with lysophosphatidic acid (LPA), a small molecule inhibitor of the Hippo pathway and an activator of YAP ([@R41]). Our data suggest that YAP and LPA contribute to maintenance of naive pluripotency in part by suppressing differentiation-inducing effects of GSK3 inhibition. Moreover, *YAP*^−/−^ human ESCs have an impaired ability to form naive colonies.
RESULTS {#S2}
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YAP Overexpression in Human ESCs and iPSCs Promotes a Naive State {#S3}
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Our previous work ([@R26]) raised the possibility that YAP might regulate human naive pluripotency, but available data from mouse studies do not support such a role. In mice, Yap has been reported to be excluded from the nucleus of ICM cells and has been implicated in trophectoderm development ([@R24]). We therefore analyzed YAP expression in human blastocysts by single-cell qRT-PCR and immunofluorescence. Interestingly, we found that YAP mRNA is upregulated in the epiblast of the blastocyst and that YAP protein is localized to the nucleus in both the ICM and the trophectoderm ([Figures 1A](#F1){ref-type="fig"}, [S1A, and S1B](#SD1){ref-type="supplementary-material"}). The nuclear distribution of YAP is distinct in these two cell populations, with a diffuse pattern in the ICM and a more heterogeneous pattern in the trophectoderm ([Figures S1A](#SD1){ref-type="supplementary-material"} and [S1B](#SD1){ref-type="supplementary-material"}). These data suggest that YAP may play an unanticipated role in human naive pluripotency in vivo.
We set out to test the role of YAP in human naive pluripotency. In our initial attempts to generate putative human naive PSCs, we transferred regular primed H9 ESCs, routinely cultured in DF12+bFGF, into serum-free N2B27-based medium supplemented with ERK inhibitor (PD0325901), GSK3 inhibitor (CHIR99021), Forskolin and human LIF (N2B27+2iFL). This is essentially the 2i medium used for culture of mouse naive PSCs ([@R40]), with the addition of the adenylyl cyclase activator Forskolin, because both our unpublished results and other published findings ([@R13]) suggested that the cyclic AMP pathway may facilitate survival of naive-like cells. Under these culture conditions, however, H9 cells rapidly differentiate and completely lose expression of the pluripotency marker alkaline phosphatase (AP) within four passages ([Figure 1B](#F1){ref-type="fig"}). We next investigated the ability of YAP to induce the naive state. We generated H9 cells overexpressing YAP in primed conditions and tested their ability to grow in the N2B27+2iFL medium, with trypsinization to single cells at every passage. Control empty-vector lentiviral infection has no effect on the transition of H9 cells to naive conditions (data not shown). Strikingly, YAP overexpression abolishes the differentiationinducing effect of the N2B27+2iFL medium, and the cells retain strong expression of AP ([Figure 1B](#F1){ref-type="fig"}). After three passages in N2B27+2iFL, the cells begin to show an elevated clonal growth rate, and they propagate readily in culture with a naive-specific dome-like colony morphology for more than 70 passages ([Figure 1C](#F1){ref-type="fig"}). Moreover, they express pluripotency markers including SSEA3, SSEA4, TRA-1-60, TRA-1-81, OCT4, and NANOG ([Figures 1C](#F1){ref-type="fig"} and [S1C](#SD1){ref-type="supplementary-material"}). Compared with H9 and H9-YAP cells cultured in primed conditions, H9-YAP cells in N2B27+2iFL have drastically increased clonal growth after trypsinization to single cells ([Figure 1D](#F1){ref-type="fig"}), with split ratios of about 1:50 every 3 to 5 days. These cells, which we call Yin-PSCs, maintain a stable karyotype ([Figure 1E](#F1){ref-type="fig"}) and form teratomas containing tissues from all three germ layers after injection into immune-deficient mice ([Figure 1F](#F1){ref-type="fig"}).
We next investigated whether Yin-PSCs can be derived using ESC lines other than H9, which is female, or using iPSCs. A male human ESC line (H1) and a female iPSC line derived from lung fibroblasts (IMR-90) were used for further studies. Similar to the procedure described earlier, we transferred H1-YAP and IMR-90 iPSC-YAP cells into the N2B27+2iFL medium and trypsinized them to single cells at each passage. Unlike H9-YAP, however, H1-YAP and IMR-90 iPSC-YAP cells in N2B27+2iFL differentiated after several passages (data not shown). These results indicate that different PSCs respond differently to the transition to naive conditions and that H9 cells may be particularly capable of making this transition. Consequently, we explored alternatives to the N2B27+2iFL medium, which was optimized for mouse naive PSCs. The mTeSR medium was specifically developed for culture of human PSCs ([@R17]) and has been widely used. We therefore tested mTeSR as the base medium, instead of N2B27. The mTeSR+2iFL medium allowed for the expansion of H1-YAP and IMR-90 iPSC-YAP cells with naive morphology and growth rates for at least passage 17 (H1-YAP) and 22 (IMR-90 iPSC-YAP) to date. Similar to H9-YAP in N2B27+2iFL, H1-YAP and IMR-90 iPSC-YAP cells grown in mTeSR+2iFL express pluripotency markers including SSEA3, SSEA4, and TRA-1-81 ([Figures S1D](#SD1){ref-type="supplementary-material"} and [S1E](#SD1){ref-type="supplementary-material"}); have normal karyotypes ([Figures S1F](#SD1){ref-type="supplementary-material"} and [S1G](#SD1){ref-type="supplementary-material"}); and form teratomas containing tissues from all three germ layers ([Figures S1H](#SD1){ref-type="supplementary-material"} and [S1I](#SD1){ref-type="supplementary-material"}). Moreover, mTeSR+2iFL medium also allows the generation of Yin-PSCs from H9 ESCs (see Figure 3), WIBR3 female ESCs (see Figure 4), and iPSCs derived from male BJ fibroblasts (data not shown). Thus, YAP overexpression promotes the generation of naive PSCs from multiple male and female human ESC and iPSC lines.
LPA Activates YAP and Promotes Generation of Transgene-free Human Naive PSCs {#S4}
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We next sought small molecules that would have effects similar to YAP overexpression to avoid the need for transgenes in the induction of the naive state. Toward this end, we explored existing data on the regulation of the Hippo pathway in other cellular contexts. The Hippo pathway kinases LATS1 and LATS2 phosphorylate YAP and lead to its degradation by the proteasome ([@R20]). Serum-borne LPA has been shown to act via Gα12/13-coupled receptors to inhibit LATS1/2, thereby leading to the activation of YAP in human transformed cell lines ([@R41]). In agreement with these findings, we found that adding LPA to H9 cells leads to an increase in the levels of YAP ([Figures 2A](#F2){ref-type="fig"} and [2B](#F2){ref-type="fig"}), although these levels are much lower compared with lentiviral YAP overexpression ([Figure S2A](#SD1){ref-type="supplementary-material"}). We transferred H9 cells to mTeSR+2iFL naive medium containing LPA and trypsinized them to single cells at each passage. In the presence of LPA, H9 cells adopt a domed-colony morphology similar to Yin-PSCs ([Figure 2C](#F2){ref-type="fig"}), express pluripotency markers ([Figure 2C](#F2){ref-type="fig"}), maintain a stable karyotype ([Figure S2B](#SD1){ref-type="supplementary-material"}), and are capable of giving rise to teratomas containing tissues from all three germ layers ([Figure 2D](#F2){ref-type="fig"}). LPA-induced naive PSCs (Lin-PSCs) have an elevated expansion rate, albeit lower than that of Yin-PSCs: they can be passaged at a 1:10 split ratio every 3 to 5 days for at least 20 passages to date. We were also able to derive Lin-PSCs from WIBR3 human ESCs (see Figure 3). In summary, transgene-free human naive PSCs can be generated using LPA to activate YAP.
Yin-PSCs and Lin-PSCs Have a Naive-Associated Transcriptional Profile Distinct from that of Primed PSCs {#S5}
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We characterized the transcriptional profiles of Yin-PSCs and Lin-PSCs and compared them to those of primed PSCs using Illumina microarrays. We analyzed H9 ESCs, H1 ESCs, and IMR-90 iPSCs cultured in primed (DF12+bFGF) medium; H9-YAP, H1-YAP, and IMR-90 iPSC-YAP cells cultured in primed medium; H9-YAP cultured in N2B27+2iFL naive medium; H9-YAP, H1-YAP, and IMR-90 iPSC-YAP cells cultured in mTeSR+2iFL naive medium; and H9 and WIBR3 cultured in mTeSR+2iFL+LPA. Pearson correlation analysis revealed that naive and primed PSCs represent two groups with distinct transcriptional profiles ([Figure 3A](#F3){ref-type="fig"}). Principal-component analysis confirmed that all six naive PSCs cluster together and are separated from the other six primed cell lines along PC1 ([Figure S3A](#SD1){ref-type="supplementary-material"}).
We next sought to identify the sets of genes that account for the distinct profiles of naive and primed PSCs. In Yin-PSCs and Lin-PSCs, 350 genes are upregulated with Log~2~ fold change (FC) \> 0.7 and p \< 0.05 ([Data S1](#SD1){ref-type="supplementary-material"}). These genes are enriched for functions in gastrulation, embryonic morphogenesis, formation of primary germ layers, and transforming growth factor β (TGF-β) signaling ([Figure S3B; Data S2](#SD1){ref-type="supplementary-material"}). Surprisingly, genes related to sterol and cholesterol biosynthesis are also highly enriched in this gene set ([Figure S3B; Data S2](#SD1){ref-type="supplementary-material"}; also see below). Conversely, 510 genes are downregulated in naive cells ([Data S1](#SD1){ref-type="supplementary-material"}). These genes are associated with functions in plasma membrane, cell motion, and positive regulation of differentiation ([Figure S3C; Data S3](#SD1){ref-type="supplementary-material"}).
A recent study ([@R15]) documents that among several alternate human PSCs, two studies ([@R31]; [@R33]) stand out as representing naive cells with similarities to human pre-implantation embryos. To directly compare the overall transcriptional profiles of Yin-PSCs and Lin-PSCs to those two studies, we used gene set enrichment analysis (GSEA). This analysis revealed that genes upregulated in naive PSCs derived by the Jaenisch group ([@R33]) or the Smith group ([@R31]) are also coordinately upregulated in Yin-PSCs and Lin-PSCs ([Figure 3B](#F3){ref-type="fig"}). The same pattern of similarity to the other two studies is observed for genes downregulated in naive PSCs ([Figure S3D](#SD1){ref-type="supplementary-material"}).
We next used qRT-PCR to assess the expression levels of specific markers associated with naive pluripotency. We chose to test the expression of NANOG, OCT4, and REX1, which are typically associated with the self-renewal and pluripotency; TFCP2L1, the knockdown of which inhibits resetting of primed cells toward naive pluripotency ([@R31]); GP130, SOCS3, and TBX3, which are related to the LIF-STAT3 pathway; and HERVH, a primate-specific endogenous retrovirus reported as a hallmark of naive-like ESCs ([@R36]). In all three cell lines examined (H9, H1, and IMR-90 iPSCs), these markers tend to be upregulated in naive cells relative to primed cells ([Figures 3C](#F3){ref-type="fig"} and [S3E](#SD1){ref-type="supplementary-material"}). The upregulation of these makers is more consistent in mTeSR+2iFL or mTeSR+2iFL+LPA than in N2B27+2iFL ([Figure 3C](#F3){ref-type="fig"}), supporting our previous observation that the mTeSR base medium is a better choice for induction and maintenance of the human naive PSC state. Taken together, these data demonstrate that Yin-PSCs and Lin-PSCs have a coordinately distinct transcriptional profile that is associated with naive pluripotency.
We then compared the transcriptional profiles of naive Yin-PSCs and Lin-PSCs and primed PSCs with those of pre-implantation stages of human development ([@R38]). We used a weighted gene co-expression network analysis (WGCNA) ([@R43]), and a rigorous information theoretic metric called variation of information ([@R19]) to measure the distance between the co-expression networks of two cell types. A major advantage of this information theoretic method lies in its ability to compare the co-expression networks as a whole without selecting a single module, which may be biased and represent only a small portion of complex interactions. Compared with other previously used methods ([@R15]), our approach (described in Supplemental Experimental Procedures) captures a more global and unbiased view of similarity between cell types. We found that transcriptionally, Yin-PSCs and Lin-PSCs resemble human pre-implantation embryos and show high similarities with the naive PSC datasets by [@R31] and [@R33]. In contrast, primed PSCs from all three labs exhibit larger variability and form an outlier group with lower similarities to pre-implantation embryos ([Figure 3D](#F3){ref-type="fig"}). Thus, treatment of human primed PSCs with YAP or LPA resets them to a naive state similar to human pre-implantation embryos.
We next sought to extract further biological insights from these expression datasets. We queried the data for genes that have high specificity of expression at the blastocyst stage and are upregulated in naive Yin-PSCs and Lin-PSCs relative to primed cells ([Figure S3F](#SD1){ref-type="supplementary-material"}). Similar to the previous gene ontology analysis ([Figure S3B; Data S2](#SD1){ref-type="supplementary-material"}), we found many of these genes to be involved in TGF-β signaling (GDF3, NODAL, FST), DNA methylation (DNMT3L, NLRP7), and cholesterol biosynthesis (DHCR24, DHCR7, IDI1) ([Figure 3E](#F3){ref-type="fig"}). DNMT3L is an epigenetic regulator previously found to be highly upregulated in naive human PSCs ([@R33]). The observation that cholesterol biosynthesis genes are highly upregulated in both naive PSCs ([Figures 3E](#F3){ref-type="fig"} and [S3B; Data S2](#SD1){ref-type="supplementary-material"}) and blastocysts ([Figure S3F](#SD1){ref-type="supplementary-material"}) suggests a potential role for this pathway in the naive state and early human development. Conversely, OTX2, DNMT3B, B2M, HLA-A, HLA-B, HLA-H, and HLA-DOA are strongly downregulated in naive cells ([Figure 3E](#F3){ref-type="fig"}). OTX2 is a pioneer transcription factor that drives the transition from the naive to the primed state in mouse ([@R4]) and was previously shown to be sharply downregulated in human naive PSCs ([@R33]). Downregulations of B2M and HLA genes in naive cells has, to our knowledge, not been previously reported and suggests that from an immunological point of view, naive cells are more undifferentiated and less immunogenic than primed cells ([@R7]; [@R8]).
Further Characterization of Naive Pluripotency in Yin-PSCs and Lin-PSCs {#S6}
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In addition to having a distinct transcriptional program, naive pluripotency is associated with unique features of the chromatin landscape and enhancer activity. Although X chromosome reactivation is a hallmark of female naive PSCs in mouse, the available data are contradictory in human cells ([@R31]; [@R33]). We nevertheless explored the X chromosome status by staining for histone 3 lysine 27 trimethylation, a reliable marker of X chromosome inactivation. We found that low-passage primed female H9 ESCs or IMR-90 iPSCs already display significant levels of X chromosome reactivation, precluding the use of this marker as a criterion for the naive state (data not shown). We did find that primed IMR-90 iPSC-YAP have mosaic X inactivation and that this is lost when the cells are converted to the naive state (data not shown). On the whole, the existing data and our analysis suggest that X chromosome reactivation may not unequivocally distinguish the naive state from the primed state in human cells ([@R31]; [@R33]; [@R35]).
Histone 3 lysine 9 trimethylation (H3K9me3) is a repressive chromatin mark highly enriched at heterochromatin, and H3K9me3 foci have been shown to be depleted in naive PSCs ([@R31]). In agreement with this finding, the condensed H3K9me3 foci observed in primed PSCs almost disappear in Yin-PSCs and Lin-PSCs ([Figures 4A](#F4){ref-type="fig"} and [S4A](#SD1){ref-type="supplementary-material"}). Western blotting confirmed a reduction in the total levels of H3K9me3 in Yin-PSCs and Lin-PSCs ([Figure 4B](#F4){ref-type="fig"}).
A further signature of naive pluripotency is the activation of the endogenous DE of OCT4. In mouse, the DE drives Oct4 expression in ESCs, the ICM, and primordial germ cells ([@R39]), while the proximal enhancer (PE) activates Oct4 expression in primed epiblast stem cells (EpiSCs) and epiblast cells ([@R32]). [@R33] established a reporter for OCT4 DE activity in the human ESC line WIBR3 by deleting the PE in an *OCT4-GFP* knockin allele. These *OCT4-ΔPE-GFP* ESCs allowed the authors to identify a cocktail of inhibitors and growth factors (termed 5i/L/A) that promotes maintenance of naive human ESCs with OCT4-ΔPE activity. Using this cell line, we found that YAP overexpression dramatically increases endogenous OCT4 DE activity in both 5i/L/A and mTeSR+2iFL media, indicating that YAP promotes naive pluripotency in multiple culture conditions ([Figure 4C](#F4){ref-type="fig"}). Taken together, our data demonstrate that Yin-PSCs and Lin-PSCs meet the key criteria of naive pluripotency.
YAP Regulates the Human Naive State and Acts in Part by Modulating Wnt Signaling {#S7}
--------------------------------------------------------------------------------
We sought to gain insights into the mechanisms by which YAP and LPA promote naive pluripotency. As mentioned earlier, H9 ESCs in the absence of YAP overexpression or LPA undergo rapid morphological differentiation when cultured in 2i medium (PD0325901+CHIR99021) after three passages ([Figure S4B](#SD1){ref-type="supplementary-material"}). We asked whether only one inhibitor or the combination of both induces differentiation. Short-term treatment of H9 cells with PD0325901 (ERK inhibitor) or CHIR99021 (GSK3 inhibitor) separately revealed that CHIR99021 is the major contributor to this effect ([Figure S4B](#SD1){ref-type="supplementary-material"}). qRT-PCR shows that CHIR99021 leads to an increase in the expression level of differentiation markers, most notably CDX2 (trophectoderm) but also T (mesoderm), SOX17 (endoderm), and SOX1 (ectoderm) ([Figure S4C](#SD1){ref-type="supplementary-material"}). We found that LPA suppresses the differentiation-inducing effects of CHIR99021 and strongly downregulates SOX17 ([Figure S4C](#SD1){ref-type="supplementary-material"}), which in addition to being an endoderm regulator, is a marker of the primed state ([@R32]). In agreement with previous data in other systems ([@R11]; [@R25]), YAP overexpressing cells display lower levels of active β-catenin ([Figure 4D](#F4){ref-type="fig"}) and Wnt target genes ([Figure 4E](#F4){ref-type="fig"}). These data suggest that YAP promotes naive pluripotency in part by suppressing differentiation-inducing effects of GSK3 inhibition.
Finally, we tested whether endogenous YAP regulates human naive pluripotency in the absence of transgene induction. We used CRISPR/Cas9 to knockout the expression of YAP in primed H9 ESCs. Western blotting confirmed the loss of YAP protein in four independent mutant clones ([Figure S4D](#SD1){ref-type="supplementary-material"}) that carry frame-shift mutations at the CRISPR/Cas9 target sites ([Figure S4E](#SD1){ref-type="supplementary-material"}). We then compared self-renewal in standard primed medium, our mTeSR 2iFL+LPA medium, and the 5i/L/A formulation of [@R33] but not the culture conditions from the protocol of [@R31], because it requires overexpression of NANOG and KLF2. We found that YAP is not required for self-renewal of primed ESCs ([Figure 4F](#F4){ref-type="fig"}). However, the ability to form naive colonies after transfer to naive media is impaired in *YAP*^−/−^ cells, most strikingly in the 5i/L/A medium ([Figure 4F](#F4){ref-type="fig"}) ([@R33]). These data lend strong support to the conclusion that YAP promotes naive pluripotency in human cells.
DISCUSSION {#S8}
==========
We show here that YAP or its activator LPA promote the transition to the naive PSC state in multiple human ESC and iPSC lines. Yin-PSCs and Lin-PSCs can be maintained long term with robust clonal growth and fulfill the key criteria of naive pluripotency. YAP therefore represents an unexpected regulator of the human naive state, with potential implications for our understanding of early human embryology. Moreover, observations made during the course of this work shed light on the conditions that underlie the successful derivation and maintenance of human naive PSCs.
First, our results indicate that different human PSCs lines can have distinct abilities to maintain naive pluripotency: (1) in N2B27+2iFL naive medium, Yin-PSCs can only be derived from H9-YAP but not H1-YAP, IMR-90 iPSC-YAP, or other cell lines ([Figure 1](#F1){ref-type="fig"}); (2) in mTeSR+2iFL+LPA naive medium, Lin-PSCs can be generated from H9 and WIBR3 ([Figure 2](#F2){ref-type="fig"}), but in the same conditions, H1 and IMR-90 iPSCs begin to differentiate after several passages (data not shown); and (3) in 5i/L/A medium, naive cells can be readily derived from H9 and WIBR3 ([@R33]) but not from H1 or IMR-90 iPSCs in our hands (data not shown). Importantly, YAP overexpression in mTeSR-based medium can convert all PSC lines tested to the naive state. However, in the absence of YAP overexpression or in sub-optimal culture media, H9 and WIBR3 cells are more easily induced to naive pluripotency compared with other cells lines tested. In mice, it is well known that the ability to derive ESCs is strongly dependent on the genetic strain. The 129 strain, or hybrids thereof, yields ESCs efficiently, and this may be related to the high incidence of spontaneous germ cell tumors in these mice ([@R2]; [@R5]). Some other strains, for example, non-obese diabetic mice, are considered non-permissive for ESC derivation under canonical culture conditions and require further modifications of the media ([@R12]). It will be interesting to determine whether there is a genetic or epigenetic predisposition to achieve ICM-like naive pluripotency in different human PSCs. Both H9 and WIBR3 are female cells, and the additional X chromosome could potentially contribute factors that facilitate maintenance of the naive state. Mouse female ESCs have both X chromosomes active, but in human cells there does not seem to be a strict correlation between XaXa status and naive pluripotency (data not shown) ([@R31]; [@R33]; [@R35]). Further research using a large panel of PSCs will be needed to explore the differential propensities of human primed PSCs to achieve a stable naive state.
Second, our work underscores the importance of the culture medium formulation in the derivation of naive PSCs, including the base medium. Yin-PSCs could not be derived in N2B27 base medium for several of the lines tested, and H9 Yin-PSCs grown in N2B27 only partially express naive state markers ([Figure 3C](#F3){ref-type="fig"}) and have intermediate levels of H3K9me3 ([Figures 4A](#F4){ref-type="fig"} and [4B](#F4){ref-type="fig"}). The mTeSR medium was superior in inducing the naive state of H9 Yin-PSCs ([Figures 3C](#F3){ref-type="fig"}, [4A](#F4){ref-type="fig"}, and [4B](#F4){ref-type="fig"}) and allowed the derivation of Yin-PSCs from multiple ESCs and iPSCs resistant to conversion in N2B27. Unlike N2B27, mTeSR is supplemented with basic fibroblast growth factor (bFGF) and TGF-β. In mouse ESCs, bFGF and TGF-β are considered critical for primed EpiSCs but not for naive pluripotency ([@R2]). However, genes related to TGF-β signaling pathway, including GDF3, NODAL, LEFTY2, SPP1, and CER1, are upregulated in Yin-PSCs and Lin-PSCs ([Figure S3B; Data S2](#SD1){ref-type="supplementary-material"}). In agreement with these findings, other groups included bFGF and TGF-β/activin in their medium to culture human naive PSCs ([@R10]; [@R33]). Unlike the case in mice, it appears that stable maintenance of the human naive PSC state requires growth factors in addition to LIF, possibly including bFGF and TGF-β. Previous studies used the mTeSR medium but failed to derive human naive PSCs with similarities to human pre-implantation embryos ([@R6]; [@R15]; [@R37]). We believe that this is due to variations in media composition and the use of different small molecules; in addition, they did not use mTeSR with YAP overexpression or LPA. Our data show that in the presence of exogenous YAP or LPA, mTeSR supports an authentic naive transcription profile resembling human pre-implantation embryos ([Figure 3D](#F3){ref-type="fig"}). The quality of our mTeSR+2iFL+LPA formulation for culturing naive cells is further highlighted by its increased resilience to YAP loss compared with 5i/L/A ([@R33]) ([Figure 4F](#F4){ref-type="fig"}). LPA may induce downstream effects, in addition to activating YAP, such as activation of the closely related protein TAZ ([@R41]). However, YAP overexpression induces a naive state with a faster growth rate and in more cell lines than exposure to LPA, likely because transgene overexpression achieves significantly higher levels of YAP than does LPA treatment ([Figure S2A](#SD1){ref-type="supplementary-material"} versus [Figure 2B](#F2){ref-type="fig"}). It will be interesting to explore other methods to induce high levels of YAP in a transgene-free manner.
Third, this work reveals that YAP is an unexpected regulator of the human naive state. YAP overexpression in primed culture conditions alone does not change colony morphology, sensitivity to trypsin ([Figure 1D](#F1){ref-type="fig"}), expression of naive markers ([Figures 3C](#F3){ref-type="fig"} and [S3E](#SD1){ref-type="supplementary-material"}), or levels of H3K9me3 ([Figures 4A](#F4){ref-type="fig"}, [4B](#F4){ref-type="fig"}, and [S4A](#SD1){ref-type="supplementary-material"}). Moreover, the transcriptional profile is not significantly altered between PSCs and PSC-YAP cells in primed medium ([Figure 3A](#F3){ref-type="fig"}). These data suggest that YAP acts in conjunction with the modulation of signaling pathways that are induced by the naive medium. In support of this notion, we found that LPA suppresses differentiation-inducing effects of GSK3 inhibition by CHIR99021 ([Figures S4B](#SD1){ref-type="supplementary-material"} and [S4C](#SD1){ref-type="supplementary-material"}). GSK3 inhibition enhances cell growth capacity and viability of mouse naive PSCs ([@R40]). However, we found that in human ESCs, GSK3 inhibition has a dual effect: it promotes survival and proliferation but also induces differentiation ([Figure S4C](#SD1){ref-type="supplementary-material"}). It has been reported that lowering the concentration of CHIR99021 is beneficial for maintenance of human naive pluripotency ([@R31]; [@R33]). Taken together, these results indicate that additional modulation of signaling is required to balance the effects of GSK3 inhibition on the naive state, and our work reveals that activation of YAP provides such balance. One effect of GSK3 inhibition is the stabilization of β-catenin and activation of the canonical Wnt pathway, both of which are countered by YAP overexpression ([Figures 4D](#F4){ref-type="fig"} and [4E](#F4){ref-type="fig"}), in agreement with studies in other systems ([@R1]; [@R11]; [@R25]). These results suggest that the combination of GSK3 inhibition with YAP activation provides the appropriate balance of Wnt signaling to sustain the naive state. Our findings parallel a report that YAP reprograms intestinal stem cells toward regeneration by antagonizing a differentiation-inducing effect promoted by high levels of Wnt signaling ([@R11]). It will be interesting to further explore the potential interactions between YAP and Wnt signaling in human naive PSCs. Moreover, YAP may in parallel cooperate with other factors downstream of 2iFL, TGF-β, or bFGF to implement the transcriptional program of the naive state. Lin-PSCs provide a platform to functionally dissect the interactions between YAP and other cellular pathways, as well as to identify other small molecules that contribute to stabilizing the human naive state.
Finally, this work raises interesting questions regarding the regulation of naive pluripotency in early human and mouse embryology. In human blastocysts, YAP protein is nuclearly localized in both the trophectoderm and the ICM ([Figures 1A](#F1){ref-type="fig"} and [S1B](#SD1){ref-type="supplementary-material"}). However, in mice, Yap has been reported to be excluded from the nucleus of ICM cells and has been implicated in trophectoderm development ([@R24]). These findings could be interpreted as Yap having no role in the development of mouse pluripotent cells. However, cytoplasmic Yap may still contribute to the regulation of the ICM, for example, by interacting with other pathways, including Wnt signaling ([@R1]). Moreover, *Yap*^−/−^ mice do not have implantation defects, which would be indicative of abnormal trophectoderm development ([@R21]). Yap and Taz may act redundantly, because both are present in the nucleus and cytoplasm during early cleavage stages, and Yap/Taz double mutant embryos arrest before the morula stage ([@R24]). Thus, an alternative possibility is that YAP activation reverts human PSCs to a pluripotent state with similarities to cleavage-stage embryos, a possibility supported by our transcriptional analysis ([Figure 3D](#F3){ref-type="fig"}). Our findings warrant further study of the role of the Hippo pathway in early mouse and human development and provide a platform for chemically and genetically dissecting human naive pluripotency.
EXPERIMENTAL PROCEDURES {#S9}
=======================
Culture of Human Primed PSCs {#S10}
----------------------------
All research described here was done with the approval of the Stanford University Institutional Review Board--RENEW Biobank and the UCSF Human Gamete, Embryo and Stem Cell Research Committee. H1 (P27) and H9 (P28) human ESCs were obtained from the WiCell Research Institute. WIBR3 human ESCs with *OCT4-ΔPE-GFP* reporter were provided by Dr. Rudolf Jaenisch. Human iPSCs were generated from BJ and IMR-90 fibroblasts (ATCC) using retroviruses (Harvard Gene Therapy Initiative) leading to the overexpression of OCT4, SOX2, KLF4, and c-MYC as described earlier ([@R27]). Human primed ESCs and iPSCs were cultured on irradiated mouse embryonic fibroblasts (MEFs) in primed medium (DF12+bFGF) consisting of 80% DMEM/F 12, 20% knockout serum replacement, 1 mM L-glutamax, 1% non-essential amino acids, 0.1 mM beta-mercaptoethanol, 1% penicillinstreptomycin, and 8 ng/ml bFGF (all from Invitrogen). Cells were passaged with collagenase IV (Invitrogen) every 7 days. For YAP overexpression, YAP cDNA was cloned into the lentiviral vector pGAMA downstream of an EF1 α promoter (EF1 α-YAP-T2A-mCherry). Lentiviruses were produced and human PSCs were infected as described earlier ([@R27]). YAP overexpressing cells were trypsinized, isolated by fluorescence-activated cell sorting for mCherry-positive cells, plated in the presence of ROCK inhibitor Y-27632 (Stemgent, 5 μM), and expanded in standard primed conditions.
Culture of Human Naive PSCs {#S11}
---------------------------
To derive human naive PSCs, primed cells were switched to naive media based on N2B27 or mTeSR. N2B27 medium consisted of a 1:1 mixture of DMEM/F12 and Neurobasal medium, with 1*%* N2 supplement, 2% B27 supplement, 1 mM L-glutamax, 0.1 mM beta-mercaptoethanol, 1× non-essential amino acids, and 1× penicillin-streptomycin (all from Invitrogen). The mTeSR1 medium was purchased from STEMCELL. N2B27 and mTeSR base media were supplemented with 2iFL: PD0325901 (Stemgent, 0.5 μM), CHIR99021 (Selleck Chemicals, 3 μM), Forskolin (Sigma, 10 μM) and recombinant human LIF(EMD Millipore, 10 ng/ml). LPA (Sigma, 10 μM) was added to naive media when indicated. The ROCK inhibitor Y-27632 (Stemgent, 5 μM) was used for the first three passages. Human naive PSCs were maintained on irradiated MEFs. To passage naive PSCs, cells were briefly washed with PBS, dissociated to single cells using TrypLE (Invitrogen), centrifuged in fibroblast medium (DMEM with 10% fetal bovine serum, 1 mM glutamax, 1× non-essential amino acids, 1× sodium pyruvate, 1× penicillin/streptomycin, and 0.06 mM β-mercaptoethanol, all from Invitrogen), and seeded onto irradiated MEFs in naive medium. The 5i/L/A medium was prepared as described earlier ([@R33]).
Supplementary Material {#S12}
======================
We are grateful to Robert Blelloch, Marco Conti, and Susan Fisher for input during the course of this work; to Alex Dunn for antibodies and discussions; and to members of the M.R.-S. lab for discussions and critical reading of the manuscript. We thank Rudolf Jaenisch for the *OCT4-ΔPE-GFP* WIBR3 human ESCs, Fong Ming Koh for providing the pGAMA vector, and Kathryn Blaschke and Yuki Ohi for initial cloning of the YAP cDNA. This work was partially supported by a Siebel Stem Cells Institute Scholarship and a Stinehart Reed Seed Grant to V.S., NIH R01 CA163336 to J.S.S., and CIRM grant RB4-06028 and NIH R01 OD012204to M.R.-S.
**ACCESSION NUMBERS**
The accession number for the microarray data reported in this paper is GEO: GSE69200.
**SUPPLEMENTAL INFORMATION**
[Supplemental Information](#SD1){ref-type="supplementary-material"} includes [Supplemental Experimental Procedures](#SD1){ref-type="supplementary-material"}, four figures, one table, and three data files and can be found with this article online at <http://dx.doi.org/10.1016/j.celrep.2016.02.036>.
**AUTHOR CONTRIBUTIONS**
H.Q. and M.R.-S. conceived the project and developed the experimental design. H.Q. carried out most of the bench experiments with technical assistance from LB. and P.W. M.H., M.P., and J.S.S. performed bioinformatic analyses; Y.L, H.Q., and L.S.Q. generated *YAP*^−/−^ ESCs; M.W., J.D.-D., and V.S. analyzed YAP expression in human blastocysts; and Z.Q. performed karyotyping analyses under the supervision of J.Y. H.Q. and M.R.-S. wrote the manuscript, with input from all authors.
{#F1}
{#F2}
![Yin-PSCs and Lin-PSCs Have a Naive-like Transcriptional Profile Distinct from that of Primed PSCs\
(A) Primed PSCs and Yin- and Lin-PSCs have distinct gene expression profiles, as shown by unsupervised hierarchical clustering. The top 1,000 genes with the highest coefficient of variation were used to cluster samples using Pearson correlation coefficients. Six human primed PSC samples include H9, H1, IMR-90 iPSCs, H9-YAP, H1-YAP, and IMR-90 iPSC-YAP cells. Six human naive PSC samples include H9-YAP in N2B27+2iFL (H9-YAP N naive), H9-YAP in mTeSR+2iFL (H9-YAP T naive), H1-YAP in mTeSR+2iFL (H1-YAP T naive), IMR-90 iPSC-YAP cells in mTeSR+2iFL (iPSC-YAP T naive), H9 in mTeSR+2iFL+LPA (H9 T+LPA naive), and WIBR3 in mTeSR+2iFL+LPA (WIBR3 T+LPA naive). Primed cells are indicated in blue. H9-YAP in N2B27+2iFL naive medium is in pink, and all other naive cells are in red.\
(B) GSEA reveals that Yin-PSCs and Lin-PSCs have gene expression profiles concordant with naive PSCs from other studies. The upper panel is the enrichment plot for the gene set of [@R33] upregulated in naive by Log~2~ FC \> 3.0. The lower panel is the enrichment plot for the gene set of [@R31] upregulated in naive by Log~2~ FC \> 2.0. Vertical black bars represent the position of genes upregulated in naive cells in the [@R31] or [@R33] studies, distributed along the differential expression values for the entire transcriptome in this study, and ranked from upregulated in Yin-PSCs and Lin-PSCs (red, left) to upregulated in parental primed PSCs (blue, right).\
(C) Yin-PSCs and Lin-PSCs express markers specific for naive pluripotency, as confirmed by qRT-PCR. Values were normalized to *GAPDH* and *UBB* and then compared to H9 in primed medium (left panel) or H1 in primed medium (right panel). Data are averages of triplicate PCR reactions, and error bars represent SD.\
(D) Hierarchical clustering shows that naive Yin-PSCs and Lin-PSCs are similar to naive cells from two other studies ([@R31]; [@R33]) and to human pre-implantation embryos. In vivo states at various developmental stages ([@R38]) are included in the clustering.\
(E) Volcano plot of significantly differentially expressed genes among the six human naive PSC samples and the six human primed PSC samples. Highlighted in red are genes with aLog~2~ FC \> 0.7 in naive and p \< 0.05. In blue are genes with a Log~2~ FC \< −0.7 and p \< 0.05 in naive. See text for a description of the specific genes indicated.](nihms766484f3){#F3}
![YAP Regulates the Human Naive State and Acts in Part by Modulating Wnt Signaling\
(A) H3K9me3 is strongly reduced in naive H9 ESCs, as seen by immunofluorescence. Upper panel: H9 and H9-YAP in DF12+bFGF primed medium. Lower panel: H9-YAP in N2B27+2iFL naive medium, H9-YAP in mTeSR+2iFL naive medium, and H9 in mTeSR+2iFL+LPA naive medium. Scale bar, 20 μm.\
(B) Decreased total amount of H3K9me3 in Yin-PSCs and Lin-PSCs was confirmed by western blotting. Tubulin was used as loading control. Values indicate densitometry analysis of the H3K9me3 level normalized to tubulin.\
(C) Flow cytometric analysis of the proportion of OCT4-ΔPE-GFP+ WIBR3 cells with or without YAP overexpression in 5i/L/A (upper panels) or mTeSR+2iFL (lower panels) media. Cells were expanded in bulk and analyzed at passage 3, in the absence of colony picking. YAP overexpression increases the ratio of OCT4-ΔPE-GFP + cells in both media.\
(D) YAP overexpression decreases levels of unphosphorylated (active) β-catenin, as shown by western blotting. Tubulin was used as loading control.\
(E) YAP overexpression decreases the expression of Wnt target genes, as shown by qRT-PCR. Values were normalized to *GAPDH* and *UBB* and then compared to H9. Data are averages of triplicate PCR reactions, and error bars represent SD.\
(F) YAP knockout impairs the ability of ESCs to form naive colonies. H9 controls and four clones of CRISPR/Cas9-generated *YAP*^−/−^ cells cultured in DF12+bFGF (primed), mTeSR+2iFL+LPA (naive), and 5i/L/A (naive, [@R33]) were trypsinized to single cells, counted, and plated onto MEFs in the presence of ROCK inhibitor. Seven days later, AP staining was performed and colony numbers were counted. Error bars represent SD. \*p \< 0.05; \*\*p \< 0.01; \*\*\*p \< 0.001.](nihms766484f4){#F4}
###### Highlights
- YAP overexpression promotes a naive state in human PSCs
- LPA partially substitutes for YAP in the derivation of transgene-free naive PSCs
- YAP regulates the human naive state by modulating Wnt signaling
- YAP is required for efficient self-renewal of human naive PSCs
[^1]: Present address: Genentech, South San Francisco, CA 94080, USA
|
Opioid receptor proteins in human brain. Detection with monoclonal anti-idiotypic antibodies.
In order to identify opioid receptor proteins, we first ascertained the presence of mu-receptors in membranes of the human cerebral frontal cortex, using binding studies performed with sufentanil. Sufentanil binding was reversed by naloxone and prevented by an anti-idiotypic opioid receptor-specific antibody. This antibody was bound specifically by proteins (molecular weights of 66 and 68 Kda) detected in frontal cortex membrane preparations by sodium dodecyl sulphate-polyacrylamide-gel electrophoresis in combination with western blot analysis. Binding of the same antibody was achieved in dot blots of homologous cerebral and cerebellar cortex preparations. |
13
In August my oldest turned 13, and wow. I cannot accurately describe a 13 year old boy except, WOW. I hesitated for so long to write this because I'm aware some day he will stumble on this blog and read all about himself, his mom, and his family, but I have to document 13 at some point.
I am technically an only child. Adding to that, I'm a female who never spent overtly large amounts of time with 13 year old boys, (my best friend Jeremy was around a lot, but I missed a lot of the tantrum melt down stuff that must have happened at home), and I'm lost with boys.
It felt as if the day he turned 13 a switch flipped, and overnight he became an entirely different person. My son is no 5' 8", he has a size 10 foot, and a size 20 attitude. His mood is insane. It goes from happy hugs, to angry door slamming, to frustration, sadness, happy, and mad all in the span of four minutes. His brain is changing and his sense of self preservation isn't growing at the same rate as his urge to be defiant. I believe girls learn faster when to stop and save themselves. My son, no way. Even with clear, loud warnings that he's approaching danger territory he will dive head first violently into what can only end in trouble. If A+B+C = Being grounded, and he gets though A, is part of the way through B with several warnings, I promise you he will still purposefully dance across C just because he can. Then when the inevitable grounding happens he will be angry and indignant, as if it's my fault he intentionally broke the rules and had to suffer the consequences. I tell him all the time, "boy, if it was me I would stop now." He doesn't though, he pushes just a little bit more, which never fails to amaze me.
Add into the mix that we are dealing with what I believe is a strong case of ADHD (he's going through testing) and the result is pure chaos. I'm ADHD and all of the things that make me impossible to live with, are occurring in him, when the two of us get into a disagreement it's a level past chaos, because neither of us know what to do. We both want the last word, we both misinterpret we both get so angry so fast because we have so many feelings, and it results in an argument that accomplishes nothing. It's like asking one blind person to help another. I can't even help myself yet kiddo, how am I supposed to help you not become me? It's a shit show to the max.
I probably need a whole separate post dedicated to the females of his generation, because they are a sad sorry specimen and I feel sorry for my son having to grow up in this social media age where girls send mixed signals, screen shots, and lies. Growing up at my age I was forced to talk on the phone to boys and friends. Forced to hear their voice, their linguistics. We undertsood tone and connotation. Kids now are misinterpreting text messages left and right, then getting face to face and not knowing how to talk to each other, and it's sad to witness.
Thirteen year old boys are learning how to hide things. They are learning to twist the truth. They are learning to be literal. If there is cheese on the counter, the tortillas are open, and the sour cream is out, and you ask "who ate a quesadilla and left this mess?" They have figured out they can say "not me," because they shaped their quesadilla like a burrito, and you didn't ask about a burrito, only a quesadilla, so technically they aren't lying. If you ask them to shake the crumbs off their place mat, they will dump their placemat straight onto the floor. When you ask in horror why they would do that, rather than shake it over the trash like they have EVERY OTHER NIGHT FOR 12 YEARS, they will reply, "you only said shake it off, not where, so I did nothing wrong, you need to give better directions." Somehow you will be left scratching your head wondering when you became the wrong one, and they became the right one, even though, you are pretty sure you're still supposed to be right.
I've spent the last month in a constant state of confusion. I know this is a phase, and soon his brain and logic will catch up with each other and level out. The only problem is, that will happen right around the time his little brother turns thirteen.
posted on Jan. 9, 2019
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The APS Dynamics series of air bearing long stroke vibration exciters provide excellent properties for low frequency excitation of accelerometers and other low frequency instruments and sensors. Some models have a horizontal air bearing table coupled to the driver unit that allows high payloads up to 23 kg e.g. for the calibration of geophones.
APS 129 Vibration Exciter
133 N (30 lbf) Long Stroke Shaker with air bearings and payload table
The APS 129 ELECTRO-SEIS® Long Stroke Shaker is a force generator specifically designed to be used for calibration and evaluation of accelerometers and other motion transducers. It provides excellent properties for low frequency excitation of such devices. This model has a horizontal air bearing table coupled to the driver unit that allows high payloads up to 23 kg e.g. for the calibration of geophones and heavy seismic sensors.
The APS 500 ELECTRO-SEIS® Long Stroke Shaker is a force generator specifically designed to be used for calibration and evaluation of accelerometers and other motion transducers. It provides excellent properties for low frequency excitation of such devices. This model has a horizontal air bearing table coupled to the driver unit that allows payloads up to 3 kg. |
#coding:utf-8
# 统计参数中每个英文单词出现的次数
# def stats_text_en(text):
# elements = text.split()
# words = []
# symbols = ',.*-!?'
# for element in elements:
# for symbol in symbols:
# element = element.replace(symbol, '')
# if len(element):
# words.append(element)
# counter = {}
# word_set = set(words)
# for word in word_set:
# counter[word] = words.count(word)
# return sorted(counter.items(), key=lambda x:x[1], reverse=True)
def stats_text_en(text):
elements = text.split()
words = []
symbols = ',.*-!?'
for element in elements:
if (element >= '\u0041' and element <= '\u005A') or (element >= '\u0061' and element <= '\u007A'):
# if len(element):
words.append(element)
counter = {}
word_set = set(words)
for word in word_set:
counter[word] = words.count(word)
return sorted(counter.items(), key=lambda x:x[1], reverse=True)
# 统计参数中每个中文汉字出现的次数
def stats_text_cn(text):
cn_characters = []
for character in text:
# unicode中 中文字符的范围
if '\u4e00' <= character <= '\u9fff':
cn_characters.append(character)
counter = {}
cn_character_set = set(cn_characters)
for character in cn_character_set:
counter[character] = cn_characters.count(character)
return sorted(counter.items(), key=lambda x:x[1], reverse=True)
en_text = '''
The Zen of Python, by Tim Peters
Beautiful is better than ugly.
Explicit is better than implicit.
Simple is better than complex.
Complex is better than complicated.
Flat is better than nested.
Sparse is better than dense.
Readability counts.
Special cases aren't special enough to break the rules.
Although practicality beats purity.
Errors should never pass silently.
Unless explicitly silenced.
In the face of ambxiguity, refuse the temptation to guess.
There should be one-- and preferably only one --obvious way to do
it.
Although that way may not be obvious at first unless you're Dutch.
Now is better than never.
Although never is often better than *right* now.
If the implementation is hard to explain, it's a bad idea.
If the implementation is easy to explain, it may be a good idea.
Namespaces are one honking great idea -- let's do more of those!
'''
cn_text = '''
如果你不觉得正则表达式很难读写的话，要么你是一个天才，要么，你不是地球人。正则表达式的语法很令人头疼，即使对经常使用它的人来说也是如此。由于难于读写，容易出错，所以找一种工具对正则表达式进行测试是很有必要的。
'''
# 测试代码
# if __name__ == '__main__':
# en_result = stats_text_en(en_text)
# cn_result = stats_text_cn(cn_text)
# print('英文单词出现的次数 ==>\n', en_result)
# print('中文汉字出现的次数 ==>\n', cn_result)
text = '''
愚公移⼭山
太⾏行行，王屋⼆二⼭山的北北⾯面，住了了⼀一個九⼗十歲的⽼老老翁，名叫愚公。⼆二⼭山佔地廣闊，擋住去路路，使他
和家⼈人往來來極為不不便便。
⼀一天，愚公召集家⼈人說：「讓我們各盡其⼒力力，剷平⼆二⼭山，開條道路路，直通豫州，你們認為怎
樣？」
⼤大家都異異⼝口同聲贊成，只有他的妻⼦子表示懷疑，並說：「你連開鑿⼀一個⼩小丘的⼒力力量量都沒有，怎
可能剷平太⾏行行、王屋⼆二⼭山呢？況且，鑿出的⼟土⽯石⼜又丟到哪裏去呢？」
⼤大家都熱烈烈地說：「把⼟土⽯石丟進渤海海裏。」
於是愚公就和兒孫，⼀一起開挖⼟土，把⼟土⽯石搬運到渤海海去。
愚公的鄰居是個寡婦，有個兒⼦子⼋八歲也興致勃勃地⾛走來來幫忙。
寒來來暑往，他們要⼀一年年才能往返渤海海⼀一次。
住在⿈黃河河畔的智叟，看⾒見見他們這樣⾟辛苦，取笑愚公說：「你不不是很愚蠢嗎？你已⼀一把年年紀
了了，就是⽤用盡你的氣⼒力力，也不不能挖去⼭山的⼀一⻆角呢？」
愚公歎息道：「你有這樣的成⾒見見，是不不會明⽩白的。你⽐比那寡婦的⼩小兒⼦子還不不如呢！就算我死
了了，還有我的兒⼦子，我的孫⼦子，我的曾孫⼦子，他們⼀一直傳下去。⽽而這⼆二⼭山是不不會加⼤大的，總有
⼀一天，我們會把它們剷平。」
智叟聽了了，無話可說：
⼆二⼭山的守護神被愚公的堅毅精神嚇倒，便便把此事奏知天帝。天帝佩服愚公的精神，就命兩位⼤大
⼒力力神揹⾛走⼆二⼭山。
How The Foolish Old Man Moved Mountains
Yugong was a ninety-year-old man who lived at the north of two high
mountains, Mount Taixing and Mount Wangwu.
Stretching over a wide expanse of land, the mountains blocked
yugong’s way making it inconvenient for him and his family to get
around.
One day yugong gathered his family together and said,”Let’s do our
best to level these two mountains. We shall open a road that leads
to Yuzhou. What do you think?”
All but his wife agreed with him.
“You don’t have the strength to cut even a small mound,” muttered
his wife. “How on earth do you suppose you can level Mount Taixin
and Mount Wanwu? Moreover, where will all the earth and rubble go?”
“Dump them into the Sea of Bohai!” said everyone.
So Yugong, his sons, and his grandsons started to break up rocks and
remove the earth. They transported the earth and rubble to the Sea
of Bohai.
Now Yugong’s neighbour was a widow who had an only child eight years
old. Evening the young boy offered his help eagerly.
Summer went by and winter came. It took Yugong and his crew a full
year to travel back and forth once.
On the bank of the Yellow River dwelled an old man much respected
for his wisdom. When he saw their back-breaking labour, he ridiculed
Yugong saying,”Aren’t you foolish, my friend? You are very old now,
and with whatever remains of your waning strength, you won’t be able
to remove even a corner of the mountain.”
Yugong uttered a sigh and said,”A biased person like you will never
understand. You can’t even compare with the widow’s little boy!”
“Even if I were dead, there will still be my children, my
grandchildren, my great grandchildren, my great great grandchildren.
They descendants will go on forever. But these mountains will not
grow any taler. We shall level them one day!” he declared with
confidence.
The wise old man was totally silenced.
When the guardian gods of the mountains saw how determined Yugong
and his crew were, they were struck with fear and reported the
incident to the Emperor of Heavens.
Filled with admiration for Yugong, the Emperor of Heavens ordered
two mighty gods to carry the mountains away.
'''
def stats_text(x):
# for a in y:
# if (a >= '\u0041' and a <= '\u005A') or (a >= '\u0061' and a <= '\u007A'):
en_result = stats_text_en(x)#调用方程
# elif '\u4e00' <= a <= '\u9fff':
cn_result = stats_text_cn(x)#调用方程
print('统计参数中每个英文单词出现的次数 ==>\n', en_result)
print('统计参数中每个中文汉字出现的次数 ==>\n', cn_result)
if __name__ == '__main__':
stats_text(text)
# if __name__ == '__main__':
# stats_text(cn_text)
|
A Gulf Business Salary Survey Shows Annual Increases in a Review of Middle East Jobs
Neither the international financial downturn, nor the economic impact of the Arab spring over the past year have taken the shine off salaries for gulf jobs in the past year. The 2012 Gulf Business salary survey of middle east jobs was calculated by taking the average salary across the region for Western, Asian and Arab expats across different sectors in the six GCC countries for the first quarter of 2012.
Alicia Buller, Editor of gulfbusiness.com commented on the outcome of the survey saying "employment in the middle east has largely mapped the upward fate of the GCC economy. In discussions with regional recruitment companies, we have learned that through tracking job vacancies, salaries in many sectors have increased. As the region's economy recovery continues apace, sales and marketing managers are bringing home the highest salaries in 2012, earning an average monthly wage of $11,560.
Although HR managers earn the second highest salaries in the region at around $11,468.6 per month, human resources was the only industry that witnessed a dramatic average salary drop year-on-year, with companies scaling back the function of HR departments. As a result, expatriate HR managers in the UAE, saw their wages slashed by 37 per cent. "Roles like organisational design, payroll and recruitment were all represented in HR headcount, but now have been rolled into one HR generalist role," said Christo Daniels, managing director of recruiter Morgan McKinley. Explaining the dramatic decline Christo went on to say "The market has corrected itself. So we're back to pre-2008 salary levels" for those in the HR sector.
Supporting a recent survey by Gulf Business, which saw CEO's salaries in the Kingdom of Saudi Arabia (KSA) topping the salaries list, this again is the case across all of the sectors investigated by Gulf Business where KSA comes out on top. Qatar salaries is where the growth is the highest, with the salary survey reporting Creative Directors seeing increases of 32% in monthly salaries as this nation begins to lay the foundations for the next decade of growth.
The results presented below show the roles that were selected to give an indicative overview of the sector in the 2012 Gulf Business salary survey:
http://www.gulfbusiness.com is the region's most intelligent and broad-ranged business website. With a unique mix of news exclusives, in-house data reports and interviews with world leading business minds, http://www.gulfbusiness.com is the go-to resource for information that supports your investment decisions. We offer more than news - we offer unparalleled insight and the real story behind the region's business activities. |
FILE - In this May 4, 2019 file photo, Michael Cohen, President Donald Trump's former personal attorney, stops to talk to a member of the media in New York. President Donald Trump's ex-personal lawyer, Michael Cohen, has lost a round in his long-shot bid to get the Trump Organization to cover all of his legal costs. (AP Photo/Jonathan Carroll, File)
FILE - In this May 4, 2019 file photo, Michael Cohen, President Donald Trump's former personal attorney, stops to talk to a member of the media in New York. President Donald Trump's ex-personal lawyer, Michael Cohen, has lost a round in his long-shot bid to get the Trump Organization to cover all of his legal costs. (AP Photo/Jonathan Carroll, File)
NEW YORK (AP) — President Donald Trump’s imprisoned ex-personal lawyer, Michael Cohen, lost a round in his longshot bid to get the Trump Organization to cover all legal costs.
Manhattan State Supreme Court Justice Joel Cohen said Thursday that the company only owes for legal costs of investigations already begun in July 2017.
That’s when Cohen asserts he reached an oral agreement to have the costs covered. His costs then rose dramatically when he was criminally charged last year.
Cohen pleaded guilty to several charges, including that he broke campaign finance laws and lied to Congress. He is serving a three-year prison term.
ADVERTISEMENT
The judge, though, said Cohen can collect additional evidence to support his bid for reimbursement from the company where he worked as executive vice president and special counsel and eventually Trump’s “fixer” from 2006 until January 2017.
The company stopped paying his legal bills after he split with the president two months after the FBI raided his residence and office in April 2018.
Although he once bragged he’d “take a bullet” for the president, Cohen met with federal prosecutors in New York and investigators for special counsel Robert Mueller, admitting he’d lied to Congress to protect Trump and paid off two women to keep them from speaking out about alleged affairs with Trump.
Cohen sued Trump Organization earlier this year, saying it owes him at least $1.9 million to cover the cost of his defense and another $1.9 million he’s been ordered to forfeit as part of his criminal case.
Cohen spokesman Lanny Davis said Friday that Cohen will try to force Trump and others to testify in the civil dispute.
“It is not shocking that Mr. Trump welches on his legal commitments to pay what he owes. He has done that all his life and gotten away with it,” Davis, based in Washington, said in a statement.
Attorney Marc Mukasey, representing Trump Organization, said the opinion makes clear that the bulk of Cohen’s claims were rejected.
“No DC spin doctor can change that. We won this round. They lost. Period,” Mukasey said in an email. |
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|
Shining design little tikes magicook kitchen ultimate cook walmart canada description is one of our best images of little tikes magicook kitchen and its resolution is 423x460 pixels. Find out our other images similar to this shining design little tikes magicook kitchen ultimate cook walmart canada description at gallery below and if you want to find more ideas about little tikes magicook kitchen, you could use search box at the top of this page. |
Q:
Always display specified number of decimal places in PHP (rounding up)
I need to display a floating point number with a specified number of decimal places (rounding up), specifically up to two decimal places even though the number has no fractional part. One way that I know is by using the sprintf() PHP function as follows.
echo sprintf("%0.2f", 123);
It returns 123.00.
echo sprintf("%0.2f", 123.4555);
returns 123.46 but the following doesn't return what I need.
echo sprintf("%0.2f", 123.455); // 5 is removed - the right-most digit.
I expect it to return 123.46 but it doesn't. It returns 123.45. Although it's not a huge difference, I somehow need to return 123.46 in both of the cases.
The round() function can do it. echo round(123.455, 2); and echo round(123.4555, 2); return 123.46 in both the cases but I can't think of using this function because if the fractional part is not present, it displays no decimal digits at all. like echo round(123, 2); gives 123 and I need 123.00.
Is there a function in PHP to achieve this?
A:
number_format(123.455, 2, '.', '')
|
Michael Saunders’ torn meniscus represents a major blow for the Toronto Blue Jays, who must now find a left fielder capable of filling in for a half-season.
Saunders had been acquired in the hopes that he’d provide 20-home run power and solid defence at the position previously occupied by Melky Cabrera. Instead, the injury likely costs the Blue Jays their starting left fielder and primary left-handed bat until the all-star break.
In the meantime, manager John Gibbons will take a long look at the other outfielders in camp and GM Alex Anthopoulos will be prepared to look around the league later this spring if the Blue Jays want reinforcements. Here’s a closer look at who the Blue Jays could place alongside Jose Bautista and centre field frontrunner Dalton Pompey in Toronto’s starting outfield:
Internal Options
The Blue Jays have many internal options, though Edwin Encarnacion and Devon Travis don’t appear to be among them:
Kevin Pillar
Bats: R | Throws: R | Age: 26 | Roster status: On 40-man
Pros: Pillar has a career batting line of .320/.362/.467 in the minor leagues and recent MLB experience at all three outfield positions. He hits left-handers and though he disappointed the team with a public display of frustration in June, he earned praise from Gibbons for his aggressive defence and baserunning later in the season.
Cons: Pillar has a career OPS of just .583 against right-handed pitching and he doesn’t walk much, so expecting him to produce every day would be asking a lot. Plus, he’s a right-handed bat and Toronto’s lineup already skews heavily to the right.
Ezequiel Carrera
Bats: L | Throws: L | Age: 27 | Roster status: non-roster invitee
Pros: Carrera’s speed allows him to cover ground on defence and steal bases (25/32 in stolen base attempts in 478 career plate appearances). Like Pillar, he has played all three outfield positions.
Cons: He hasn’t hit much (career OPS of .645) and he has even splits, so he’s not a logical platoon candidate.
Chris Dickerson
Bats: L | Throws: L | Age: 32 | Roster status: non-roster invitee
Pros: Dickerson has a left-handed bat and a career on-base percentage of .335 in seven seasons. He has a career OPS of .746 against right-handed pitching and as a bonus, most of his MLB experience comes in left field.
Cons: His offence has dropped off in recent seasons (.652 OPS since 2013), and he hasn’t hit left-handed pitching much in the course of his career (.629 OPS).
Andy Dirks
Bats: L | Throws: L | Age: 29 | Roster status: non-roster invitee
Pros: Dirks has had success hitting MLB pitching and has a career OPS of .751 against right-handers.
Cons: He’s in minor-league camp continuing to rehab from a back injury, so he’s not a realistic option for now. If his recovery goes well, he’ll be worth watching given his history of production and left-handed bat.
Caleb Gindl
Bats: L | Throws: L | Age: 26 | Roster status: non-roster invitee
Pros: Gindl has 101 minor-league home runs and a minor-league OPS of .810. Still just 26, he bats from the left side of the plate.
Cons: The former Brewers outfielder has just 178 plate appearances at the big-league level. Counting on him would be risky.
Danny Valencia
Bats: R | Throws: R | Age: 30 | Roster status: On 40-man
Pros: Valencia hits left-handed pitching (career OPS of .870) with more authority than just about anyone else the Blue Jays could find. Gibbons expects him to get some reps in left.
Cons: He’s a corner infielder who has never played in the outfield as a big leaguer and has just four games of minor league experience in left field.
Free Agency
This late in the off-season there’s very little available on the free agent market. Even the top option available doesn’t look like a fit in Toronto:
Dayan Viciedo
Bats: R | Throws: R | Age: 25 | Roster status: free agent
Pros: Viciedo has 66 big league home runs, including 21 last year, to go along with an impressive .837 OPS against left-handed pitching. The team that signs him can control his rights through the 2017 season.
Cons: He’s viewed as a poor defender, and the numbers back that assessment up. He’s nothing special against right-handed pitching and he hasn’t posted an above-average OPS since 2010. Plus, the free agent Scott Boras client might prefer to play somewhere he’s assured of getting playing time all season long. All things being equal Toronto would presumably prefer a left-handed bat.
Trade Candidates
The Red Sox, Padres and Dodgers could all part with outfield depth, but it’s hard to imagine Boston dealing with Toronto. While Andre Ethier could be squeezed out in Los Angeles, there’s no reason the Blue Jays would choose to spend $56 million on a player coming off of the worst season of his career. The Padres might not mind dealing Cameron Maybin ($16 million in future commitments remaining) or Carlos Quentin ($8 million salary, 2014 knee injury), but neither player looks like a fit for Toronto. One of their teammates, on the other hand, could at least be a consideration later in the spring:
Will Venable
Bats: L | Throws: L | Age: 32 | Roster status: San Diego Padres
Pros: The left-handed hitting Venable has a career .751 OPS against right-handers, but he no longer has a starting role in San Diego. He generated at least 1.5 wins above replacement each season from 2009-2013 and even hit 22 homers in 2013. The Padres had enough confidence in his defence to make him a regular centre fielder in spacious Petco Park last year.
Cons: Venable posted a career-worst .613 OPS last year (well below league average even considering his home park) and dealt with some back soreness late in the season. He has a career OPS of .633 against lefties, so he’s best used in a platoon. He earns $4.25 million in 2015 and while that’s a reasonable salary considering his track record, the Blue Jays don’t appear to have tons of payroll flexibility.
Unfortunately for the Blue Jays, there doesn’t appear to be much out there. Relying on some combination of Pillar, Carrera, Dickerson and potentially Dirks might be necessary even if they’d project as a below-average combination in left field. Saunders’ return can’t come soon enough. |
1. Overview
===========
In this chapter, we broadly sketch the range of marine toxins that interact with voltage-gated sodium (Na~V~) channels, outlining their functional effects and discussing their actions in the context of recognized ligand binding sites on the channel. Four other articles in this issue provide more specialized treatments of different groups of toxins: tetrodotoxin resistance and adaptive mutations in targeted species (Geffeny and Ruben), ciguatoxins (Nicholson and Lewis), and conotoxins (Layer and McIntosh). We organize our presentation in terms of functional effects of the toxins, such as pore blockers and gating modifiers, and within these functionally circumscribed groups, we consider both peptide and non-peptide agents. Generally, the non-peptides are smaller metabolites, which are concentrated in food chains that may span from bacteria to vertebrates, and become of particular concern for human health and economic reasons during the phytoplankton blooms commonly known as "red tides" \[[@b139-marinedrugs-04-00157]\]. In contrast, the peptides of interest generally are larger molecules, which are elaborated in several phyla of eukaryotes, in specialized structures such as nematocysts or venom glands. The identification and classification of the Na~V~ channel receptors, through which both peptide and non-peptide toxins and modulators act, has progressed through definitions based strictly on functional interactions to, in some cases, identification of specific amino acid residues and atomic interactions involved. Where possible, we present our overview of functional groups of Na~V~ channel targeted toxins in the context of the relevant, recognized receptors on the channel.
2. Structure of Na~V~ channels
==============================
Eukaryotic Na~V~ channels are integral membrane proteins consisting of a main structural α subunit of \~2000 amino acids \[[@b22-marinedrugs-04-00157]--[@b24-marinedrugs-04-00157]\], and one or more β subunits \[[@b70-marinedrugs-04-00157]; [@b71-marinedrugs-04-00157]\]. Na~V~ channels are members of a family of voltage-gated ion channels which also includes calcium (Ca~V~) and potassium (K~V~) channels. The voltage-gated channels are members of a larger superfamily of P loop channels, which include the smaller inwardly rectifying K^+^ channels. The simplest members of the voltage-gated channel family are homotetrameric, and include a number of delayed rectifier K~V~ channels and certain prokaryotic Na~V~ channels \[[@b108-marinedrugs-04-00157]; [@b118-marinedrugs-04-00157]\]. Homotetrameric channels are presumably the evolutionary predecessors of the 4-domain members of the voltage-gated channel family.
The α subunit of Na~V~ channels ([Figure 1](#f1-marinedrugs-04-00157){ref-type="fig"}) is made up of four homologous domains, I-IV, each of which possesses six transmembrane helices, S1--S6, with cytoplasmic N- and C-termini. The cytoplasmic, III-IV connecting loop forms the fast inactivation gate of the channel \[[@b122-marinedrugs-04-00157]\]. Each of the four major domains can be sub-divided into a voltage sensing domain (S1--S4) and a pore-forming P domain (S5--S6). Within each P domain, the S5--S6 connector loops into the membrane to form, in sequence from its N- to C- terminal end, a random-coiled "turret", short supporting P helix, the lining outer pore including the narrowest part -- the selectivity filter, and a P-S6 connector. The P domain forms part or all of the receptors for a number of pore-blocking toxins and drugs, including guanidinium toxins and μ-conotoxins. The voltage-sensor domain includes a conspicuous S4 segment, with Arg or Lys residues, spaced generally at every third position, and comprising most of the charges contributing to gating charge movement generated during voltage-sensitive channel gating. A complementary acidic residue in S2 also makes some contribution to gating current \[[@b128-marinedrugs-04-00157]\]. Channel opening following voltage activation appears to occur by a conformational change near the crossing of S6 helices towards the cytoplasmic end of the conducting pore. Inactivation occurs on several time scales: fast -- gated by the III-IV linker latching to a receptor near the cytoplasmic end of the S6 segments, and a complex of slow inactivation processes which appear, at least, to involve conformational changes in the selectivity filter near the outer end of the pore \[[@b147-marinedrugs-04-00157]; [@b149-marinedrugs-04-00157]\]. Na~V~ channels typically show more than 10-fold selectivity for Na^+^ ions over other physiological ion species \[[@b63-marinedrugs-04-00157]\], based on a narrow selectivity filter \[[@b63-marinedrugs-04-00157]\], whose primary element is a ring of residues, DEKA \[[@b126-marinedrugs-04-00157]\], contributed by the DI-DIV respectively, arranged clockwise as viewed from the extracellular end of the conducting pore \[[@b37-marinedrugs-04-00157]; [@b84-marinedrugs-04-00157]\].
3. Drug and toxin receptors on Na~V~ channels
=============================================
Beginning in the 1960s and 1970s with the pioneering studies of Narahashi, Moore, Catterall and colleagues, ligand sites on Na~V~ channels have been identified and classified. Key pharmacological targets in Na~V~ channels tend to be clustered on the functionally important structures, which are intimately associated with activation and inactivation gating, and with ion conduction and selectivity. Nine receptors are widely recognized, as listed in [Table 1](#t1-marinedrugs-04-00157){ref-type="table"}.
In [Figure 2](#f2-marinedrugs-04-00157){ref-type="fig"}, we loosely map the nine receptor sites on to a cartoon derived from the recent crystal structure of the voltage-gated K^+^ channel, K~V~1.2, in [Figure 2](#f2-marinedrugs-04-00157){ref-type="fig"}. The K~V~1.2 structure \[[@b90-marinedrugs-04-00157]\] is the only available, high resolution structure of a voltage-gated eukaryotic channel, and thus provides the most up to date clues as to the likely structure of the four-domain Na~V~ and Ca~V~ channels. In the discourse which follows, we collect the different toxins into functional groups, each of which is cross-referenced to the receptor site with which it interacts, where this is known.
4. Na~V~ channel blockers and other inhibitors
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4.1. Receptor site 1
--------------------
We will define as pore "blockers" toxins which inhibit ion transport by sterically and/or electrostatically occluding the ion conducting pore of the channel. The best known Na~V~ pore blockers are tetrodotoxin (TTx), saxitoxin (STx) and the μ-conotoxins (see below). Receptor site 1 is located in the outer vestibule of the channel and is formed by the P loops from the four domains of the channel (see [Figs. 1](#f1-marinedrugs-04-00157){ref-type="fig"} and [2](#f2-marinedrugs-04-00157){ref-type="fig"}). Historically, the functional criterion for a toxin or drug to be considered to act at site 1 has been competition for binding with TTx or STx. The similar functional effects of chemically different blockers notwithstanding, the specific channel residues that make the most important contacts with different toxins and drugs will depend on the size and structure of the blocker. Thus, smaller heterocyclic toxins such as TTx and STx have less points of interaction with the pore than larger peptide molecules like the μ-conotoxins, which have a more complex set of contacts between ligand and receptor. The strongest known interactions of all of these toxins are in the vestibule-lining P loops within 3 or 4 residues on the C-terminal side of the residues making up the DEKA "inner ring" of the selectivity filter. Particularly important for binding of the GIII μ-conotoxins are the "outer ring" acidic residues located 3 (domains I, II, and IV) or 4 (domain III) residues C-terminal from the DEKA ring. In addition, extrapore residues have been shown to affect both affinity and selectivity among different channel isoforms \[[@b28-marinedrugs-04-00157]; [@b85-marinedrugs-04-00157]\]. Identified interactions of μ-conotoxin GIIIA have been recently reviewed in detail by French and Terlau \[[@b52-marinedrugs-04-00157]\].
Studies on rat brain channels identified the following domain I residues as important for high affinity TTx block: D384, E387, Y385 \[[@b100-marinedrugs-04-00157]; [@b143-marinedrugs-04-00157]\]. Here, we cite rNa~V~1.2 numbering, in which the inner DEKA ring is made up of D384, E942, K1422, and A1714. A somewhat different set of channel residues provided the most important interactions for STx. These included E942 and E945 (domain II), and K1422 and D1426 (domain III) \[[@b143-marinedrugs-04-00157]\]. A more recent, detailed analysis of interactions of TTx and STx with Na~V~1.4 has been provided by Dudley and colleagues \[[@b29-marinedrugs-04-00157]; [@b30-marinedrugs-04-00157]; [@b110-marinedrugs-04-00157]; [@b111-marinedrugs-04-00157]\].
Different channel isoforms from brain, heart and muscle have a different sensitivity to TTx, STx, and to μ-conotoxins. In TTx sensitive (TTx-s) channels in brain and adult skeletal muscle, an aromatic residue appears essential for high affinity block by TTx. In skeletal muscle (rNa~V~1.4), this is Y401, corresponding to F385 in a rat brain isoform (rNa~V~1.2), while the homologous residue in the relatively TTx-resistant (TTx-r) heart channel is C374 (rNa~V~1.5), as reviewed by Denac and coworkers \[[@b35-marinedrugs-04-00157]\]. A similar amino acid, located in the P loop regions, is associated with TTx sensitivity in different neuronal channels. In dorsal root ganglia neurons, F385 is found in TTx-s Na~V~ channels, while C or S is present in the homologous position in TTx-r channels, \[[@b104-marinedrugs-04-00157]\]. An earlier study found that mutation of E403Q in the rat skeletal muscle sodium channel, which essentially abolishes TTx and STx block, reduced sensitivity to μ-conotoxin GIIIA and GIIIB only about 4-fold \[[@b137-marinedrugs-04-00157]\].
Thus, different toxins may produce similar pharmacological effects by interacting with different subsets of residues within the same larger surface on the target channel molecule. The key to selective targeting of drugs may lie in a deeper understanding of the non-overlapping portions of larger receptor sites. Ecologically, Na~V~ channel blockers may play either defensive or offensive roles \[[@b120-marinedrugs-04-00157]\].
4.2. Non-peptide Na~V~ channel pore blockers and inhibitors
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### 4.2.1. Tetrodotoxin
Tetrodotoxin is one of the best known marine toxins because of health concerns based on its involvement in fatal food poisoning, its unique chemical structure, and its specific action of blocking Na~V~ channels of excitable membranes \[[@b27-marinedrugs-04-00157]; [@b64-marinedrugs-04-00157]; [@b164-marinedrugs-04-00157]; [@b167-marinedrugs-04-00157]\]. The toxin, whose name was derived from the order of fish with which it is most commonly associated, the Tetraodontiformes. There are more than 40 species of tetraodon pufferfish, known in Japan as fugu \[[@b27-marinedrugs-04-00157]\]. Other marine organisms, including polyclad flatworms \[[@b120-marinedrugs-04-00157]\], and some terrestrial poisonous animals, have also been found to store TTx. However, bony fish from the family Tetraodontidae are especially well known to cause tetrodotoxin poisoning. These fish do not possess a venom apparatus, but TTx may be found in all organs of the body. The occurrence and distribution of TTx among different phylogenic lines of organisms gave evidence for speculation that TTx and its derivatives originated from symbiotic microorganisms. Indeed, a number of bacteria, including the genera *Aeromonas* and *Alteromonas*, *Escherichia coli*, *Photobacterium phosphoreum*, *Plesiomonas shigelloides*, *Pseudomonas sp.* and some *Vibrio sp*. have been shown to produce TTx (reviewed in \[[@b51-marinedrugs-04-00157]; [@b79-marinedrugs-04-00157]; [@b164-marinedrugs-04-00157]\]).
TTx is of amphoteric nature with an unusual tricyclic structure ([Figure 3-A](#f3-marinedrugs-04-00157){ref-type="fig"}). It possesses both cationic (guanidine) and anionic (acid hydroxyl) groups. TTx binds with high affinity \[dissociation constant (*K~d~*) in the nM concentration range\] to the external surface of Na~V~ channels by binding to site 1 of these channels \[[@b27-marinedrugs-04-00157]\]. The positively charged guanidinium group interacts with a negatively charged carboxyl group at the mouth of the Na~V~ channel on the extracellular side of plasma membranes of excitable membranes. When it does so, the inward flow of Na^+^ through the channel pore is blocked, leading to inhibition of action potential generation and propagation \[[@b64-marinedrugs-04-00157]; [@b79-marinedrugs-04-00157]\]. Seven derivatives of TTx have been detected in puffer fish, newts and poisonous frogs. These TTx derivatives vary in their potencies \[[@b164-marinedrugs-04-00157]\]. The value of this particular toxin in electrophysiological research is profound. Recent models of the molecular structure of the Na~V~ pore have been strongly based on interactions with this toxin, and Na~V~ channels are often divided broadly into two pharmacological classes, TTx-s and TTx-r.
### 4.2.2. Saxitoxin
Paralytic shellfish poisoning (PSP) is a deadly affliction that results from the accidental consumption of some potent natural neurotoxins, typically via contaminated seafood \[[@b114-marinedrugs-04-00157]\]. Among all seafood poisoning, PSP poses the most serious threat to public health, and the economic damage caused by accumulation of toxins in shellfish is immeasurable (see \[[@b79-marinedrugs-04-00157]\] and references therein). Saxitoxin (STx) and its analogs are collectively called paralytic shellfish toxins (PST) and are considered the causative agents for PSP. The name STx was derived from the mollusc in which it was first identified, *Saxidomus giganteus*\[[@b79-marinedrugs-04-00157]\]. Toxins are present in dinoflagellates such as *Alexandrium sp*., *Pyrodinium bahamense var. compressum* and *Gymnodinium catenatum* \[[@b88-marinedrugs-04-00157]; [@b135-marinedrugs-04-00157]\] during red tides, which causes STx to be concentrated by filter-feeding shellfish and subsequently, to be conveyed to humans when they consume the shellfish. Neurological symptoms occur shortly after the time of ingestion, and, in extreme cases, can lead into death \[[@b166-marinedrugs-04-00157]\]. Although it has been generally considered that PST are associated with dinoflagellates, there is evidence that heterotrophic bacteria are responsible for toxin synthesis in these organisms \[[@b31-marinedrugs-04-00157]; [@b55-marinedrugs-04-00157]; [@b92-marinedrugs-04-00157]; [@b148-marinedrugs-04-00157]\].
The saxitoxins are a family of water-soluble neurotoxins and are among the most potent toxins known. Information on the toxicity of saxitoxins is mainly restricted to acute toxicity in mammals and humans (reviewed in \[[@b79-marinedrugs-04-00157]\]). For example, the LD~50~ values (lethal dose/concentration for 50% of population) of STx by intravenous, intraperitoneal and oral routs in mice are 2.4 μg/kg, 10 μg/kg and 263 μg/kg, respectively. Saxitoxins are tricyclic compounds ([Figure 3-B](#f3-marinedrugs-04-00157){ref-type="fig"}) and their molecular skeletons are structurally related to TTx, but with two guanidinium moieties \[[@b131-marinedrugs-04-00157]\] in STx compared to the one guanidinium moiety in TTx. More than 20 analogs have been described \[[@b79-marinedrugs-04-00157]\]. Like the case of TTx, saxitoxins are well documented non-peptide neurotoxins that are highly selective blockers of Na~V~ channels in excitable cells at site 1, thereby affecting nerve and muscle impulse generation in animals \[[@b27-marinedrugs-04-00157]; [@b64-marinedrugs-04-00157]; [@b131-marinedrugs-04-00157]; [@b164-marinedrugs-04-00157]; [@b167-marinedrugs-04-00157]\]. Recently a new, exceptionally potent derivative of saxitoxin has been described \[[@b165-marinedrugs-04-00157]\].
### 4.2.3. Meroditerpenoids
Brown algae (Phaeophyceae) produce a variety of secondary metabolites possessing many different structural varieties and biological activities (\[[@b50-marinedrugs-04-00157]\] and reviews therein). The genus *Stypopodium* is a tropical group of the Phaeophyceae well-known for its rich complement of polycyclic diterpenoids fused to oxidized aromatic rings (meroditerpenoids) \[[@b50-marinedrugs-04-00157]\]. These terpenoid metabolites are useful chemotaxonomic markers because of their structural complexity and genetic origins \[[@b56-marinedrugs-04-00157]\]. Meroditerpenoids display potent biological activities, with toxic and enzyme-modulating functions, which may be of biomedical and pharmacological utility \[[@b155-marinedrugs-04-00157]\]. Three new meroditerpenoids, 2β,3α-epitaondiol ([Figure 3-C-1](#f3-marinedrugs-04-00157){ref-type="fig"}), flabellinol ([Figure 3-C-2](#f3-marinedrugs-04-00157){ref-type="fig"}) and flabellinone ([Figure 3-C-3](#f3-marinedrugs-04-00157){ref-type="fig"}), from *Stypopodium flabelliforme* were assayed to have neurotoxic and Na~V~ channel modulation activity \[[@b123-marinedrugs-04-00157]\]. In this study, these compounds were cytotoxic to NCI-H460 cells with an LD~50~ of 24, 9, and 14 μM, respectively. In a Na~V~ channel modulation assay using the neuro-2a neuroblastoma cell line, with STx as a control inhibitor, these compounds showed detectable Na~V~ channel blocking activity at 0.7, 2, and 7 μM, respectively. Overall, these meroditerpenoid metabolites show a broad range of biological activities, including being toxic to fish and brine shrimp, and to some human cancer cells. Some of this toxicity may be due to a blocking of Na~V~ channels \[[@b50-marinedrugs-04-00157]; [@b123-marinedrugs-04-00157]\].
4.3. Peptide Na~V~ channel pore blockers and other inhibitors
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### 4.3.1. μ-Conotoxins
Conotoxins in general, and μ-conotoxins in particular, are found in the venom of predatory tropical marine cone snails, genus *Conus*. Venom is a primary weapon used by these molluscs to capture prey (small fish or invertebrates) and to defend themselves. Venoms of all cone snails are complex and an individual species may express 100--200 venom peptides. Toxic components of the venom are mostly small peptides \[[@b106-marinedrugs-04-00157]\], which are synthesized in a tubular venom duct. All cone snails have specialized radular teeth that penetrate the skin of prey and inject venom. These teeth work as a harpoon and sharp needles. After the venom injection, the prey becomes quickly paralyzed and is now available for consumption. Some fish-hunting species (e.g., *Conus geographus*) are dangerous to humans, and fatalities have been recorded in the medical literature \[[@b144-marinedrugs-04-00157]\].
μ-Conotoxins are highly basic, cysteine-rich peptides which have three disulphide bridges in the three loop framework. The amino acid sequences of seven μ-conotoxins showed in [Figure 4](#f4-marinedrugs-04-00157){ref-type="fig"}, and some basic properties of these μ-conotoxins are displayed in [Table 2](#t2-marinedrugs-04-00157){ref-type="table"}.
The number of recognized μ-conotoxins is rapidly increasing, thanks to a combination of molecular cloning techniques to identify new sequences, and application of improved synthetic procedures to produce oxidized, active conformations of the folded toxins (see [Table 3](#t3-marinedrugs-04-00157){ref-type="table"}). NMR-derived 3D structures of GIIIA, PIIIA and SmIIIA are shown in [Figure 5](#f5-marinedrugs-04-00157){ref-type="fig"}. Discovery of new toxins is revealing increased functional diversity in the μ-conotoxin family. In addition, recent work shows that there is a divergence of the disulfide framework generating structural diversity among the μ-conotoxins \[[@b32-marinedrugs-04-00157]\]. At present time, no μ-conotoxins are used directly in a clinical application. However, discovery of new isoform-specific μ-conotoxins from *Conus* venoms, or constructs not existing in nature, offers a promising way to neurologically active drugs \[[@b1-marinedrugs-04-00157]\]. Discoveries of μ-conotoxins SmIIIA, SIIIA and KIIIA open new opportunities for creation of specific drugs for pain relief. These toxins block the TTx-r Na~V~ channels that are responsible for pain signal propagation in dorsal root ganglia neurons.
### 4.3.2. μO-Conotoxins
The μO- and δ-conotoxins are unusually hydrophobic peptides, which belong to the O-superfamily of conotoxins. The δ-conotoxins inhibit inactivation of Na~V~ channels, while μO-conotoxins affect both Na^+^ and Ca^2+^ currents \[[@b48-marinedrugs-04-00157]\]. μO-conotoxins were first isolated from the cone snail, *Conus marmoreus* \[[@b48-marinedrugs-04-00157]; [@b95-marinedrugs-04-00157]\]. *C. marmoreus* is a molluscivorous (snail hunting) cone snail which can be found in the waters of the Philippines \[[@b95-marinedrugs-04-00157]\]. To date, only two μO-conotoxins have been discovered, the MrVIA and MrVIB, both from *C. marmoreus*. Both of these toxins are 31 residues long, with three intramolecular disulphide bonds. They show high sequence homology with only two residues not conserved between the two toxins. The 3D solution structures of these toxins were first determined using simulated annealing procedures and based on NMR data \[[@b34-marinedrugs-04-00157]\]. The μO-conotoxins inhibit Na~V~ channels as well as molluscan calcium channels \[[@b48-marinedrugs-04-00157]\].
The chemical structure of μO-conotoxins has similarities with δ-conotoxins, and the ω-conotoxins (which target calcium channels and not discussed further in this chapter) \[[@b34-marinedrugs-04-00157]\]. The block of Na~V~ channels by the μO-conotoxins seems to be independent of site 1, at which TTx, STx, and the μ-conotoxins bind, and shows no effect on either activation or inactivation of the channel \[[@b146-marinedrugs-04-00157]\]. Competition studies showed that the μO-conotoxins have no effect on the binding of \[^3^H\]STx. Furthermore, targeting of μO-conotoxins differs significantly from the μ-conotoxins. As well as inhibiting TTx-s Na~V~ channels from brain (Na~V~1.2) with IC~50~ (concentration producing 50% inhibition) values of 200 nM \[[@b146-marinedrugs-04-00157]\], they also block TTx-r Na~V~ channels from the rat dorsal root ganglion (probably Na~V~1.8) with IC~50~ values of 82.8 nM. The equivalent TTx-r channels in humans are responsible for transmission of pain sensation, which makes μO-conotoxins a very promising therapeutic agents \[[@b34-marinedrugs-04-00157]\]. However, the molecular mechanisms of interaction of the μO-conotoxins with Na~V~ and Ca~V~ channels are not yet well understood.
### 4.3.3. Unclassified conotoxins, GS and TVIIA
The unusual properties of some conotoxins do not allow them to be grouped within the known families \[[@b144-marinedrugs-04-00157]\]. For example, TVIIA from the venom of *Conus tulipa,* a 30-residue polypeptide, displays high sequence identity with conotoxin GS, from venom of *Conus geographus*. Although there are reports indicating that GS binds to the TTx receptor in rat skeletal muscle, no more detailed functional studies have appeared. Their overall structure suggests that GS and TVIIA represent a distinct subgroup of the family which includes the Ca~V~-targeted *ω*-conotoxins \[[@b62-marinedrugs-04-00157]\].
4.4. Lipopeptide Na~v~ channel inhibitors
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### 4.4.1. Jamaicamides
Screening extracts from marine Dinoflagellate *Lyngbya majuscule* revealed a number of potently bioactive metabolites (\[[@b20-marinedrugs-04-00157]\] and reviews therein). Jamaicamides A-C ([Figure 6-A](#f6-marinedrugs-04-00157){ref-type="fig"}) are recently characterized polyketide-peptide neurotoxins from *L. majuscule*\[[@b38-marinedrugs-04-00157]\]. The latter authors examined the neurotoxic activity of crude extracts as well as purified jamaicamide compounds. Neither jamaicamide A nor B showed significant brine shrimp toxicity, while jamaicamide C was only modestly active at 10 ppm (25% lethality).
In the goldfish toxicity assay, jamaicamide B was the most active (100% lethality at 5 ppm after 90 min), followed by jamaicamide C (100% lethality at 10 ppm after 90 min). Interestingly, jamaicamide A was the least active fish toxin (sublethal toxicity at 10 ppm after 90 min). Also, Jamaicamide compounds exhibited cytotoxicity to both the H-460 human lung and neuro-2a mouse neuroblastoma cell lines. Using a bioassay method, modified from Manger et al. \[[@b91-marinedrugs-04-00157]\], it has been suggested Na~V~ channel modulation by jamaicamides A-C \[[@b38-marinedrugs-04-00157]\]. The LD~50~s from these bioassays were approximately 15 μM for all three compounds in both cell lines. All three compounds also inhibited Na~V~ channel activity at 5 μM, producing approximately half the response of STx applied at 0.15 μM. None of the jamaicamides were shown to activate the tested Na~V~ channels. Overall, jamaicamides show a spectrum of biological activities consistent with their functioning as defense metabolites, including Na~v~ channel blocking activity, and arthropod and fish toxicity. Further work should be done to study the molecular interaction of jamaicamide compounds with Na~V~ channels.
### 4.4.2. Kalkitoxin
Kalkitoxin (KTx) is a neurotoxic, thiazoline-containing lipopeptide (see [Figure 6-B](#f6-marinedrugs-04-00157){ref-type="fig"}) from a Caribbean dinoflagellate, *Lyngbya majuscule*\[[@b160-marinedrugs-04-00157]\]. This toxin acts exclusively as a potent blocker of activated TTx-s Na~V~ channels in mouse neuron-2a cells (50% block occurred at IC~50~ = 1 nM, compared to the STx IC~50~ = 8 nM; \[[@b160-marinedrugs-04-00157]\]). In another study, KTx produced *N-*methyl-D-aspartate (NMDA) receptor-dependent cytotoxicity in rat cerebellar granule neurons, with an LD~50~ of 3.86 ± 1.91 nM \[[@b9-marinedrugs-04-00157]\]. It is somewhat surprising that the agonist, antillatoxin (ATx, see below), also induced cytotoxicity that was prevented by non-competitive NMDA receptor antagonists. Nevertheless, the cytotoxicity responses to ATx and KTx displayed distinct temporal patterns \[[@b9-marinedrugs-04-00157]\], in that ATx induced an acute response, whereas KTx produced delayed cytotoxicity. Thus, cytotoxicity may be induced by different pathways in these two cases. Additionally, KTx is highly active in an inflammatory disease model which measures IL-1β-induced secreted phopholipase A~2~ secretion from HepG2 cells (IC~50~ = 27 nM; \[[@b160-marinedrugs-04-00157]\]). Recently, KTx was shown to interact with TTx-s Na~V~ channels at site 7 in cerebellar granule neuron cultures \[[@b81-marinedrugs-04-00157]\]. Consistent with previous work, KTx may be a valuable tool in efforts to more clearly define the structure-function relationships of these Na~V~ channels, and may provide possible leads for analgesic and neuroprotection drug discovery.
5. Gating modifiers
===================
5.1. Non-peptide Na~V~ channel modulators
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### 5.1.1. Alkaloid inhibitors of Na^+^ channels
Marine organisms are known to produce compounds with novel chemical structures and interesting biological activities. Apart from algae, cone snails, sea anemones and many other organisms, sponges are the source of the greatest diversity of marine natural products (see references \[[@b15-marinedrugs-04-00157]; [@b50-marinedrugs-04-00157]\] and previous reviews cited therein). Alkaloid compounds found in tropical *Agelas* sponges have been shown to be active on muscle and nerve membrane receptors and channels, including Na~V~ channels, and are excellent pharmacological tools to study the physiology and biophysics of these macromolecules \[[@b119-marinedrugs-04-00157]\]. Morales and Rodriguez \[[@b96-marinedrugs-04-00157]\] reported that Caribbean sponges of the genus *Agelas* contain alkaloids including monomers of clathrodin (CLA, [Figure 7-A](#f7-marinedrugs-04-00157){ref-type="fig"}) and dibromosceptrin (DBS, [Figure 7- B](#f7-marinedrugs-04-00157){ref-type="fig"}). Both compounds have guanidine moieties linked to pyrrol groups with bromide substitutions ranging from none (CLA) to four (DBS). Use of the whole-cell configuration of the patch-clamp technique revealed that these compounds have neurotoxic activity \[[@b119-marinedrugs-04-00157]\]. Both compounds decreased the average maximum amplitude of inward Na^+^ current by 27--40% on cells isolated from sympathetic ganglia of chick embryo to test the CLA and DBS effect on provoked Na^+^ currents. In this study, neither compound altered the voltage dependence of current activation.
However, the voltage dependence of current inactivation was shifted toward more negative potentials by DBS. In contrast, CLA shifted this voltage dependence of inactivation toward more positive potentials. Time for current reactivation was not altered by CLA but was slightly prolonged by DBS. Similarly, DBS was more effective than CLA in prolonging the time course of current decay. Voltage clamp experiments on frog muscle showed that both CLA and DBS alter the voltage-dependent ionic currents, with CLA causing an early potentiation followed by total inhibition, and DBS exerting an immediate current blockade \[[@b119-marinedrugs-04-00157]\].
CLA and DBS effects on ionic channels were examined using CLA and DBS in radioligand binding studies, which showed that DBS inhibited nearly 90% of \[^3^H\]-STx binding to rat brain synaptosomes while CLA inhibited only 30% \[[@b119-marinedrugs-04-00157]\]. Thus, CLA and DBS are Na~V~ channel neurotoxins which bind to a site that inhibits STx binding. Nevertheless, further investigation is needed to specify the molecular target of each toxin. Functionally, CLA and DBS modulate Na~V~ channels by different mechanisms; DBS, a dimer with four bromide substitutions, acted on the voltage-dependence of inactivation, while CLA, the monomer without bromide substitutions, was directed towards the channel ionic conductance. Recently, DBS has been shown to disrupt the cellular calcium homeostasis, by targeting Ca~V~ channels (IC~50~ \~μM) in PC12 cells \[[@b11-marinedrugs-04-00157]\]. This potent effect of DBS on Ca^2+^ influx and Ca^2+^ levels in neurons and sensory cells is consistent with that the previously reported feeding deterrent activity of brominated pyrrole alkaloids in *Agelas* sponges against predatory reef fish (reviewed by \[[@b87-marinedrugs-04-00157]\]). Furthermore, chemoreception, sensing bromopyrrole alkaloids in sea water, was exhibited by sensory neurons in the rhinophore of the sea slug *Aplysia punctata*\[[@b11-marinedrugs-04-00157]\].
### 5.1.2. Brevetoxins
The brevetoxins, are part of a large family of dinoflagellate-derived polyketide toxins which pose a threat to human health through the consumption of tainted seafood. This family also includes ciguatoxin, okadaic acid and the related dinophysis toxins, pectenotoxins, yessotoxin and the azaspir acids \[[@b136-marinedrugs-04-00157]\]. Ingestion of bivalve molluscs contaminated with brevetoxins leads to neurotoxic shellfish poisoning (NSP), the symptoms of which include nausea, cramps, paresthesias of lips, face and extremities, weakness and difficulty in movement, paralysis, seizures and coma \[[@b4-marinedrugs-04-00157]; [@b39-marinedrugs-04-00157]; [@b94-marinedrugs-04-00157]\]. Inhalation of aerosolized brevetoxins from sea spray results mainly in respiratory irritation as well as dizziness, tunnel vision and skin rashes \[[@b4-marinedrugs-04-00157]; [@b112-marinedrugs-04-00157]\].
Brevetoxins (PbTx-1 to PbTx-10) are potent lipid-soluble polyether neurotoxins produced by the marine dinoflagellate, *Karenia brevis* (formerly known as *Gymnodium breve* or *Ptychodiscus breve*; \[[@b2-marinedrugs-04-00157]\]). These organisms are associated with 'red tide' blooms in the Gulf of Mexico and in New Zealand \[[@b69-marinedrugs-04-00157]\]. Brevetoxins exert a variety of actions *in vivo* affecting both the PNS as well as the CNS, probably due to their high lipid solubility and ability to penetrate the blood brain barrier \[[@b78-marinedrugs-04-00157]\]. The brevetoxins are a suite of polyether ladder type compounds which have two parent backbone structures, brevetoxin A and brevetoxin B, each with several side chain variants \[[@b3-marinedrugs-04-00157]\] ([Figure 8-A](#f8-marinedrugs-04-00157){ref-type="fig"}). Brevetoxin 1, PbTx-1 from group A, is the most active ichthyotoxic brevetoxin analog with IC~50~ values ranging between 3 and 4 nM \[[@b2-marinedrugs-04-00157]\].
Brevetoxins are known to interact specifically with neurotoxin receptor site 5 on the α subunit of Na~V~ channels \[[@b2-marinedrugs-04-00157]\]. This interaction with the α subunit causes a shift in the voltage dependence of channel activation to more negative potentials and inhibits channel inactivation, thereby producing neuronal depolarization at rest \[[@b26-marinedrugs-04-00157]; [@b113-marinedrugs-04-00157]; [@b116-marinedrugs-04-00157]; [@b117-marinedrugs-04-00157]; [@b129-marinedrugs-04-00157]\]. In addition, brevetoxins augment Na^+^ influx through Na~V~ channels because of the shift in activation, and by prolonging channel opening, resulting in a dose-dependent depolarization of excitable membranes \[[@b72-marinedrugs-04-00157]\]. Bottein Dechraoui and Ramsdell \[[@b16-marinedrugs-04-00157]\] showed that type A (PbTx-1) and type B (PbTx-3 and PbTx-2) brevetoxins, as well as ciguatoxins, target both cardiac and muscle channels. Type B brevetoxins show isoform selectivity, presenting a lower affinity for the cardiac (Na~V~1.5) than the skeletal muscle (Na~V~1.4) Na~v~ channel isoforms expressed in Human Embryonic Kidney (HEK) cells. The lower affinity of type B brevetoxins for heart Na~v~ channels may result from a more rigid backbone structure than that found in type A brevetoxins and in ciguatoxins. On the other hand, PbTx-2 augmented NMDA receptor function and, therefore, may exacerbate NMDA receptor-mediated pathologic sequelae associated with neurodegenerative diseases \[[@b36-marinedrugs-04-00157]\]. Furthermore, a series of naturally occurring fused-ring polyether compounds with fewer rings than brevetoxin, known as brevenals, were shown to exhibit antagonistic properties and counteract the effects of the brevetoxins in neuronal and pulmonary model systems \[[@b3-marinedrugs-04-00157]\]. This finding supports the idea that the toxicity of the red tide blooms depends on the amount of each toxin present as well as the spectrum of molecular activities elicited by each toxin.
### 5.1.3. Ciguatoxins
The term ciguatera originated in the Caribbean areas to designate intoxication induced by the ingestion of the marine snail *Turbo pica* (called cigua), first described by Cuban ichthyologists (reviewed by \[[@b109-marinedrugs-04-00157]\]). Today, the term is widely used to denote a fish-poisoning that result from ingestion of ciguatoxic fish found mainly in tropical and subtropical regions \[[@b83-marinedrugs-04-00157]\]. Human victims are the end link in a food chain cascade where ciguatoxins are accumulated in a variety of consumed coral reef fishes \[[@b82-marinedrugs-04-00157]\]. Ciguatoxins (CigTx) are lipid-soluble, heat-stable, highly oxygenated cyclic polyether marine toxins originally produced in coral reef areas by the benthic dinoflagellate *Gambierdiscus toxicus*. Ciguatoxins are responsible for a complex human food poisoning, characterized by gastrointestinal, neuronal and cardiovascular disturbances with no immunity and symptoms may persist for months or years \[[@b79-marinedrugs-04-00157]\]. The symptoms of ciguatera fish poisoning overlap those of the brevetoxins with temperature reversal as supposedly unique for ciguatoxins \[[@b112-marinedrugs-04-00157]\]. Moreover, epidemiology of the CigTx poisoning is complex and impossible to predict outbreaks with global health concern. Worldwide coral bleaching, together with man-made factors (such as tourism, industrial constructions, sewage and eutrophication) and environmental factors (such as earthquakes and hurricanes) create a more favorable environment for *G. toxicus* blooms and therefore trigger ciguatera outbreaks \[[@b79-marinedrugs-04-00157]\].
More than 20 CigTx analogs have been found, and grouped according to their origins and carbon backbone, as Pacific (P-CigTx; [Figure 8-B](#f8-marinedrugs-04-00157){ref-type="fig"}) or Caribbean (C-CigTx; [Figure 8-B](#f8-marinedrugs-04-00157){ref-type="fig"}) ciguatoxins \[[@b93-marinedrugs-04-00157]; [@b109-marinedrugs-04-00157]\]. These polyether toxins are highly toxic to fish (LD~50~ 1 μg/kg; \[[@b79-marinedrugs-04-00157]\]) and to mammals (LD~50~ for mouse near 1 μg/kg; \[[@b83-marinedrugs-04-00157]\]). Interestingly, the more oxidized form, P-CigTx, is up to 10-fold more toxic than the less oxidized form, C-CigTx \[[@b83-marinedrugs-04-00157]; [@b164-marinedrugs-04-00157]\]. This increase in potency amplifies the effective level of more oxidized forms of CigTx accumulated by fish. Extensive experimental studies of Pacific ciguatoxins, using whole-cell patch clamp of rat dissociated dorsal root ganglion neurons, have shown that P-CigTx-1 causes TTx-s Na~V~ channels to open at more negative membrane potentials than normal. By contrast, TTx-r Na~V~ channels recover from inactivation more quickly, enabling an earlier transition to the open state \[[@b138-marinedrugs-04-00157]\]. These properties, combined with the high lipid solubility of the toxin explain, at least in part, the pathogenic nature of the neurological symptoms, including the pathogenesis of sensory neurological disturbances associated with ciguatoxic fish poisoning.
Pharmacological studies have revealed that ciguatoxins activate Na~V~ channels in the nM to pM range \[[@b7-marinedrugs-04-00157]; [@b12-marinedrugs-04-00157]; [@b16-marinedrugs-04-00157]; [@b83-marinedrugs-04-00157]; [@b89-marinedrugs-04-00157]\]. Specifically, ciguatoxins cause a hyperpolarizing shift in the voltagedependence of the channel activation, increasing the open probability of Na~V~ channels at normal resting membrane potentials \[[@b7-marinedrugs-04-00157]; [@b12-marinedrugs-04-00157]; [@b89-marinedrugs-04-00157]\]. These toxic effects lead to a TTx-s, Na^+^-dependent membrane depolarization, and repetitive or spontaneous action potentials, in various axons and skeletal muscle fibers \[[@b16-marinedrugs-04-00157]; [@b83-marinedrugs-04-00157]; [@b93-marinedrugs-04-00157]\]. Ciguatoxins in common with brevetoxins selectively target a common receptor site, receptor site 5, on Na~V~ channel proteins \[[@b12-marinedrugs-04-00157]; [@b89-marinedrugs-04-00157]; [@b93-marinedrugs-04-00157]\]. Because of their potency, ciguatoxins can be useful pharmacological tools to study Na~V~ channels, as are TTx, STx and PbTx. Moreover, an increase of Na^+^ influx through activation of these channels at the resting membrane potential, is not only able to enhance nerve excitability but also may cause water movements across the cell membrane \[[@b93-marinedrugs-04-00157]\]. These toxins may be useful tools to study the Na^+^-dependent mechanisms of volume changes and their homeostasis in nerve preparations.
### 5.1.4. Ostreotoxin-3
More than 20 species of marine dinoflagellates produce toxins that are among the most potent, nonpertinacious toxin known \[[@b20-marinedrugs-04-00157]; [@b49-marinedrugs-04-00157]; [@b159-marinedrugs-04-00157]; [@b164-marinedrugs-04-00157]\]. These dinoflagellate toxins have been implicated in human intoxications resulting from consumption of poisonous fish and shellfish \[[@b159-marinedrugs-04-00157]; [@b164-marinedrugs-04-00157]\]. The benthic dinoflagellate, *Ostreopsis lenticularis,* is the producer of this Na~V~ channel activating toxin, Ostreotoxin-3 \[OTx-3; \[[@b44-marinedrugs-04-00157]\]\]. Toxicity of OTx-3 was first revealed when *O. lenticularis* cells treated with acetone before methanol extraction showed a 10-fold increase in mouse toxicity \[[@b44-marinedrugs-04-00157]\]. Experiments in chick embryo sympathetic neurons demonstrated that OTx-3 extracts were acting on TTx-s Na~V~ currents \[[@b44-marinedrugs-04-00157]\]. The extract affected the voltage-dependence by shifting the activation and inactivation currents to more negative potentials but its major effect was on inactivation. In the presence of μ-conotoxin GIIIA, the remaining Na^+^ current was not altered by OTx-3 extracts. Meunier et al. \[[@b44-marinedrugs-04-00157]\] performed intracellular recording experiments which demonstrated that OTx-3-enriched extracts depolarized frog skeletal muscle and decreased the amplitude of endplate potentials without affecting the nerve impulse. This effect was partially blocked by 10 μM TTx and totally blocked by μ-conotoxin GIIIA. Thus, the toxic effect of *O. lenticularis* extracts may be due to the presence OTx-3 that recognized TTx-s Na~V~ currents. OTx-3 is a unique dinoflagellate toxin that can discriminate between nerve and skeletal muscle.
5.2. Peptide Na~V~ channel gating modifiers
-------------------------------------------
### 5.2.1. Antillatoxin
Blooms of the dinoflagellate, *Lyngbya majuscule,* have been associated with various adverse effects on human health, including respiratory irritation, eye inflammation, and severe contact dermatitis in exposed individuals \[[@b21-marinedrugs-04-00157]; [@b97-marinedrugs-04-00157]\]. These effects are associated with the production of toxic substances by *L. majuscule* such as lyngbyatoxins \[[@b21-marinedrugs-04-00157]; [@b131-marinedrugs-04-00157]; [@b164-marinedrugs-04-00157]\] and debromoaplysiatoxin \[[@b97-marinedrugs-04-00157]; [@b131-marinedrugs-04-00157]\]. Other toxic secondary metabolites target Na~V~ channels, (see [Table 1](#t1-marinedrugs-04-00157){ref-type="table"}); these include antillatoxin \[[@b107-marinedrugs-04-00157]\], kalkitoxin \[[@b9-marinedrugs-04-00157]; [@b160-marinedrugs-04-00157]\] and jamaicamides A-C \[[@b38-marinedrugs-04-00157]\]. The diversity of these natural products gives them potential for importance as biochemical and pharmacological tools.
Antillatoxin (ATx) is a structurally unusual cyclic lipopeptide ([Figure 9](#f9-marinedrugs-04-00157){ref-type="fig"}), which has been reported to be among the most ichthyotoxic metabolite isolated to date from a marine dinoflagellate. It is exceeded in potency only by the brevetoxins \[[@b107-marinedrugs-04-00157]\]. ATx ichthyotoxic activity with LD~50~ value of 0.05 μg/ml using fish toxicity bioassay \[[@b107-marinedrugs-04-00157]\]. Using cerebellar granule cells, ATx produced concentrationdependent cytotoxicity with LD~50~ value of 20.1 ± 6.4 nM \[[@b9-marinedrugs-04-00157]\]. In the latter study, the neurotoxic response of ATx was prevented by co-application with noncompetitive antagonists of the NMDA receptor such as MK-801 (or dizocilpine) and dextrorphan. This neurotoxic effect of ATx was antagonized by TTx, consistent with an interaction of ATx with Na~V~ channels \[[@b86-marinedrugs-04-00157]\]. ATx-induced stimulation of Ca^2+^ influx in cerebellar granule cells was similarly prevented by TTx. Additional, more direct, evidence that the Na~V~ channel serves as the molecular target for ATx was provided by the demonstration that ATx stimulation of \[^3^H\]batrachotoxin binding increases ^22^Na^+^ influx in cerebellar granule cells \[[@b86-marinedrugs-04-00157]\]. Together, these results suggest that ATx is a novel activator of Na~V~ channels, most probably acting at site 4. The precise recognition site for ATx on the Na~V~ channel, however, remains to be defined. It has been suggested that development of antagonists targeted at the ATx lipopeptide site may provide another means of inhibiting Na~V~ channels, and thereby a new strategy for the discovery of anticonvulsant and neuroprotectant drugs \[[@b86-marinedrugs-04-00157]\].
Recently, a new *N*-methyl homophenylalanine analog of ATx was identified and denoted as antillatoxin B (ATx-B; \[[@b101-marinedrugs-04-00157]\], [Figure 9](#f9-marinedrugs-04-00157){ref-type="fig"}). Both ATx and ATx-B are potent activators of the Na~V~ channel in mouse neuro-2a neuroblastoma cells, with half-maximal activation at EC~50~ values of 0.18 and 1.77 μM, respectively. In addition, ATx B is strongly ichthyotoxic to goldfish, with an LD~50~ of 1.0 μM. It seems likely that substitution of a larger *N*-methyl homophenylalanine residue in ATx-B for an *N*-methyl valine residue in ATx accounts for the 10-fold decrease in ATx-B's potency in compare to ATx \[[@b101-marinedrugs-04-00157]\].
5.3. Peptide gating modifiers
-----------------------------
### 5.3.1. Sea anemone toxins
Sea anemones are a member of the phylum Cnidaria, which have stinging organelles known as nematocysts, housing tiny harpoons, on their tentacles. Sea anemones have adapted their venom apparatus for use in both protection and prey capture. They have been known to capture both small fish and crustaceans. Toxins produced by sea anemones encompass many targets including both K~V~ and Na~V~ channels, while some species have cytolysins. Sea anemones have a wide variety of Na~V~ channel toxins that affect inactivation from the extracellular side of the channel. Sea anemone toxins were first isolated as cardiac stimulators and neurotoxins and these are the two actions that have been studied the most. Sea anemone toxins affecting Na~V~ channels range in size from 3--5 kDa and have been isolated from many different species \[[@b102-marinedrugs-04-00157]\]. Sea anemone toxins bind to Na~V~ channels of excitable tissue and preferentially act on the open state to inhibit inactivation of the channel \[[@b35-marinedrugs-04-00157]\]. Sea anemone toxins bind to site 3 on the Na~V~ channel \[[@b27-marinedrugs-04-00157]\] in domain IV on the S3--S4 linker. The binding to this linker prevents the necessary movement of the voltage sensing S4 segment during fast inactivation. Sea anemone toxins bind to a receptor which partially overlaps that of scorpion toxins, as seen in binding studies of the interaction between the sea anemone toxin, AneTx II, and the scorpion toxin, LqTx \[[@b121-marinedrugs-04-00157]\].
Sea anemone toxins, because of their large variety, can be split into three distinct groups called Type-1, Type-2 and Type-3. These groups are distinguished based on both their size and the genus from which they were isolated. Type-1 and Type-2 sea anemone toxins usually range from about 46--49 amino acids in length. Type-1 toxins were isolated from the family *Actiniidae,* mostly from the genera *Anemonia* and *Anthopleura*. Both of these genera produce several neurotoxins that affect Na~V~ channels. For example, AFT I, AFT II \[[@b141-marinedrugs-04-00157]\], Anthopleurin-A \[[@b142-marinedrugs-04-00157]\], Anthopleurin-B \[[@b115-marinedrugs-04-00157]\], Anthopleurin-Q \[[@b53-marinedrugs-04-00157]\], and APE 1 to APE 5 \[[@b17-marinedrugs-04-00157]\], are produced by *Anthopleura* spp., while AneTx I, AneTx II, AneTx V \[[@b125-marinedrugs-04-00157]; [@b161-marinedrugs-04-00157]; [@b162-marinedrugs-04-00157]\] are produced by members of the genus *Anemonia*. Type-2 toxins have been isolated from two genera *Heteracti* and *Stichodacyla*. Examples of type-2 toxins are RTX I to RTX V \[[@b168-marinedrugs-04-00157]--[@b171-marinedrugs-04-00157]\], Rp II \[[@b152-marinedrugs-04-00157]\], Rp III \[[@b44-marinedrugs-04-00157]\] and ShI \[[@b75-marinedrugs-04-00157]\]. Type-1 toxins, like Type-2 toxins, have 3 disulphide bonds \[[@b102-marinedrugs-04-00157]\]. Within each type, these two toxin subclasses show high sequence identity (\>60%), but they show only about 30% identity between Type-1 and Type-2 toxins. Alignment of Type-1 and Type-2 toxins reveals a conserved Arg-14. It is believed that the loop of residues surrounding the Arg-14 is important in the binding of these toxins to the channel \[[@b127-marinedrugs-04-00157]\]. The C-terminus is more basic in the Type-2 toxins based on the addition of several lysines and a compensating truncation of the N-terminus \[[@b102-marinedrugs-04-00157]\]. In all, of the Type-1 and Type-2 toxins for which structures have been determined to date, all contain a four-stranded anti-parallel β-sheet in their secondary structure, with no apparent helical structure, as shown in [Figure 10](#f10-marinedrugs-04-00157){ref-type="fig"}. Competition studies of these two types of toxins suggest that they bind to distinct yet close receptor sites, given that some toxin pairs show competition between the two groups, while others do not \[[@b102-marinedrugs-04-00157]\].
Type-3 toxins comprise a small group of short polypeptides produced by sea anemones. Some examples of Type-3 toxins are PaTx from *Parasicyonis actinostoloides*\[[@b99-marinedrugs-04-00157]\], AneTx III from *Anemonia sulcata*\[[@b8-marinedrugs-04-00157]\], as well as three others from *Dofleinia armata* (Da I and Da II) and *Entacmaea ramsayi* (Er I) \[[@b66-marinedrugs-04-00157]\]. Type-3 toxins are usually composed of 27--31 residues, all so far with high sequence homology, with AneTx III and PaTx showing the lowest amino acid identity of approximately 50% \[[@b66-marinedrugs-04-00157]\]. Similar to Type-1 and Type-2 toxins, Type-3 toxins seem to bind to a receptor which overlaps position on site 3, and cause a slowing of the inactivation of Na~V~ channels.
### 5.3.2. Goniopora Toxin
Goniopora toxin (GPT) was first isolated from the marine coral, *Goniopora spp.* GPT is a polypeptide toxin of approximately 12,000 Da \[[@b60-marinedrugs-04-00157]\]. Electrophysiological experiments have shown GPT to prolong the action potential in heart, without significantly affecting its amplitude, or the resting membrane potential \[[@b54-marinedrugs-04-00157]\]. GPT inhibited inactivation of the cardiac Na~V~ channels, thus causing an increased permeability to Na^+^. The resultant broadening of the action potential leads to cardiac arrhythmias. These physiological effects are similar to those of several other Na~V~ channel toxins, including sea anemone toxins and α-scorpion toxins, even though there is little or no sequence homology among them \[[@b60-marinedrugs-04-00157]\].
In N18 neuroblastoma cells, GPT shifts the conductance-voltage relationship to the left, and thus causes activation of sodium currents in response to an unusually small depolarizing stimulus \[[@b58-marinedrugs-04-00157]\]. This result is similar to that produced by the *Leiurus* scorpion toxin. GPT also shifts the steady state inactivation curve of the Na~V~ channels to the right without altering its shape, in contrast to sea anemone and scorpion toxins, which cause a reduction in the steepness of the inactivation curve while not shifting the midpoint appreciably \[[@b57-marinedrugs-04-00157]\]. Depolarization has a marked affect on the affinity of GPT. The voltage dependence of GPT action reflects an e-fold increase in *K~d~* per 48.3 mV of depolarization \[[@b57-marinedrugs-04-00157]\]. Again, this result differs from that observed for sea anemone toxins, which shows much steeper voltage dependence. Thus, GPT may bind preferentially with different voltage-sensitive states, or alter different voltage-sensitive transitions of the channel.
GPT shows no competitive binding with the scorpion toxins which bind to site 3. Thus, it has been determined that GPT must bind to a distinct site (site 8) to that of the scorpion toxins, even though they both preferentially slow channel inactivation.
### 5.3.3. B-toxins
The B-toxins were isolated from the mucus secreted by the marine heteronemertine *Cerebratulus lacteus*\[[@b74-marinedrugs-04-00157]\]. *C. lacteus* is a ribbon worm found off the Atlantic coast of North America. B-toxins bind to Na~V~ channels in crustaceans, but had no effect when they were injected into an insect (cockroach) or a mammal (mouse) \[[@b74-marinedrugs-04-00157]\]. They appear to be selective for crustacean neuronal action potentials. The B-toxins, with molecular masses of \~6,000 Da, are a group of neurotoxins comprised of 4 subtypes, B-I to B-IV of which the B-I toxin (49 residues) contains three intrachain disulfide bonds, while B-II, B-III and B-IV (53 or 54 residues) contain four intrachain disulphide bonds \[[@b74-marinedrugs-04-00157]\]. These B-toxins act by delaying the inactivation of neuronal Na~V~ channels, as do the α-scorpion and sea anemone toxins that act at site 3 \[[@b27-marinedrugs-04-00157]\]. There is little sequence similarity between B-toxins and the α-scorpion and sea anemone toxins \[[@b13-marinedrugs-04-00157]\]. The B-toxin is composed of two anti-parallel α-helices cross-linked by disulphide bonds forming a hairpin structure, while α-scorpion and sea anemone toxins are mainly β secondary structures \[[@b6-marinedrugs-04-00157]\]. Of the four B-toxins, B-II shows the highest toxicity and is some 15-fold higher than that of B-IV, despite their high overall sequence similarity \[[@b74-marinedrugs-04-00157]\].
To date, the best studied of the B-toxins is B-IV, which is the most abundant form. The B-IV toxin was first sequenced by Blumenthal and Kem in 1976 \[[@b14-marinedrugs-04-00157]\] and it is reported to be the first marine invertebrate polypeptide neurotoxin sequenced. The NMR solution structure of the B-IV toxin has been solved by Norton and colleagues \[[@b6-marinedrugs-04-00157]\] and is shown in [Figure 10](#f10-marinedrugs-04-00157){ref-type="fig"}. There are many charged residues, which could play a role in interacting with the Na~V~ channel α subunit. Site-directed mutagenesis of the B-IV toxin has shown that neutral replacement of its arginine residues can almost abolish its biological activity \[[@b153-marinedrugs-04-00157]\]. Specifically, replacement of Arg-17 and Arg-25 \[[@b67-marinedrugs-04-00157]\], in the N-terminal helix and the hairpin region respectively, led to at least a 700-fold loss in activity. Furthermore, replacement of Trp-30 with a non-aromatic residue caused a greater than 40-fold decrease in toxicity, whereas aromatic substitutions caused less than 5-fold decrease in toxicity \[[@b154-marinedrugs-04-00157]\].
### 5.3.4. δ-Conotoxins
Cone snail δ-conotoxins \[[@b144-marinedrugs-04-00157]\], are a group of peptides consisting of about 30 amino acid residues, which exert a similar effect on Na~V~ channels. This effect is the inhibition of the fast inactivation of Na^+^ currents, which causes a marked prolongation of action potentials \[[@b47-marinedrugs-04-00157]; [@b61-marinedrugs-04-00157]\]. This results in a hyperexcited state of the affected cells, which can eventually lead to a massive electrical hyper-excitation in the complete organism. δ-Conotoxins belong to the O-superfamily and have the same cysteine framework as the μO- and ω-conotoxins, that target Na~V~ and Ca~V~ channels, respectively \[[@b144-marinedrugs-04-00157]\]. This disulfide bonding pattern gives these peptides an inhibitory cysteine knot motif which is found in a variety of biological active peptides from different organisms \[[@b103-marinedrugs-04-00157]\].
Olivera and collaborators have coined the term "cabal" for a group of toxins, present in a venom, which acts together toward a specific physiological end. The set of venom peptides that almost instantaneously immobilize a fish by eliciting the seizure-like symptoms is referred to as the "lightning-strike cabal" \[[@b105-marinedrugs-04-00157]\]. δ-Conotoxins, which in effect cause a dramatic increase in electrical activity of axons, may well be a key venom component in the lightning-strike cabal \[[@b132-marinedrugs-04-00157]; [@b145-marinedrugs-04-00157]\].
It has not yet been established how widely distributed δ-conotoxins are among cone snails, especially fish-hunting cones. Every Indo-Pacific fish-hunting cone snail species examined, that is known to use a "harpoon-and-line" strategy for prey capture, expressed δ-conotoxin in its venom duct \[[@b18-marinedrugs-04-00157]\]. Several δ-conotoxins from fish- and snail-hunting *Conus* species have been identified and the biological importance of these peptides for the capture of prey seems evident. Similar to other conotoxin families which interact with Na~V~ channels, δ-conotoxins target specific isoforms of Na~V~ channels with major differences among vertebrate and invertebrate systems ([Table 5](#t5-marinedrugs-04-00157){ref-type="table"}). δ-PVIA is a 29 amino acid peptide, from the fish-hunting cone snail *C. purpurascens,* which slows fast inactivation of Na~V~1.2-mediated currents expressed in the *Xenopus* expression system as well as of Na^+^ currents recorded from hippocampal neurons in culture \[[@b145-marinedrugs-04-00157]\]. More recently, it has been shown that the peptide also affects Na~V~1.4- and Na~V~1.6-mediated currents \[[@b124-marinedrugs-04-00157]\]. By using rat brain synaptosomes, it was demonstrated that δ-PVIA competes with δ-TxVIA for the same receptor site, even though δ-TxVIA is non-toxic in vertebrate systems. When δ-PVIA is administered to fish, it causes contraction of specific muscles resulting in a characteristic extension of the mouth, which was termed "lockjaw syndrome" \[[@b132-marinedrugs-04-00157]\]. Although δ-PVIA elicits excitatory symptoms in both mice and fish, this peptide is inactive in molluscs, even at doses 100-fold higher. During the envenomation of a prey fish, the excitatory effects of δ-PVIA act synergistically with the K~V~ channel-blocking peptide κ-PVIIA, resulting in the almost immediate, titanic paralysis of the prey \[[@b145-marinedrugs-04-00157]\].
δ-TxVIA from *C. textile* was originally called the "King Kong" peptide because it causes a characteristic dominant behaviour in lobster upon injection \[[@b65-marinedrugs-04-00157]\]. This peptide prolongs inactivation of Na^+^ currents only in molluscan neuronal membranes, whereas in vertebrates, δ-TxVIA binds to Na~V~ channels but without any toxic effects *in vivo* and *in vitro* \[[@b45-marinedrugs-04-00157]; [@b46-marinedrugs-04-00157]\]. Thus, δ-TxVIA can be used as molecular probe to discriminate between molluscan and mammalian Na~V~ subtypes on the basis of structural differences and activity but not binding \[[@b130-marinedrugs-04-00157]\]. δ-NgVIA, isolated from piscivorous snail *C. nigropunctatus*, competes with δ-TxVIA for binding to rat brain synaptosomes and molluscan central nervous system, and strongly inhibits Na^+^ current inactivation in snail neurons, as does TxVIA \[[@b47-marinedrugs-04-00157]\].
δ-GmVIA, isolated from *C. gloriamaris*, causes action potential broadening in *Aplysia* neurons \[[@b133-marinedrugs-04-00157]\]. This peptide also affects Na~V~1.2 and Na~V~1.4 at micromolar concentrations but does not affect Na~V~1.6-mediated Na^+^ currents. A 26-residue peptide (Am 2766) has been isolated and purified from the venom of the molluscivorous snail, *Conus amadis*\[[@b140-marinedrugs-04-00157]\]. Conotoxin Am 2766, reported by the same group, belongs to the δ-conotoxin family and inhibits the decay of the Na^+^ current in brain rNa~V~1.2 channels, stably expressed in Chinese Hamster Ovary (CHO) cells. The δ-conotoxin family member from *C. striatus*, δ-SVIE inhibited fast inactivation of Na~V~ channels in dissociated frog sympathetic neurons, and prolonged action potentials on the frog neuromuscular junction \[[@b18-marinedrugs-04-00157]\]. In the same work, δ-SVIE was a potent excitotoxin, when injected into mice, and competed with δ-TxVIA and δ-PVIA for binding to rat brain membranes in autoradiographic experiments. δ-SVIE proved to be highly potent against rNa~V~1.4 channels expressed in mammalian cells with a *K~d~* value in the nanomolar range \[[@b80-marinedrugs-04-00157]\]. Both δ-SVIE and δ-PVIA conotoxins slowed the time-course of inactivation of Na^+^ currents and shifted the voltage-dependence of activation and steady-state inactivation to more hyperpolarized potentials in frog sympathetic neurons \[[@b157-marinedrugs-04-00157]\].
δ-EVIA, a 32-residue polypeptide from *C. ermineus*, is the first conotoxin known to inhibit Na~V~ channel inactivation in neuronal membranes from amphibian and mammals (subtypes rNa~V~1.2, rNa~V~1.3 and rNa~V~1.6) without affecting rat skeletal muscle (subtype rNa~V~1.4) and human cardiac muscle (subtype hNa~V~1.5) Na~V~ channels \[[@b5-marinedrugs-04-00157]\]. The NMR structures of δ-EVIA and δ-TxVIA were solved by Volpon et al. \[[@b150-marinedrugs-04-00157]\] and Kohno et al. \[[@b77-marinedrugs-04-00157]\], respectively. Of particular interest in the structure of δ-conotoxins, is the relatively high number of conserved hydrophobic residues exposed on the surface of the toxins. There is some evidence that extracellular binding of these peptides is important to affect inactivation of the channels and that the hydrophobicity of these peptides is probably important for their action. Previous competition experiments measuring the binding of radioactively labeled toxins to membrane preparations containing Na~V~ channels have suggested that their molecular receptor, site 6, is distinct from that of scorpion α-toxins \[[@b46-marinedrugs-04-00157]; [@b47-marinedrugs-04-00157]; [@b130-marinedrugs-04-00157]\]. The molecular target of δ-conotoxins action on Na~V~ channels was recently identified. Leipold et al \[[@b80-marinedrugs-04-00157]\], showed that δ-conotoxin SVIE interacts with a conserved hydrophobic triad (YFV) in the domain IV voltage sensor of mammalian Na~V~ channels. These findings support the hypothesis of hydrophobic interaction of δ-conotoxins with Na~V~ channels \[[@b77-marinedrugs-04-00157]; [@b150-marinedrugs-04-00157]\]. In Na~V~ channels, the S3--S4 linker in domain IV is known to harbor parts of both receptor sites 3 and 6, where site 3 is located more toward S3 and site 6 toward S4 (see [Figure 2](#f2-marinedrugs-04-00157){ref-type="fig"}). This channel section forms the major part of a "receptor site", i.e., receptor site 3 for α-scorpion toxins and receptor site 6 for δ-conotoxins. With a second moiety, the toxins attack the DIV voltage sensor, whose movement is tightly coupled to the process of inactivation \[[@b80-marinedrugs-04-00157]\].
Earlier studies have shown that a δ-conotoxin from the venom of a mollusc-hunting cone snail, δ-TxVIA, does not compete for binding with site 3 toxins \[[@b46-marinedrugs-04-00157]\]. Additionally, a much larger peptide from the venom of *Conus striatus*, CsTx, with an activity similar to that of δ-SVIE, only partially competed with the site 3 α-scorpion toxin LqTx \[[@b59-marinedrugs-04-00157]\]. For these reasons, the receptor site for δ-conotoxins has been defined as site 6 \[[@b27-marinedrugs-04-00157]\]. In the same context, bulky δ-conotoxins, such as δ-SVIE bind in the S3-- S4 linker in domain IV and may overlap between site 3 and site 6. Likewise, it has been shown for α-scorpion toxins that critical residues for site 3 binding are found in the S3--S4 linker in domain IV \[[@b121-marinedrugs-04-00157]\]. The α-scorpion toxin receptor site suggests a mechanism by which these toxins exert their effects; namely, binding of toxin to site 3 inhibits the movement of the S4 voltage sensor in domain IV \[[@b27-marinedrugs-04-00157]; [@b121-marinedrugs-04-00157]\]. "Voltage-sensor trapping" appears to be a mechanism employed by a variety of peptide toxins that interact with Na~V~ channels \[[@b25-marinedrugs-04-00157]\], and these results suggest that δ-conotoxins act in a similar fashion.
### 5.3.5. *Conus striatus* toxin
*Conus striatus* toxin (CsTx), a 25,000 Da polypeptide toxin from the marine cone snail *Conus striatus*, was first isolated by Kobayashi, Ohizumi and colleagues \[[@b76-marinedrugs-04-00157]\]. CsTx binds to Na~V~ channels causing a slowing of Na~V~ channel inactivation in both muscle and nerves \[[@b40-marinedrugs-04-00157]; [@b43-marinedrugs-04-00157]\] as well as spontaneous activity in the cardiac musculature \[[@b41-marinedrugs-04-00157]\], while showing no effects on the activation of the channel \[[@b59-marinedrugs-04-00157]\]. CsTx induces a shift in the voltage dependence of steady state inactivation to more negative membrane potentials \[[@b59-marinedrugs-04-00157]\], which is opposite the effect of Goniopora toxin \[[@b57-marinedrugs-04-00157]\]. CsTx has been shown to have a positive inotropic effect in the heart \[[@b42-marinedrugs-04-00157]\] similar to that of Goniopora toxin. The work by Gonoi et al. \[[@b59-marinedrugs-04-00157]\] showed that CsTx appears to bind in a one-to-one fashion with the channel and its action seems to be voltage dependent with an e-fold increase in apparent *K~d~* per 19 mV depolarization. CsTx has a similar mode of action to the δ-conotoxins, although it only partially competed with the site 3 scorpion toxin α-LqTx \[[@b59-marinedrugs-04-00157]\]. This suggests that there may in fact be a partial overlap between the δ-conotoxins and CsTx \[[@b47-marinedrugs-04-00157]\]. Similar to the α-scorpion toxins, CsTx enhances toxin binding to site 2 (e.g., batrachotoxin binding) through an allosteric mechanism, though to a lesser degree than do the α-scorpion toxins \[[@b59-marinedrugs-04-00157]\].
6. Concluding remarks
=====================
In this article, we have attempted to outline the remarkable variety of Na~V~ channel-targeted toxins which occur naturally in the marine environment. In trying to make our coverage reasonably comprehensive, but still keep the article concise, we have often cited more detailed reviews in specific areas, rather than comprehensively citing original references. Regarding the choices made, we ask patience and understanding of the authors and colleagues who have produced the myriad of excellent, painstaking primary studies, which ultimately provided the basis for this chapter.
The marine ecosystem offers a source of chemically and functionally diverse toxins that interact with Na~V~ channels. These have already offered considerable insight into the structure and function of the channel protein and provide a rich array of potential pharmacological agents for experimental studies, as well as inspiration for future drug design.
This work supported by operating grants from CIHR, and from the HSF of Alberta, NWT and Nunavut. R.J.F. is an AHFMR Medical Scientist.
*Samples Availability:* Available from the authors.
AneTx
: anemone toxin (often abbreviated ATX in other papers)
ATx
: antillatoxin
B toxins
: ribbon worm toxins
Ca~V~, Na~V~, and K~V~
: voltage-gated ion channels selective for calcium, sodium or potassium, respectively
NMDA
: *N-*methyl-D-aspartate
CigTx
: ciguatoxin
CLA
: clathrodin
CNS
: central nervous system
PNS
: peripheral nervous system
DBS
: dibromosceptin
EC~50~
: concentration producing 50% of the maximal effect
GPT
: *Goniopora* (coral) toxin
KTx
: kalkitoxin
IC~50~
: concentration producing 50% inhibition
NSP
: neurotoxic shellfish poisoning
LD~50~
: lethal dose/concentration for 50% of population
K*~d~*
: dissociation contant
OTx
: ostreotoxin
PbTx-n
: brevetoxins where n = 1--10
PSP/PST
: paralytic shellfish poisoning/toxins
STx
: saxitoxin
TTx
: tetrodotoxin
TTx-s
: TTx sensitive
TTx-r
: TTx resistant
{#f1-marinedrugs-04-00157}
![Na~V~ channel receptor sites mapped onto the structure of K~V~1.2. **A.** Side-view of K~V~1.2 with P loops modified to resemble more closely the likely structure of Na~V~ channel P loops, which allow block by agents such as STx, TTx, and μ-conotoxin. Only DII and DIV shown; S1--S3 red, S4 blue and S5-P loop-S6 cyan. **B.** Top view of K~V~1.2 showing all four domains with domains DII and DIV colored as in A. The eye at the bottom shows the point of view for part A. The figures were produced using VMD software \[[@b68-marinedrugs-04-00157]\] and final images rendered with POV-ray (<http://www.povray.org/>).](marinedrugs-04-00157f2){#f2-marinedrugs-04-00157}
![Chemical structures of non-peptide Na~V~ channels blockers. **A.** Tetrodotoxin, and **B.** Saxitoxin, both of which are tricyclic, guanidinium-derived marine toxins. **C.** Meroditerpenoids from the marine brown alga *Stypopodium flabelliforme,* which act as Na~V~ channel modifiers: **1.** 2β,3α-Epitaondiol; **2.** Flabellinol; **3.** Flabellinone. The structures of the meroditerpenoids were reproduced from Sabry et al. \[[@b123-marinedrugs-04-00157]\], with permission.](marinedrugs-04-00157f3){#f3-marinedrugs-04-00157}
{#f4-marinedrugs-04-00157}
![NMR-derived structures for three μ-conotoxins. Atomic coordinates were taken from RCSB Protein Data Base \[[@b10-marinedrugs-04-00157]\]; coordinates used were as follows: GIIIA, 1TCG; PIIIA, 1RD1, structure \#19; SmIIIA, 1Q2J, structure \#19. Software for figure generation was as in [Figure 2](#f2-marinedrugs-04-00157){ref-type="fig"}. The conotoxin molecules are oriented in similar directions with an axis along the R14 side-chain facing down. In the lower set, images are rotated 180 degrees around the R14 axis with respect to the upper set. Positively charged residues are shown in blue; negatively charged residues are shown in red. Residue numbering follows the consensus numbering from the alignment in [Figure 4](#f4-marinedrugs-04-00157){ref-type="fig"}.](marinedrugs-04-00157f5){#f5-marinedrugs-04-00157}
![Chemical structures of some Na~V~ channel peptide blockers. **A**. Jamaicamides A-C: lipopeptides from dinoflagellate *Lyngbya majuscula*. **B**. Kalkitoxin: a thiazoline-containing lipopeptide toxin also from dinoflagellate *L. majuscula*. The structures of jamaicamides were reproduced from Edwards et al.\[[@b38-marinedrugs-04-00157]\], with permission. The structure of kalkitoxin was reproduced from LePage et al.\[[@b81-marinedrugs-04-00157]\], with permission.](marinedrugs-04-00157f6){#f6-marinedrugs-04-00157}
![Chemical structures of non-peptide gating modifiers of Na~V~ channels. **A.** Clathrodin (CLA) and **B.** Dibromosceptrin (DBS) alkanoid toxins from *Agelas* sponge. The chemical structure of CLA was reproduced from Morales and Rodriguez \[[@b96-marinedrugs-04-00157]\], with permission; the structure of DBS was reproduced from Bickmeyer et al \[[@b11-marinedrugs-04-00157]\], with permission.](marinedrugs-04-00157f7){#f7-marinedrugs-04-00157}
![Molecular structures of polyether ladder toxins which are Na~V~ channel modifiers. **A.** Brevetoxins A and B are isolated from marine dinoflagellate, *Karenia brevis.***B.** Ciguatoxins (Pacific; P-CigTx and Caribbean; C-CigTx) from marine dinoflagellate, *Gambierdiscus toxicus*. Structures of brevetoxins were reproduced from Baden et al. \[[@b3-marinedrugs-04-00157]\], with permission. Structures of ciguatoxins were reproduced from Pearn \[[@b109-marinedrugs-04-00157]\], with permission.](marinedrugs-04-00157f8){#f8-marinedrugs-04-00157}
![The cyclic lipopeptide structures of antillatoxins, ATx and ATx-B, from *Lyngbya majuscula*. The structures of antillatoxins were reproduced from Li et al. \[[@b86-marinedrugs-04-00157]\], with permission.](marinedrugs-04-00157f9){#f9-marinedrugs-04-00157}
![Examples of peptide toxin backbone structures shown with disulphide bonds (green) created with VMD \[[@b68-marinedrugs-04-00157]\] of B-IV \[[@b6-marinedrugs-04-00157]\], AneTx Ia \[[@b158-marinedrugs-04-00157]\], μO-conotoxin MrVIB \[[@b34-marinedrugs-04-00157]\] and δ-conotoxin TxVIB \[[@b77-marinedrugs-04-00157]\].](marinedrugs-04-00157f10){#f10-marinedrugs-04-00157}
######
Neurotoxins that target the Na~V~ channels and their corresponding receptor sites.
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Receptor Site Physiological Effect Putative location Toxin Organism
---------------------------------------------------------------------------------------- -------------------------------------------------------------- --------------------------------------------------------------------------- ---------------------------------------------------------------------------------- -----------------------------------------------------------------------------------------------------
1 Pore blocker P loop at DI, DII, DIII, DIV Tetrodotoxins Puffer fish (Tetraodontiformes), starfish, molluscs, tunicates, dinoflagellates, symbiotic bacteria
Saxitoxins Shellfishes, Red tide dinoflagellates and symbiotic bacteria
μ-Conotoxins Cone snails
2 Persistent activation gating; DI-S6 Batrachotoxin \[Dendrobatid "poison dart" frogs\]
Depolarization of resting potentials DII:S6 Veratridine \[In the seed of *Schoenocaulon officinale* and in rhizome of *Veratrum album*\]
Repetitive firings DIII:S6 Aconitine \[In the root of *Aconitum* plants\]
DIV:S6 Grayanotoxin \[In plants of the family *[Ericaceae]{.ul}*;\]
3 Prolonged Na^+^ channel opening DIV:S3--S4 α-Scorpion toxins \[Scorpion *spp.*\]
DI:S3--S4 Loop Sea anemone toxins Sea anemones *spp.*
Inactivation gating modifier DIV:S5--S6 Loop δ-Atracotoxins \[Funnel-web spider *Hadronyche versuta*\]
4 Agonist ? Antillatoxin Dinoflagellate *Lyngbya majuscule*
Shifts in activation gating; repetitive firings DII:S3--S4 Loop β-Scorpion toxins \[Scorpion *spp,*\]
5 Shift in activation gating DI:S6 Brevetoxins Red tide dinoflagellate *Karenia brevis*
DIV:S5 Ciguatoxins Red tide dinoflagellate *Gambierdiscus toxicus* and tropical coral fishes
6 Prolonged Na^+^ channel opening DIV:S3--S4 δ-Conotoxins Cone snails
7 Inhibitor, not a pore blocker ? Kalkitoxin Dinoflagellate *Lyngbya majuscule*
Persistent activation gating; depolarization of resting potentials; repetitive firings DI-S6\ DDT and analogs, Pyrethroids \[Insecticide chemicals\]
DII-S6\
DIII-S6
8 Inactivation gating modifier ? Goniopora genus *Goniopora*
Prolonged Na^+^ channel opening ? Conus striatus toxin *Conus striatus*
9 Inhibition of Na^+^ permeability DI-S6\ Local anesthetics, Anticonvulsants, Antidepressants \[Chemicals from various sources\]
DIII-S6\
DIV-S6
N.I. Inhibitor, not a pore blocker ? μO-Conotoxins Cone snails
N.I. Inactivation gating modifier ? B-Toxins Ribbon worm (*Cerebratulus lacteus*)
N.I. Inhibitor, not a pore blocker ? Meroditerpenoids Brown algae
N.I. Inactivation gating modifier ? Clathrodin Sponge (genus *Agelas*)
N.I. Inactivation gating modifier ? Dibromosceptrin Sponge (genus *Agelas*)
N.I. Antagonist ? Jamaicamides A-C Dinoflagellate *Lyngbya majuscule*
N.I. Inactivation gating modifier ? Ostreotoxin-3 Dinoflagellate *Ostreopsis lenticularis*
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
**Note:** Site 1--9 after references \[[@b27-marinedrugs-04-00157]; [@b151-marinedrugs-04-00157]; [@b167-marinedrugs-04-00157]\]. Neurotoxins with unknown binding receptor sites are categorize as N.I. (Not identified). Neurotoxins not originating from marine organisms are mentioned within square brackets \[ \].
######
Some characteristics of known μ-conotoxins.
μ-Conotoxins Conus species \# of residues Nominal net charge (using R, K=1, H=+0.5, D=−1) Major tissue or channel subtype(s) targeted References
-------------- ---------------------- ---------------- ------------------------------------------------- -------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------
**GIIIA** *C. geographus* 22 6 Rat muscle \[[@b98-marinedrugs-04-00157]\]
**GIIIB** *C. geographus* 22 7 Rat muscle, rat brain \[[@b98-marinedrugs-04-00157]\]
**GIIIC** *C. geographus* *22* *7* Rat muscle \[[@b33-marinedrugs-04-00157]; [@b98-marinedrugs-04-00157]\]
**PIIIA** *C. purpurascens* *22* *6.5* Rat muscle, rat brain, human brain \[[@b98-marinedrugs-04-00157]; [@b134-marinedrugs-04-00157]\]
**SmIIIA** *C. stercusmuscarum* *22* *5.5* TTx-r (amphibian) skeletal muscle, sympathetic and dorsal root ganglia (DRG) neurons \[[@b19-marinedrugs-04-00157]; [@b73-marinedrugs-04-00157]; [@b156-marinedrugs-04-00157]\]
**SIIIA** *C. striatus* *20* *2.5* TTx-r (amphibian) sympathetic and DRG neurons \[[@b19-marinedrugs-04-00157]\]
**KIIIA** *C. kinoshitai* *16* *3.5* TTx-r (amphibian) sympathetic and DRG neurons \[[@b19-marinedrugs-04-00157]\]
######
Some characteristics of known μO-conotoxins.
μO-Conotoxins *Conus* species Number of residues Subtype Targeted Reference
--------------- ----------------- -------------------- -------------------------------------------------------------------------------------------------------- --------------------------------------------------------------
**MrVIA** *C. marmoreus* 31 Inhibits TTx-r Na~V~ channels rat dorsal root ganglia, TTx-s Na~V~ channels, molluscan Ca^2+^ channels \[[@b34-marinedrugs-04-00157]; [@b95-marinedrugs-04-00157]\]
**MrVIB** *C. marmoreus* 31 Inhibits TTx-r Na~V~ channels rat dorsal root ganglia, TTx-s Na~V~ channels, molluscan Ca^2+^ channels \[[@b34-marinedrugs-04-00157]; [@b95-marinedrugs-04-00157]\]
######
Two unclassified conotoxins.
Unclassified Conotoxins *Conus* species Number of residues Subtype Targeted Reference
------------------------- ----------------- -------------------- -------------------------------------- ----------------------------------
**TVIIA** *C. tulipa* 30 Not established \[[@b62-marinedrugs-04-00157]\]
**GS** *C. geographus* 34 Muscle Na^+^ blocker receptor site 1 \[[@b163-marinedrugs-04-00157]\]
######
Representatives of δ-conotoxins and their subtype targets.
---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
δ-Conotoxin *Conus* species Natural prey No. of residues Subtype Targeted Reference
------------- --------------------- -------------- ----------------- ----------------------------------------------------------------------------------------------------------------------------- ------------------------------------------------------------------------------------------------------------------------
**PVIA** *C. purpurascens* Fish 29 Vertebrate preparations only (including fish, frog and mammalian Na~V~1.2; Na~V~1.4 and Na~V~1.6). \[[@b132-marinedrugs-04-00157]; [@b157-marinedrugs-04-00157]\]\
\[[@b124-marinedrugs-04-00157]; [@b145-marinedrugs-04-00157]\]
**EVIA** *C. ermineus* Fish 32 Amphibians and mammalian preparations (rNa~V~1.2, rNa~V~1.3 and rNa~V~1.6 but not muscular rNa~V~1.4 and cardiac hNa~V~1.5) \[[@b5-marinedrugs-04-00157]; [@b150-marinedrugs-04-00157]\]
**SVIE** *C. striatus* Fish 31 Diverse (Molluscan and Amphibian sympathic neurons) \[[@b18-marinedrugs-04-00157]; [@b157-marinedrugs-04-00157]\]
**Am2766** *C. amadis* Molluscs 26 Diverse \[molluscan and mammalian preparations (rNa~V~1.2)\]. \[[@b140-marinedrugs-04-00157]\]
**TxVIA** *C. textile* Molluscs 27 Molluscan subtype and rat brain neuronal membranes but not toxic to vertebrate system \[[@b45-marinedrugs-04-00157]--[@b47-marinedrugs-04-00157]; [@b65-marinedrugs-04-00157]; [@b77-marinedrugs-04-00157]\]
**GmVIA** *C. gloriamaris* Molluscs 29 Diverse (molluscan subtype and mammalian Na~V~1.2 and Na~V~1.4 but not Na~V~1.6-mediated Na~+~ currents). \[[@b61-marinedrugs-04-00157]; [@b133-marinedrugs-04-00157]\]
**NgVIA** *C. nigropunctatus* Molluscs 31 Diverse (molluscan and more potent to mammalian preparations) \[[@b47-marinedrugs-04-00157]\]
---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
[^1]: These authors contributed equally to this article.
|
The 12 Ties that Bind Long-Term Relationships
That crazy thing we call love is perhaps one of the most studied and least understood areas in psychology. One reason is that many studies of romantic relationships are carried out not in real life, but in the lab. Making matters worse, many of these studies involve dating relationships between samples of convenience, consisting of undergraduate students. Though these students are certainly capable of close relationships, many of them haven’t matured enough to know themselves, much less what they want out of a romantic partner.
What better way to find out about love than to survey the experts? Not the psychology experts—the expert members of couples who have been married 10 years or longer. The surprising findings of this study, reported in the prestigious journal Social Psychological and Personality Science, showed not only that many people were still in love even after 10 years of marriage, but also which factors predicted the strength of their passion. As reported by Stony Brook University psychologist K. Daniel O’Leary (2012) and his research team, the findings provided a stark contrast to the typically glum view we have of long-term marriages. Rather than being doomed to a bland, mediocre existence, these couples endorsed their positive feelings toward their spouses with hearty (dare I say) enthusiasm. A whopping 40 percent of those married 10 years or more stated that they were “Very intensely in love”—the highest rating on the scale. Another 15 percent gave their marriages the second-highest rating on the love intensity scale. Perhaps even more surprisingly, those who stuck together for 30 years and more also gave their marriages high ratings with 40 percent of women and 35 percent of men saying that they were very intensely in love. Clearly, many couples are able to maintain high levels of passion as the decades go by well into their middle and later years.
Just as clearly, not everyone felt the same degree of intensity about their spouses. The researchers turned next to trying to predict which relationships would be marked by the strongest degree of intensity. Psychological theories of love focus on such quintessential features as passion, commitment, closeness, early experiences in relationships, emotional needs, and ability to communicate. These are, of course, important to the health of any relationship. However, when it comes down to predicting which relationships will make it for the long haul, the questions become almost equally pragmatic as romantic.
Earlier research by psychologist Arthur Aron, who collaborated in this study, suggested that the people who are most intensely in love are the ones who feel a strong romantic attraction, but who also enjoy engaging in “self-expanding” joint activities that are novel and challenging. Based on findings from fMRI studies, the researchers also thought that strong love would involve regular strong doses of dopamine, the neurotransmitter that pumps up the brain’s reward circuits. The investigators couldn’t measure dopamine through a telephone survey, so instead they used questions that would tap into the amount of pleasure partners felt when they were around each other.
A few caveats about the study might have already come to your mind. First, and most importantly, the study was conducted only on couples who stayed together. The unhappy couples would have divorced and therefore not qualified for the research. On top of that, the couples obviously agreed to be in the study, so it’s possible that the unhappiest ones simply didn’t want to confront the questions about their marriages—although it’s also possible that the unhappy ones would have welcomed the opportunity to complain about their spouses. In either case, the researchers believed that the bias of wanting to look either very happy or very unhappy didn’t play a major role in affecting the results. One way that they made this assurance was by making the questions as focused on behavior as possible and therefore less subject to reporting bias. The study also has the obvious limitation of being conducted on partners in heterosexual marriages which may not be typical of all relationships.
Now that you’ve learned the basics of this fascinating study, it’s time to put your relationship to the test. See how you would rate your closest romantic relationship (marriage or otherwise) on these 12 key dimensions:
Thinking positively about your partner. Having positive thoughts about your partner means that you focus on the good, not the bad, in your partner’s personal qualities and character. Ruminating about the things that bother you can only lead you to magnify the small foibles which will make your partner even more irritating to you than you would otherwise feel. People in good relationships engage in “sentiment override,” meaning that they remember more of the favorable than the unfavorable experiences they’ve shared together.
Thinking about your partner when apart. When you leave your partner for the day, the evening, or for an extended period of time, do you forget about his or her existence? Is it out of sight and out of mind for you? If so, this may be a sign that you’re not that much in love. You don’t have to spend every second apart sighing longingly, but the fact that your partner isn’t there should at least cross your mind some of the time during the course of the average day.
Difficulty concentrating on other things when thinking about your partner. If you’re able to set aside your thoughts about your partner without much effort, this suggests that your partner takes up only a small amount of cognitive load. Multitasking isn’t particularly desirable when it comes to musing over your loved one. In the O'Leary study, this factor was particularly important for men.
Enjoying novel and challenging activities. Like definitely attracts like when it comes to personal interests and hobbies. Spending time together is important, as you’ll see below, but it’s how you spend your time that influences your relationship satisfaction even more. Aron’s self-expansion model, tested in empirical research, suggests that couples can improve their love for each other when they spend their time together exploring new and challenging activities. The O'Leary study identified this factor as especially relevant for men. If you’re going to go bungee jumping for the first time, your relationship will benefit when you and your partner face this challenge together. If you’re not up to bungee jumping, seek out mentally challenging ways to spice up your daily routines.
Spending time together. If you love someone, you want to spend time with that person, and the more time you spend together, the more your love will grow. The time you spend should include some new and challenging activities, as shown in point #4. However, even spending time together in mundane household activities can enhance your love's intensity. That basement remodeling you’ve been intending to get started can actually become a way for you and your partner to strengthen your emotional bonds. Cooking, gardening, grocery shopping, and even cleaning the house are other ways to bolster your love for each other. This was another factor that, in the O'Leary study, was more important for men.
Expressing affection. Feeling love toward your partner is important, but so is expressing that love in physical ways. It’s not wise to play hard to get when your goal is to build the passion in your relationship. The affection you show doesn’t have to be elaborate or overly gushy. A touch on the shoulder or kiss on the cheek is enough to build your relationship’s intensity.
Being turned on by your partner. Those tiny touches of affection can not only boost your emotional connection to your partner, but also stoke the sexual fires within. The respondents reporting the most intense love for their partner in the O’Leary study said that they felt their bodies responding when their partner touched them. This doesn’t mean a full-out sexual encounter has to follow from that touch on the cheek. Feeling a warm, tingling sensation from your partner’s physical presence is enough to keep the fire inside stoked until the time is right for sexual activity.
Engaging in sexual intercourse. It should come as no surprise that having intercourse is a positive expression of a love’s intensity. People in love are more likely to have sex with each other on a regular basis. The O’Leary study showed, however, that part of the reason for the positive association between sex and love is that people who are happiest in their relationships both love their partners more and have sex more frequently. Whatever the cause, the point is that sexual activity builds and maintains feelings of love and even happiness that endure over time.
Feeling generally happy. People who feel happier about life also have stronger feelings of love toward their partners. We can’t determine whether people who are in love therefore feel happier or vice versa from the survey data in the O’Leary study (and the finding was more true of women than men). However, the finding suggests that if you’re experiencing personal distress, this can leak out and cause your relationship to suffer. Similarly, if your relationship is in trouble, your personal happiness will suffer as well. Either way, it's important for you to seek help before these negative effects take a heavy toll on your mental health.
Wanting to know where your partner is at all times. Being intensely in love, for men, is associated with wanting to know your partner’s whereabouts. This component of intense love may seem a bit like stalking. But to put a positive spin on it, if you want to know where your partner is, this reflects the fact that your partner isn't very far from your thoughts.
Obsessively thinking about your partner. Being slightly obsessed with your partner turns out to be positively related to intense love, at least for women. The women most in love in the O’Leary study didn’t particularly care about knowing their partner’s whereabouts. However, they were more likely to engage in obsessive thinking about their partner more generally.
Having a strong passion for life. People who approach their daily lives with zest and strong emotion seem to carry these intense feelings over to their love life as well. If you want your relationship to have passion, put that emotional energy to work in your hobbies, interests, and even your political activities. Your brain's reward centers respond similarly to love as to getting excited about your other daily interests.Getting "fired up" in these areas of life translates into firing up the feelings you have toward your partner and in the O'Leary study seemed to matter more for men.
The formula for keeping love alive in your closest relationship is a complicated one. The study by the O’Leary team, in identifying these 12 factors, provides new evidence to show that not only can long-term couples get along with each other, but they can maintain their passion for many decades. Close relationships are the centerpiece of our sense of identity and are fundamental to our feelings of fulfillment. They can even benefit our health, The relationship conflict that can ensue can also affect your health, as we know from research on marital problems and obesity. By changing your thoughts and your behavior about these relationships, you can keep them fresh and vital for years.
Follow me on Twitter @swhitbo for daily updates on psychology, health, and aging. Feel free to join my Facebook group, "Fulfillment at Any Age," to discuss today's blog, or to ask further questions about this posting.
I look forward to reading the study in its entirety. And, I will be sharing your article with my clients that I do marriage education with as we often focus on learning life and resiliency skills so they can have healthier relationship dynamics.
Perusing the comments that took 1 or 2 of the ties out of context I wanted to give more feedback on what I took away from reading through the 12 ties. What stood out to me was that in a healthy, long-term relationship the partners are very much interested in the ins and outs of each other’s day. I did not take this to mean co-dependent, obsessive, or enmeshed. I've known my husband since we were 17, and we're in our 30s now. We've been a couple for a little over 10 years. Raising a family together, we often ask about one another's schedule; but it isn't for scheduling purposes or because we need to control one another. We are genuinely interested in each other's day-to-day activities and interactions with others--co-workers, friends, family, and strangers. It is not stalking either. Discussing our activities away from one another keeps us on the same page, and provides examples to continue discussing our ongoing dialogue of themes, purpose, and relationship dynamics that we're curious to know one another's thoughts upon. We also feel closer to one another, because although our work and hobbies take us away from one another, we're still interested in how each other is dealing with work and hobbies. This is because the other side (the public side) that we don't see as a couple living together provides context to how we’re faring as we tackle our goals, innermost struggles, and life lessons we need to learn and overcome in life. When you’re in a long-term relationship I believe you constantly have a mirror held up to your face—and you get to see your quirks, strengths, and faults—challenging you to be a better, more compassionate and loving person for one another.
This brings me to my next point! I was surprised to see that one of the ties did not speak about either: (1) showing appreciation for the partner on a daily basis, or (2) encouraging and challenging our partner to grow into the best version of them. This has been pivotal for us in our relationship. Acknowledging out loud (not just thinking or physical touch) to one another or sharing with others our gratitude of each other reminds us on a daily basis that we've made the choice to commit to one another, and make each day together the best it can be as we walk side-by-side through life. As we continue to grow in maturity as individuals seeking out our own interests and purpose; it is because of our encouragement of one another to go after our dreams, or to comment on strengths/weaknesses, and to keep each other accountable that has made us not only a closer couple, but better people.
I'm female and very independent. I NEED my alone time and cannot function well without it nor am interested in what my partner is doing every hour of the day. I like thinking about my own projects and intellectual pursuits without obsessing on them. I'm a whole person first and only desire a partner who enriches that. That said, I tend to be the more logical in the relationship and love to communicate. I'm also highly affectionate and supportive.
When a union cannot be good anymore, when it cannot grow, detracts from my life; it's time to cut it off. I don't want enemies of my exes and don't see the point of feeling angry when it's done. My ex husband was petulant when we divorced and he was the one who wanted out! And he was right, it was time to let it go.
I'm glad I'm different from the usual type but not contemptuous of those who fill the mold. I would very much like to hear about couples who aren't typical and still make it work.
Dear Anonymous, I've pointed out to others who had similar concerns that it's "wanting," not "needing" or "demanding." Think of it this way, the opposite is not caring where your partner is. Hope this helps! Best, Susan
I think it is so sad that so many people will end a relationship when they "fall out of love". In my younger days I ended many relationships for this reason and it was such a waste. I really expected to meet somebody that I would stay "in love" with forever and didn't realise this never happens. Or we jump out of a perfectly good relationship or marriage because we fall in love with somebody else. Looking back, I don't think that's enough of a reason any more.
my ex-boyfriend dumped me 8 months ago after I caught him of having an affair with someone else and insulting him. I want him back in my life but he refuse to have any contact with me. I was so confuse and don't know what to do, so I visited the INTERNET for help and I saw a testimony on how a spell caster help them to get their ex back so I contact the spell caster and explain my problems to him.. he cast a spell for me and assure me of 24hr that my ex will return to me and to my greatest surprise the third day my boyfriend came knocking on my door and beging for forgiveness. I am so happy that my love is back again and not only that, we are about to get married. Once again thank you Dr kizzekpe, you are truly talented and gifted contact his email: kizzekpespells@outlook.com.
This is the kind of shit we will continue to see here because PT refuses to moderate the site. No moderators is why I not only stopped posting, but rarely read PT online anymore.
If they don't give a shit about the integrity of the site, spammers and nuts will take over and they have.
Psychology Today please start using moderators. You've lost any sense of credibility allowing posts like the crazy crappy above and the unmoderated attacks and rambling crazy posts that apoears everywhere else on the site. |
Our economy has been through the wringer lately, and most people are looking for ways to cut back on their budgets.
Making sure that you have a little extra money saved in the bank is more important than ever.
Saving Money Isn’t Always Easy
For many of us our budgets already seem pretty tight, and it’s hard to imagine where we’ll be able to find more areas to cut. If you look, however, you too can find ways to cut back.
Here are a few practical ways that you save some extra money this year.
50 Easy Ways To Save Money Every Month
10 Practical Ways To Save Money
Cut The Cable TV
Cutting your cable TV can save you a lot of money, and not just once, but every month.
The average cable bill can run anywhere from $40-$120 every month. Add that up over a year and you’ve saved from $480-$1440! Instead of watching cable, watch your favorite shows from most networks on a service like Hulu Philo or Sling, and then add in free streaming services to fill in the gaps.
Set up a cord cutting package like we have at our house, where you watch free broadcast TV using an antenna and DVR, use a cable TV alternative and free streaming services, while also using a media server to watch your own media like Plex.
Using a software like Media Mall’s Playon software, you can stream most of your favorite streaming services that you’re paying for and record them to watch later. The cost? A one time fee of $40 for Playon.
Take A Personal Day To Find Better Insurance Rates
One thing that I’ll do every couple years is take a personal day from work so that I can take an entire day just to focus on our insurance coverages, shop around and find better rates.
For example, last time I did this I was able to find better coverage on our auto and homeowner’s insurance, for about $1100 less per year!
Cancel Subscription Services And Use Cheaper Alternatives
One thing we’ve done in the past at our house is cancel our netflix subscription, and move to a cheaper alternative, renting movies at a Redbox.
For Netflix we were paying close to $15/month, and only getting 2-3 movies a month. In comparison for the same amount of movies rented at the Redbox less than a mile from our house, it cost us just over $3. If you can find a Redbox free rental code (which are readily available), it can be even cheaper!
Use this tactic for other subscription services like newspapers or magazines. Instead of paying subscription fees, just buy it on the newstand for the rare occasion that you want to read it.
Buy Things Used
Instead of buying that new car for 20 grand, buy a 2-3 year old car with low mileage of the same make and model for about half price.
I did this when buying my car recently, and we saved probably about 12-14 thousand dollars! The tip works for other things as well. Try it when buying clothing, books, electronics or other high ticket purchases.
Pack Your Lunches And Limit Eating Out
I used to think this tip was silly until we tried it at our house. After doing our budget we realized just how much we were actually spending on lunches and dining out together. Let’s just say it was a lot more than we thought it was.
Even cut this spending in half and you’ve probably saved a couple hundred/month.
Save Money At The Movies
If you’re a movie buff like my wife and I, you can find a lot of ways to save money when you go to the movies. Go to a matinee, see the movie at a second run theater, buy packages of tickets at a reduced rate, bring your own snacks, seek out free family movie days in the summer or join movie watcher loyalty clubs. Wow, that was a mouthful. Check out the link for more!
Maintain Things
Keep up on the regular scheduled maintenance for your car (oil changes, tire inflation, check fluid levels), as well as regular maintenance on your home.
Keeping up on the maintenance may not feel like you’re saving money (in fact you may be spending some), but it can mean that you’ll save hundreds or thousands of dollars down the line because your things will last longer.
Give Yourself A Waiting Period
Are you prone to going out and buying things on a whim? Give yourself a waiting period within which you can’t make a purchase. The more susceptible you are to spontaneous purchases, the longer your waiting period should be.
I like to wait at least 24 hours before making a decision to buy something, longer if the price tag is higher. Saving up and paying cash is an even better idea, often you’ll find by the time you’ve saved up for the item, you don’t really want it anymore.
Don’t Shop When You’re Hungry, And Make A List
One mistake that I make all the time is that I tend to go grocery shopping when I’m ravenously hungry. When I do that I often end up buying a bunch of groceries that we don’t need, and that sometimes spoil before we can even eat them. Go shopping after eating a meal, and only shop with a list. Don’t buy anything that isn’t on your list. For more ways to save on your groceries, check out this post.
Save By Asking For A Discount
Often you can get a discount on the services you use, and the things you buy just by asking. For example, call up your internet company and ask for a discount on your monthly bill. Often they’ll give you a reduced promotional rate for a limited time, or a reduced rate to not jump ship to another provider. Another one we’ve used is to ask for a discount on medical bills. Often if you call up the hospital billing department you can save 10-20% off of your bill just by asking, and paying cash. We did this last year for some of my wife’s medical bills.
If you’re not sure you want to ask for a discount yourself, there are a ton of bill negotiation services that can get your rates lowered, for a percentage of the savings.
There Are Always More Ways To Save. Be Creative
There are 10 ways you can save money, just by making small changes to your lifestyle, or by making a few phone calls. It should be relatively quick and painless, and could lead to hundreds of dollars in savings.
So give it a try!
Do you have a quick and easy tip on how to save money? Let us know what it is in the comments! |
require 'simple_config'
require 'rails'
module SimpleConfig
class Railtie < ::Rails::Railtie
rake_tasks do
namespace :simpleconfig do
desc "Initialize SimpleConfig configurations."
task :setup do
abort("Already found config/settings. Have you already run this task?.") if File.exist?("config/settings")
mkdir("config/settings")
mkdir("config/initializers") unless File.exist?("config/initializers")
environments = Dir["config/environments/*.rb"].map { |f| File.basename(f, ".rb") }
environments << "application"
environments.each { |env| touch("config/settings/#{env}.rb") }
cp(
File.expand_path("../../../templates/configuration.rb", __FILE__),
"config/initializers/configuration.rb"
)
end
end
end
end
end
|
require 'mxx_ru/binary_unittest'
path = 'test/so_5/mbox/delivery_filters/exception_in_filter'
MxxRu::setup_target(
MxxRu::NegativeBinaryUnittestTarget.new(
"#{path}/prj.ut.rb",
"#{path}/prj.rb" )
)
|
9.30.2011
Berry cake, it´s tea time!
Here in the southern hemisphere spring has just begun and with that, seasonal fruits. But not everything is happy. In our beloved Buenos Aires it´s not easy to get berries, perhaps in a grocery store some fresh cranberries. Actually, raspberries and blackberries are not easy to be found, but Argentina is a producer of these fruits, but we are also exporters.
The solution to this was the people of Arandanos Argentinos that sell these and other precious fruit in bags of 1 kg and at a great price!. The thing I like is that the fruit is not a big ball of frozen fruit, but separated ones and they keep pretty good form when defrozed and won´t lose much fluid. This is due to IQF freezing, Individual Quick Freezing. |
1. Field of the Invention
The present invention relates to digital data backup systems. More particularly, the invention concerns a technique for performing an expedited data backup by creating a duplicate set of pointers to a current dataset already identified by an original pointer set, then designating the dataset as a backup dataset, and thereafter preventing changes to the pointed-to-data and the duplicate pointers, where changes to the current dataset are nonetheless effected by storing new data and modifying the original pointer set alone.
2. Description of the Related Art
With the increasing tide of digital information today, computer users encounter more data than ever to transmit, receive, and process. Data transmission and receipt speeds are continually increasing with each new advance in modems, fiber optics, ISDN, cable television, and other technology. Processing speeds are similarly advancing, as evidenced by the frequent introduction new products by the microprocessor industry.
In addition to transmitting, receiving, and processing data, storing data is another critical need for many users. In fact, many users demand high performance data storage systems to contain huge amounts of data, and to quickly access the data. Engineers are constantly making significant improvements in their storage systems by reducing storage density and increasing storage speed.
For many businesses, data storage is such as critical function that data loss cannot be tolerated. As a result, different techniques and systems for data backup have become widespread. Some examples include the peer-to-peer remote copy system ("PPRC") and extended remote copy system ("XRC"), both developed by International Business Machines Corp. ("IBM").
In many applications, it is not only essential to have backup data, but to have quick recovery from backup data in the event of data failure. Some applications that rely on the ability to quickly access stored data include automated teller networks of banks, financial information of stock brokers, reservation systems of airlines, and the like. In applications such as these, slow recovery from failed data can mean lost revenue.
Data backup/recovery occurs in various contexts including an "on-line" environment and an "off-line" environment. In the on-line environment, stored data is continually available to users, and backup operations must therefore be conducted in the "background." This can slow users' access to their data, including operations such as storing new data, updating existing data, and retrieving stored data. From the user's perspective, slower data access is a disadvantage because it causes frustration and lengthens the time needed to complete projects that require data access. From the system manufacturer's perspective, slower data access is a disadvantage because it makes the storage system less competitive with other manufacturer's storage systems.
Aside from the backup completion time, another concern in the on-line environment is the time needed to recover from backup data when the original data fails. When stored data does fail, it is important to restore the data from the backup copy as quickly as possible. From the user's perspective, data recovery time is part of the data access time, which should be as brief as possible.
In the off-line context, data storage jobs are consolidated for more efficient processing together during a batch processing "window." The storage system usually goes "off-line" during the batch processing window, and is therefore unavailable to serve requests other than the pre-consolidated jobs being processed. Data backups may be performed regularly during the batch processing window, in serial fashion with the other jobs underway. Consequently, the data backups increase the overall size of the batch processing window, therefore lengthening the time that the system is unavailable to users.
Any off-line recovery that is required during the batch processing window similarly lengthens the time that the storage system is unavailable to users.
As shown above, a number of different backup systems already exist, and certain of these systems constitute significant advances and even enjoy widespread commercial success today. Nonetheless, IBM continually works to improve the performance and efficiency of data backup systems. Some areas of particular focus include minimizing the backup and recovery times in the on-line and off-line storage environments. |
NEW DELHI: The Allahabad high court is today scheduled to pronounce its verdict on a petition seeking that the CBI investigate Uttar Pradesh chief minister Adityanath 's involvement in a 2007 Gorakhpur riots case. Here is all you need to know about the case:* In 2007, Adityanath – then just a Lok Sabha MP - was arrested on charges of disturbing the peace and violating prohibitory orders after he, along with his supporters, gathered to mourn the killing of a man in clashes between two communities.* Following his arrest, his supporters from the Hindu Yuva Vahini, an extremist Hindu youth group, founded by Adityanath, ransacked public property and torched a train compartment reserved for the physically challenged in Krishi Express. A bus was also set ablaze in Deoria, even as police lathi-charged mobs in Azamgarh and Kushinagar.* On November 2, 2008, an FIR was lodged in Cantonment police station of Gorakhpur. In the FIR, it was alleged that Adityanath, then Gorakhpur Mayor Anju Chaudhri, then MLA Radha Mohan Agarwal and another person had incited communal violence and riots in Gorakhpur in 2007 through “hate speeches”.* Adityanath, who heads the sprawling Gorakhnath temple beside having been a five-time BJP MP from Gorakhpur, was named in the FIR, along with Chaudhari and Agarwal, according to PTI.* Parvez Parwaz, who was a complainant in the FIR, along with Asad Hayat, a witness in the case, filed a petition in Allahabad High Court in 2008.* The duo requested the Allahabad high court to direct an investigation by an independent agency into the FIR on the ground that "one cannot be a judge in his own case".* However, ignoring this legal point, the government on May 3, 2017, refused to grant sanction to prosecute Adityanath, who was by then UP CM, contending that the petitioners need not have approached the court because other remedies, such as filing a protest petition, were available.* The government denied the permission to prosecute the CM on the grounds that the video recording of the purported hate speech of Adityanath was tampered with.* Adityanath, who is booked under IPC 153A for making a hate speech, could be tried only after his prosecution is sanctioned by the state government. |
Save this picture! Courtesy of University of Washington Department of Architecture website, http://arch.be.washington.edu/
In a posthumous 1990 essay “A Black Box: The Secret Profession of Architecture”, Reyner Banham warned of architecture’s corrosive trend toward insulating itself from discussions outside of the discipline. Decades later, architecture finds itself in an even more dire state of affairs. Despite a transformed global context, the same paternalistic model of studio culture that has existed since the Beaux Arts remains in place. “Studio culture”, as currently practiced, promotes an outdated and parochial understanding of how design knowledge is produced, valuing expertise over synthesis and image over process and practice.
It also affects the health and wellness of students. Over ten years ago, the AIAS (American Institute of Architecture Students) and NAAB (National Architectural Accrediting Board) created a new requirement for accreditation, requiring all schools to address these precise concerns through a written policy on studio and learning culture. However, many schools of architecture across the country still do not educate students about this policy nor seem to follow it.
While there are certainly creative strengths and a generalized camaraderie fostered by traditional studio models, they do not adequately prepare students for navigating the global present. We believe there is an urgent need to reconfigure the institution of studio in order to address the pressing academic and professional issues of our time. We are putting forth what we feel are the guiding principles which must inform a progressive studio culture: agency, balance, flexibility, diversity, interactivity, interdisciplinarity, and sustainability. It is our hope these principles spur debate and much needed action for fundamentally transforming studio culture.
Agency
Students are under tremendous social, economic, and cultural pressures in school. Because of this, most do not realize they could have far greater agency in the formation of their education. The default tendency is for students to uncritically accept the premises in a given curriculum, syllabus, or studio problem, thus negating their stake. This acceptance appears to be necessary in order to focus on the task at hand, much like the way a subordinate in a professional office operates. This is in no way meant to be pejorative but rather to highlight that these behaviors are so inculcated that students often do not realize how little they are shaping or participating within them. This begs us to ask what role faculty members can play in helping students to realize their agency and utilize it. The studio contract (see flexibility) is one way to intervene in this relationship, but others are needed in order to foster a culture of action that can translate into an engaged profession.
Balance
A recent study on mental health in architecture school paints a bleak picture of the experience of studio culture. The idea that “all-nighters” are a necessary part of any project work schedule is an accepted and often expected practice. While few studio professors believe this is a wise use of time, among students the practice of staying up all night, sometimes multiple nights to meet deadlines, persists. That most architecture school buildings maintain 24-hour accessibility doesn’t help the matter. The NAAB Handbook is quite clear in its support of a balanced life, however the advice is habitually ignored. Architects from Virtruvius to Le Corbusier have claimed to hold the responsibility of teaching society how to live productive, artful lives. But if architects can’t maintain these standards themselves, a great degree of hypocrisy persists. Maintaining a healthy, balanced life is a critical component of 21st century studio culture.
Flexibility
While the architecture studio is still a site for a range of creative transactions, the ways in which students work are often informed by inherited constraining habits. As educators, we teach students to be nimble thinkers and designers, moving between various digital platforms, modeling and mapping software, and honing their public presentation personas. But what does it mean to be flexible when it comes to life-work balance? And more importantly, how do students learn to be flexible?
Overturning ingrained practices can be incredibly difficult, but instituting a negotiated contract is a promising method for catalyzing change. In a studio class led by this article’s co-author, Lori Brown, at Syracuse University last fall, Brown proposed a contract with her second-year undergraduate architecture students. Openly negotiated with all of the students, the basic tenets included banning all-nighters as well as texting and watching videos during studio class time. Additionally, an agreed upon schedule was decided on, enabling students to work and make it to their non-studio courses alert and well-rested.
Diversity
A 21st century studio culture must take on a more inclusive understanding of knowledge practices if it is to serve a globalized community. The dominant studio model traces its lineage back to Euro-American precedents like the Beaux Arts, the Bauhaus, and, in the US, the Texas Rangers, but these are inadequate even in an American context, where a large portion of architecture students identify themselves as “international”. Likewise, the fact that these early studio models served primarily white male students should make us question the assumptions and power structures embedded within studio culture. Proponents of the disciplinarity of architecture praise the virtues of “the canon”. But why should a student from China, for example, be heavily invested in the work of Andrea Palladio or Peter Eisenman? These are certainly valid and well-supported models, but they should be considered just a few among many. The need for diversity in studio culture goes beyond merely accommodating demographic shifts. In a globalized world, it is no longer possible to think simply in terms of the local. Learning to not only cope, but thrive within diverse cultural and social contexts is fundamental to a renewed studio culture.
Interactivity
As discussed above, the studio is a site of tremendous creative energy. Unfortunately, the ways in which this energy is channeled and the ways it is evaluated is incredibly hierarchical and non-interactive. The “jury” model of reviewing work is a relic from another era. Despite technological breakthroughs in recent decades encouraging unprecedented levels of social interactivity and new forms of representation, the staid jury model has remained the unquestioned centerpiece of architectural education. Creative work in the 21st century calls for ways of learning which encourage participation and dialogue rather than judgment and discipline. This might be phrased as bottom-up versus top-down "expert" form of teaching. Studio instead seems like a job with a “boss” rather than a place to play and experiment with different modes of critique, discussion and learning environments. Transforming this atmosphere is necessary for a reinvigorated studio culture.
Interdisciplinarity
What additional areas of education do architecture students need in the 21st century and how are we preparing them for the ever-evolving landscapes of practice? Interdisciplinary educational models are imperative for the future of the profession. If architects are to remain vital to the built environment, we must cross disciplinary boundaries in order to broaden the discipline’s role politically, socially, and materially. In the face of rapid technological change, it’s imperative that architects learn to work collaboratively with a widening expanse of experts in other fields. Retreating into a disciplinary bubble is not an option.
Sustainability
While the need for sustainable built environments is certainly a pressing issue that architects continue to grapple with, less talked about is the idea that the studio culture which produces architects itself is premised on a wholly unsustainable model. Central to this model is the fact that we are teaching students to undervalue their time. Students are aware of the unspoken expectation that you must work however long it takes to finish their work. This directly translates into undervalued professional practice, the norm of unpaid internships, incredibly long hours, and dreadfully low wages in comparison to other technical professions. What role does value play - the value of our time, the value of our work, and the value of our life? We are all complicit in the perpetuation of this unsustainable cycle. As we are in part responsible for this, we must dramatically change it. Architecture schools need to seriously reckon with this system and invent alternative models - or we will continue to involute into a blacker box.
Sources
AIAS Studio Culture Task Force, 2002. The Redesign of Studio Culture A Report of the AIAS Studio Culture Task Force, Washington D.C.: American Institute of Architecture Students.
Architecture Lobby, http://architecture-lobby.org/.
Banham, Reyner. 1990. “A Black Box: The Secret Profession of Architecture,” New Statesman & Society, October 12.
Brown, Lori A. 2011. “Introduction,” Feminist Practices: Interdisciplinary Approaches to Women in Architecture. Surrey, England: Ashgate Publishing Limited.
Caragonne, Alexander, 1995. The Texas Rangers: Notes from the Architectural Underground. Cambridge MA and London: MIT Press,
Godlewski, Joseph. 2011. “On the Persistence of Juried Architectural Reviews,” Crit 72.
Linder, Mark. 2005. “TRANSdisciplinarity” Hunch #9.
NAAB Handbook 2009
Whelan, Jennifer. "Mental Health in Architecture School: Can the Culture Change?" 21 Apr 2014. ArchDaily. Accessed 05 May 2014. <http://www.archdaily.com/?p=498397> |
Fellow Bloggers
Tuesday, February 21, 2006
The Motivation Mill
I resumed my gym yesterday. I am not sure if I'll have the luxury of working out while I am at the Indian School of Business. Unlike most other people, I like working out on the treadmill - both for the obvious and the not-so-obvious reasons. The obvious reason is that the treadmill is the most effective way to get rid of that excess fat and the easiest way to remain in good shape. It’s also a very good cardio exercise. However, I like it more for the not-so-obvious reason. Working out on the treadmill (and watching myself doing that in the mirror that faces it in my gym) motivates me to great levels. My best laid plans regarding writing the GMAT, GMAT strategies, ISB application and subsequently the ISB interview, all owe their synthesis to my workout sessions on the treadmill. That’s why I have re-christened the treadmill. I now call it the Motivation Mill.
Wednesday, February 08, 2006
And then ISB happens..
7th Jan, 2006 was a landmark day in my life. I got selected for admission to the Indian School of Business, Hyderabad. With this, I come within striking distance of realising my long cherished dream.. and boy.. am I excited or am I excited??? I have been made to understand, however, that its going to be one hectic year with a very rigorous schedule. From the peaceful Abu Dhabi life, to the most extreme form of slogging that stares me in the eye, it will be quite a transition though. Nevertheless, I am looking forward to it :-) |
# Copyright Niantic 2020. Patent Pending. All rights reserved.
#
# This software is licensed under the terms of the DepthHints licence
# which allows for non-commercial use only, the full terms of which are made
# available in the LICENSE file.
from __future__ import absolute_import, division, print_function
import os
import argparse
file_dir = os.path.dirname(__file__) # the directory that options.py resides in
class MonodepthOptions:
def __init__(self):
self.parser = argparse.ArgumentParser(description="Monodepthv2 options")
# PATHS
self.parser.add_argument("--data_path",
type=str,
help="path to the training data",
default=os.path.join(file_dir, "kitti_data"))
self.parser.add_argument("--log_dir",
type=str,
help="log directory",
default=os.path.join(os.path.expanduser("~"), "tmp"))
# TRAINING options
self.parser.add_argument("--model_name",
type=str,
help="the name of the folder to save the model in",
default="mdp")
self.parser.add_argument("--split",
type=str,
help="which training split to use",
choices=["eigen_zhou", "eigen_full", "odom", "benchmark"],
default="eigen_zhou")
self.parser.add_argument("--num_layers",
type=int,
help="number of resnet layers",
default=18,
choices=[18, 34, 50, 101, 152])
self.parser.add_argument("--dataset",
type=str,
help="dataset to train on",
default="kitti",
choices=["kitti", "kitti_odom", "kitti_depth", "kitti_test"])
self.parser.add_argument("--png",
help="if set, trains from raw KITTI png files (instead of jpgs)",
action="store_true")
self.parser.add_argument("--height",
type=int,
help="input image height",
default=192)
self.parser.add_argument("--width",
type=int,
help="input image width",
default=640)
self.parser.add_argument("--disparity_smoothness",
type=float,
help="disparity smoothness weight",
default=1e-3)
self.parser.add_argument("--scales",
nargs="+",
type=int,
help="scales used in the loss",
default=[0, 1, 2, 3])
self.parser.add_argument("--min_depth",
type=float,
help="minimum depth",
default=0.1)
self.parser.add_argument("--max_depth",
type=float,
help="maximum depth",
default=100.0)
self.parser.add_argument("--use_stereo",
help="if set, uses stereo pair for training",
action="store_true")
self.parser.add_argument("--frame_ids",
nargs="+",
type=int,
help="frames to load",
default=[0, -1, 1])
# DEPTH HINT options
self.parser.add_argument("--use_depth_hints",
help="if set, apply depth hints during training",
action="store_true")
self.parser.add_argument("--depth_hint_path",
help="path to load precomputed depth hints from. If not set will"
"be assumed to be data_path/depth_hints",
type=str)
# OPTIMIZATION options
self.parser.add_argument("--batch_size",
type=int,
help="batch size",
default=12)
self.parser.add_argument("--learning_rate",
type=float,
help="learning rate",
default=1e-4)
self.parser.add_argument("--num_epochs",
type=int,
help="number of epochs",
default=20)
self.parser.add_argument("--scheduler_step_size",
type=int,
help="step size of the scheduler",
default=15)
# ABLATION options
self.parser.add_argument("--v1_multiscale",
help="if set, uses monodepth v1 multiscale",
action="store_true")
self.parser.add_argument("--avg_reprojection",
help="if set, uses average reprojection loss",
action="store_true")
self.parser.add_argument("--disable_automasking",
help="if set, doesn't do auto-masking",
action="store_true")
self.parser.add_argument("--predictive_mask",
help="if set, uses a predictive masking scheme as in Zhou et al",
action="store_true")
self.parser.add_argument("--no_ssim",
help="if set, disables ssim in the loss",
action="store_true")
self.parser.add_argument("--weights_init",
type=str,
help="pretrained or scratch",
default="pretrained",
choices=["pretrained", "scratch"])
self.parser.add_argument("--pose_model_input",
type=str,
help="how many images the pose network gets",
default="pairs",
choices=["pairs", "all"])
self.parser.add_argument("--pose_model_type",
type=str,
help="normal or shared",
default="separate_resnet",
choices=["posecnn", "separate_resnet", "shared"])
# SYSTEM options
self.parser.add_argument("--no_cuda",
help="if set disables CUDA",
action="store_true")
self.parser.add_argument("--num_workers",
type=int,
help="number of dataloader workers",
default=12)
# LOADING options
self.parser.add_argument("--load_weights_folder",
type=str,
help="name of model to load")
self.parser.add_argument("--models_to_load",
nargs="+",
type=str,
help="models to load",
default=["encoder", "depth", "pose_encoder", "pose"])
# LOGGING options
self.parser.add_argument("--log_frequency",
type=int,
help="number of batches between each tensorboard log",
default=250)
self.parser.add_argument("--save_frequency",
type=int,
help="number of epochs between each save",
default=1)
# EVALUATION options
self.parser.add_argument("--eval_stereo",
help="if set evaluates in stereo mode",
action="store_true")
self.parser.add_argument("--eval_mono",
help="if set evaluates in mono mode",
action="store_true")
self.parser.add_argument("--disable_median_scaling",
help="if set disables median scaling in evaluation",
action="store_true")
self.parser.add_argument("--pred_depth_scale_factor",
help="if set multiplies predictions by this number",
type=float,
default=1)
self.parser.add_argument("--ext_disp_to_eval",
type=str,
help="optional path to a .npy disparities file to evaluate")
self.parser.add_argument("--eval_split",
type=str,
default="eigen",
choices=[
"eigen", "eigen_benchmark", "benchmark", "odom_9", "odom_10"],
help="which split to run eval on")
self.parser.add_argument("--save_pred_disps",
help="if set saves predicted disparities",
action="store_true")
self.parser.add_argument("--no_eval",
help="if set disables evaluation",
action="store_true")
self.parser.add_argument("--eval_eigen_to_benchmark",
help="if set assume we are loading eigen results from npy but "
"we want to evaluate using the new benchmark.",
action="store_true")
self.parser.add_argument("--eval_out_dir",
help="if set will output the disparities to this folder",
type=str)
self.parser.add_argument("--post_process",
help="if set will perform the flipping post processing "
"from the original monodepth paper",
action="store_true")
def parse(self):
self.options = self.parser.parse_args()
return self.options
|
The Sunday Telegraph reports this evening that the Government plans to introduce a Bill on prisoner voting this coming Thursday. The newspaper says that the Ministry of Justice's Bill will give Parliament the choice of three options:
Votes for prisoners who've been imprisoned for four years or less
Votes for prisoners who've been imprisoned for six months or less
No votes for prisoners at all
What is unclear is how the Government would proceed if MPs decide, as one might predict, to vote for the third option, not to give prisoners the vote, and the Court decides to fine the Government. The fact that the Government appears to be willing to be fined by Europe rather than defy the will of Parliament will seem a positive step for many Conservatives.
If the different options of the Bill are presented as a free vote, as one would expect, Cabinet members will also be free to vote as they wish, and it will be a point of interest as to how Ministers choose to vote. David Cameron's vote will be watched especially closely. A month ago at PMQs he said:
"I do not want prisoners to have the vote, and they should not get the vote—I am very clear about that. If it helps to have another vote in Parliament on another resolution to make it absolutely clear and help put the legal position beyond doubt, I am happy to do that. But no one should be in any doubt: prisoners are not getting the vote under this Government."
This statement would make it seem inconsistent for the Prime Minister to do anything other than vote for the third option in the Bill.
Others who will be closely watched will be George Osborne, Michael Gove, Iain Duncan Smith, and Owen Paterson. Chris Grayling and Dominic Grieve, the Government's main law officers, may feel obliged to vote for either of the first two options (or indeed, may not). Some Tory MPs will note that if Grayling and Grieve consider the third option to be legal, they should be able to vote for it themselves. The Cabinet would certainly look a little silly if they were to put the no-votes option to the House, but none of them actually voted for it. On the other hand, Cabinet splits will be on display if they do vote in different ways.
The three-option Bill is an attempt by Ministers to square the Government's legal obligation to respect the Court's view that prisoners should be given the vote with the political reality, which is that the Government must respect the Commons' view, must not get on the wrong side of Conservative backbenchers and grassroots, and must not fall out with the centre-right media and, of course, most voters.
It is not the perfect solution, and many MPs will still feel uneasy with even the possibility of giving some prisoners the vote. However, if the Bill includes a third option, giving the House of Commons the ability to reaffirm its opposition to any prison voting, it will prove a far more suitable compromise than a Bill not giving that option at all. |
Compact discs are now manufactured, sold, and used in very large volume. It is a prevailing practice to package the discs on an individual basis. During shipment and prior to sale there are important requirements for protecting the discs, with respect both to physical damage to the disc itself and also possible contamination of the disc by dirt entering the package. It is customary to provide a shrink-wrapped plastic cover for the package in which the disc is contained, leaving the ultimate buyer to first remove the plastic cover before taking the disc our of the package.
Further, the package must be functionally effective for the ultimate consumer, not only for storage of the disc prior to use, but for re-storing the disc after it has been played. Ease of retrieving the disc from the package, and later returning it to the package, are important. |
The meteor explosion was captured on a Japanese weather satellite’s camera Description:Simon Proud, University of Oxford/Japan Meteorological Agency
It may not look like much, but this orangey brown puff of smoke high is the aftermath of the third largest meteor explosion to have impacted Earth in modern times.
The huge meteor explosion hit Earth in December but was only spotted by researchers last week, and now we have visual evidence thanks to the camera of the geostationary Japanese Himawari-8 weather satellite.
The meteor’s smoke cloud was recorded at 2350 GMT in the same location over the Bering Sea that was recorded by NASA’s monitoring sensors.
A slightly zoomed crop of the image Simon Proud, University of Oxford/Japan Meteorological Agency
The smoke trail is almost vertical, showing that it entered the atmosphere very steeply, and it’s possible to see a long, thin shadow cast by the smoke cloud against the Earth’s cloud layer below.
Simon Proud, an aviation safety fellow and meteorologist at the University of Oxford, who shared the image on Twitter, said, “I’m sure it’s the meteor trace.”
He said, “It appears in the images at the right time, it is in the right location, the smoke column is almost vertical, and the smoke is very high. Much higher than any clouds in that region and too high to be a contrail.”
The giant fireball hit the atmosphere with the force of 173 kilotons of TNT, ten times the force of the atomic bomb which the US dropped on Hiroshima at the end of the second world war.
A black and white image of the meteor explosion Description:Simon Proud, University of Oxford/Japan Meteorological Agency
The explosion is the third-largest in modern times, after an explosion over the Russian Chelyabinsk region in 2013 and a massive explosion that occurred in Siberia, Russia, in 1908, known as the Tunguska event. That air burst was so powerful that it flattened an estimated 80 million trees over an area of more than 2000 square kilometres.
Read more: Huge meteor explosion over Earth last year went unnoticed until now |
Butyric acid production from lignocellulosic biomass hydrolysates by engineered Clostridium tyrobutyricum overexpressing xylose catabolism genes for glucose and xylose co-utilization.
Clostridium tyrobutyricum can utilize glucose and xylose as carbon source for butyric acid production. However, xylose catabolism is inhibited by glucose, hampering butyric acid production from lignocellulosic biomass hydrolysates containing both glucose and xylose. In this study, an engineered strain of C. tyrobutyricum Ct-pTBA overexpressing heterologous xylose catabolism genes (xylT, xylA, and xylB) was investigated for co-utilizing glucose and xylose present in hydrolysates of plant biomass, including soybean hull, corn fiber, wheat straw, rice straw, and sugarcane bagasse. Compared to the wild-type strain, Ct-pTBA showed higher xylose utilization without significant glucose catabolite repression, achieving near 100% utilization of glucose and xylose present in lignocellulosic biomass hydrolysates in bioreactor at pH 6. About 42.6g/L butyrate at a productivity of 0.56g/L·h and yield of 0.36g/g was obtained in batch fermentation, demonstrating the potential of C. tyrobutyricum Ct-pTBA for butyric acid production from lignocellulosic biomass hydrolysates. |
Measham railway station
Measham railway station is a disused railway station that formerly served the village of Measham, North West Leicestershire from 1874 to 1931. The station was on the Ashby and Nuneaton Joint Railway. The station is the only building on the Ashby - Shackerstone section to still be in situ. The trackbed has since been filled in and is now a footpath to Moira. The goods shed is also still standing at Measham.
{
"type": "FeatureCollection",
"features": [
{
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"properties": {},
"geometry": {
"type": "Point",
"coordinates": [
-1.5093,
52.7039
]
}
}
]
}
References
http://www.midlandrailway.org.uk/occasional-papers/donisthorpe/
http://www.shackerstonefestival.co.uk/ANJR/Hdonisthorpe_station.htm
https://www.pastscape.org.uk/hob.aspx?hob_id=509044
http://podahistory.blogspot.com/2014/07/donisthorpe-railway-station.html
Category:Disused railway stations in Leicestershire
Category:Former Midland Railway stations
Category:Former London and North Western Railway stations
Category:Railway stations opened in 1874
Category:Railway stations closed in 1931 |
Tuscaloosa man arrested on charge of raping 11-year-old girl
View full sizePatrick Bernard White, above, was arrested and charged for first-degree rape, first-degree sodomy and three counts of sexually abusing a person under 12-years-old. (TPD)
TUSCALOOSA, Alabama -- Tuscaloosa Police Juvenile Investigators arrested a suspect on a first-degree rape charge, a sexual abuse of a child under 12 years old charge and three counts of first-degree sodomy.
The arrests stem from an incident that occurred in the 3600 block of East McFarland Boulevard on March 21.
Police said the victim is an 11-year-old female.
Patrick Bernard White, 22, of Tuscaloosa was arrested at 1:45 p.m. at the Tuscaloosa Police Department on Monday. White was transported to the Tuscaloosa County Jail and held on a $270,000 bond. |
Razor Candi posted to Blue Blood VIP in a set by Bodó Janos Attila called Pinstripe Glasses. This set posted at the same time as a BarelyEvil members-only feature spotlight interview with Razor Candi. BarelyEvil is included in all Blue Blood VIP memberships.
No comments yet. |
Implement encoding and decoding for the rail fence cipher.
The Rail Fence cipher is a form of transposition cipher that gets its name from
the way in which it's encoded. It was already used by the ancient Greeks.
In the Rail Fence cipher, the message is written downwards on successive "rails"
of an imaginary fence, then moving up when we get to the bottom (like a zig-zag).
Finally the message is then read off in rows.
For example, using three "rails" and the message "WE ARE DISCOVERED FLEE AT ONCE",
the cipherer writes out:
```text
W . . . E . . . C . . . R . . . L . . . T . . . E
. E . R . D . S . O . E . E . F . E . A . O . C .
. . A . . . I . . . V . . . D . . . E . . . N . .
```
Then reads off:
```text
WECRLTEERDSOEEFEAOCAIVDEN
```
To decrypt a message you take the zig-zag shape and fill the ciphertext along the rows.
```text
? . . . ? . . . ? . . . ? . . . ? . . . ? . . . ?
. ? . ? . ? . ? . ? . ? . ? . ? . ? . ? . ? . ? .
. . ? . . . ? . . . ? . . . ? . . . ? . . . ? . .
```
The first row has seven spots that can be filled with "WECRLTE".
```text
W . . . E . . . C . . . R . . . L . . . T . . . E
. ? . ? . ? . ? . ? . ? . ? . ? . ? . ? . ? . ? .
. . ? . . . ? . . . ? . . . ? . . . ? . . . ? . .
```
Now the 2nd row takes "ERDSOEEFEAOC".
```text
W . . . E . . . C . . . R . . . L . . . T . . . E
. E . R . D . S . O . E . E . F . E . A . O . C .
. . ? . . . ? . . . ? . . . ? . . . ? . . . ? . .
```
Leaving "AIVDEN" for the last row.
```text
W . . . E . . . C . . . R . . . L . . . T . . . E
. E . R . D . S . O . E . E . F . E . A . O . C .
. . A . . . I . . . V . . . D . . . E . . . N . .
```
If you now read along the zig-zag shape you can read the original message.
|
/**
* \file error.h
*
* \brief Error to string translation
*
* Copyright (C) 2006-2010, Brainspark B.V.
*
* This file is part of PolarSSL (http://www.polarssl.org)
* Lead Maintainer: Paul Bakker <polarssl_maintainer at polarssl.org>
*
* All rights reserved.
*
* This program is free software; you can redistribute it and/or modify
* it under the terms of the GNU General Public License as published by
* the Free Software Foundation; either version 2 of the License, or
* (at your option) any later version.
*
* This program is distributed in the hope that it will be useful,
* but WITHOUT ANY WARRANTY; without even the implied warranty of
* MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the
* GNU General Public License for more details.
*
* You should have received a copy of the GNU General Public License along
* with this program; if not, write to the Free Software Foundation, Inc.,
* 51 Franklin Street, Fifth Floor, Boston, MA 02110-1301 USA.
*/
#ifndef POLARSSL_ERROR_H
#define POLARSSL_ERROR_H
/**
* Error code layout.
*
* Currently we try to keep all error codes within the negative space of 16
* bytes signed integers to support all platforms (-0x0000 - -0x8000). In
* addition we'd like to give two layers of information on the error if
* possible.
*
* For that purpose the error codes are segmented in the following manner:
*
* 16 bit error code bit-segmentation
*
* 1 bit - Intentionally not used
* 3 bits - High level module ID
* 5 bits - Module-dependent error code
* 6 bits - Low level module errors
* 1 bit - Intentionally not used
*
* Low-level module errors (0x007E-0x0002)
*
* Module Nr Codes assigned
* MPI 7 0x0002-0x0010
* GCM 2 0x0012-0x0014
* BLOWFISH 2 0x0016-0x0018
* AES 2 0x0020-0x0022
* CAMELLIA 2 0x0024-0x0026
* XTEA 1 0x0028-0x0028
* BASE64 2 0x002A-0x002C
* PADLOCK 1 0x0030-0x0030
* DES 1 0x0032-0x0032
* CTR_DBRG 3 0x0034-0x003A
* ENTROPY 3 0x003C-0x0040
* NET 11 0x0042-0x0056
* ASN1 7 0x0060-0x006C
* MD2 1 0x0070-0x0070
* MD4 1 0x0072-0x0072
* MD5 1 0x0074-0x0074
* SHA1 1 0x0076-0x0076
* SHA2 1 0x0078-0x0078
* SHA4 1 0x007A-0x007A
* PBKDF2 1 0x007C-0x007C
*
* High-level module nr (3 bits - 0x1...-0x8...)
* Name ID Nr of Errors
* PEM 1 8
* X509 2 21
* DHM 3 6
* RSA 4 9
* MD 5 4
* CIPHER 6 5
* SSL 6 2 (Started from top)
* SSL 7 31
*
* Module dependent error code (5 bits 0x.08.-0x.F8.)
*/
#ifdef __cplusplus
extern "C" {
#endif
/**
* \brief Translate a PolarSSL error code into a string representation,
* Result is truncated if necessary and always includes a terminating
* null byte.
*
* \param errnum error code
* \param buffer buffer to place representation in
* \param buflen length of the buffer
*/
void error_strerror( int errnum, char *buffer, size_t buflen );
#ifdef __cplusplus
}
#endif
#endif /* error.h */
|
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In some areas of CTM
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leave CTM Software's web site. The linked web sites are not under
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endorsement by CTM Software of the web site. |
Q:
flac: "ERROR: input file has an ID3v2 tag" (it doesn't)
I'm trying to build a rather longwinded chain of programs and libraries that culminates in using a speech-to-text API to run an mp3 file into human-readable text. I was surprised to find very few APIs that do this online - the only working thing I found was the speech2text project: https://github.com/taf2/speech2text which hooks into Google's unofficial Speech-To-Text API.
This actually worked at first. I did a few manual conversions and was pleased with the results. However, since attempting to automate the chain of processes in Java, it's stopped working properly.
EDIT - the following error messages are technically sourcing from flac itself, not speech2text. Attempting to convert these files using flac only and not speech2text also results in the id3v2 error message, so the error is not really to do with speech2text (although speech2text might be the source of the erroneous tags)
Java reports this as the error (after having called speech2text using a ProcessBuilder and printing out the streams):
/Library/Ruby/Gems/1.8/gems/speech2text-0.3.4/lib/speech/audio_inspector.rb:50:in initialize': undefined methodfirst' for nil:NilClass (NoMethodError)
from /Library/Ruby/Gems/1.8/gems/speech2text-0.3.4/lib/speech/audio_splitter.rb:77:in new'
from /Library/Ruby/Gems/1.8/gems/speech2text-0.3.4/lib/speech/audio_splitter.rb:77:ininitialize'
from /Library/Ruby/Gems/1.8/gems/speech2text-0.3.4/lib/speech/audio_to_text.rb:15:in new'
from /Library/Ruby/Gems/1.8/gems/speech2text-0.3.4/lib/speech/audio_to_text.rb:15:into_text'
from /Library/Ruby/Gems/1.8/gems/speech2text-0.3.4/bin/speech2text:11
from /usr/bin/speech2text:19:in `load'
from /usr/bin/speech2text:19
However, attempting to run the command manually on the same file actually gives me this:
ERROR: input file ./chunk-abortion-test-audio-0.mp3 has an ID3v2 tag
/Library/Ruby/Gems/1.8/gems/speech2text-0.3.4/lib/speech/audio_splitter.rb:59:in to_flac': failed to convert chunk: ./chunk-abortion-test-audio-0.mp3 with flac ./chunk-abortion-test-audio-0.mp3 (RuntimeError)
from /Library/Ruby/Gems/1.8/gems/speech2text-0.3.4/lib/speech/audio_to_text.rb:18:into_text'
from /Library/Ruby/Gems/1.8/gems/speech2text-0.3.4/lib/speech/audio_to_text.rb:17:in each'
from /Library/Ruby/Gems/1.8/gems/speech2text-0.3.4/lib/speech/audio_to_text.rb:17:into_text'
from /Library/Ruby/Gems/1.8/gems/speech2text-0.3.4/bin/speech2text:11
from /usr/bin/speech2text:19:in `load'
from /usr/bin/speech2text:19
Of course the irony here is that I've actually cleaned the file of id3v2 tags using
id3v2 --delete-all at a Mac terminal. So something screwy is going on.
Can anyone suggest what might be happening? Also, given that speech2text hasn't seen an update in a year, I feel like there must be a newer speech-to-text solution that people are using. So if there's something better out there please let me know.
Cheers!
EDIT - Incidentally, if anyone's interested the mp3 file originated from stripping a .flv file using ffmpeg.
A:
This is now two separate problems. The ID3v2 issue I have only been able to resolve by sidestepping the use of .mp3 files and using .wav instead. The Java output is still an issue so I'm shifting that to a new Question.
|
104 B.R. 529 (1989)
In the Matter of LUMPKIN SAND AND GRAVEL, INC., Debtor.
KAL-O-MINE INDUSTRIES, INC., and Lumpkin Sand and Gravel, Inc., Plaintiffs,
v.
Wilson M. CAMP, II, Defendant.
In the Matter of CAMP LIGHTWEIGHT, INC., Debtor.
KAL-O-MINE INDUSTRIES, INC., and Lumpkin Sand and Gravel, Inc., Plaintiffs,
v.
Wilson M. CAMP, II, Defendant.
Bankruptcy Nos. 87-40005-COL, 85-40160-COL, Adv. Nos. 89-4033, 89-4034.
United States Bankruptcy Court, M.D. Georgia, Columbus Division.
August 25, 1989.
*530 Jerome L. Kaplan, Wesley J. Boyer, Macon, Ga., for Lumpkin Sand and Gravel, Inc. and Kal-O-Mine Industries, Inc.
James A. Elkins, Jr., Columbus, Ga., for Wilson M. Camp, II.
Stephen M. Bailey, Denver, Colo., for Ventures Plus.
Ernest Kirk, II, Columbus, Ga., for Trustee.
STATEMENT OF THE CASE
ROBERT F. HERSHNER, Jr., Chief Judge.
Camp Lightweight, Inc., Debtor ("Camp Lightweight"), filed a petition under Chapter 11 of the Bankruptcy Code on March 22, 1985. Camp Lightweight filed a disclosure statement on March 20, 1986. An addendum to the disclosure statement was filed and approved by the Court on April 23, 1986. A second addendum was filed on May 8, 1986 and approved on May 15, 1986. Camp Lightweight filed an amended plan of reorganization on June 23, 1986. A modification of the amended plan was filed on August 19, 1986. The Court entered an order confirming the plan on August 19, 1986.
Lumpkin Sand and Gravel, Inc., Debtor ("Lumpkin Sand"), filed a petition under Chapter 11 of the Bankruptcy Code on January 6, 1987. Lumpkin Sand filed its disclosure statement and plan of reorganization on March 2, 1988. The Court approved the disclosure statement on March 31, 1988. Mr. Wilson M. Camp, II, Defendant, filed an objection to confirmation of the plan on April 20, 1988. On September 9, 1988, the Court entered an order overruling Defendant's objection and ordered that Defendant be forever barred from claiming ownership of certain property which Defendant had conveyed to Kal-O-Mine Resources, Inc. Kal-O-Mine Industries, Inc. ("Kal-O-Mine"), the sole shareholder of Lumpkin Sand, filed a disclosure statement and plan of reorganization on September 20, 1988, which adopted Lumpkin Sand's disclosure statement and plan. The plan was orally modified at the confirmation hearing on September 26, 1988. The Court conditionally confirmed the plan on November 17, 1988. On January 13, 1989, the Court entered an order determining that Lumpkin Sand is the owner of a certain 579.66-acre tract of land in Muscogee County, Georgia, bordering on the Chattahoochee River (the "Lumpkin property").
On April 6, 1989, Kal-O-Mine and Lumpkin Sand, Plaintiffs, filed a "Complaint for Declaratory Judgment, for Damages, and for Preliminary and Preliminary Injunctions" ("Complaint") against Defendant. Kal-O-Mine and Lumpkin Sand filed an adversary proceeding in the Lumpkin Sand case and one in the Camp Lightweight case. The two adversary proceedings are exactly the same and seek the same relief from Defendant. The Court joined the two adversary proceedings for trial. Kal-O-Mine alleges that it owns all real and personal property and equipment leases previously owned by Camp Lightweight. Lumpkin Sand alleges that it owns the riverbed *531 and minerals in and under the riverbed adjoining the Lumpkin property to the extent the riverbed and minerals may be privately owned. Lumpkin Sand claims it owns all the fixtures, equipment, and other personal property on the Lumpkin property.
Kal-O-Mine and Lumpkin Sand allege in their adversary proceedings that Defendant has interfered with their business and reorganization plans by telling third parties that Defendant owns the real estate and personal property. They ask the Court to declare that they own the real estate, riverbed, and personal property, to enjoin Defendant from asserting a claim of ownership to said property, to enjoin Defendant from interfering with Lumpkin Sand's and Camp Lightweight's plans of reorganization, and to award damages for Defendant's liable and slander concerning title to said real estate.
Kal-O-Mine and Lumpkin Sand filed an amendment to their complaint on April 24, 1989. The amendment asks the Court to award them damages for conversion of property for minerals and topsoil removed from the Lumpkin property. Defendant timely filed his answer on May 26, 1989.[1] A hearing was held on April 25, 1989. The Court entered an order on April 26, 1989 which preliminarily enjoined Defendant in accordance with oral instructions issued by the Court in open court at the conclusion of the hearing held on April 25, 1989.
Kal-O-Mine and Lumpkin Sand filed a Motion for Preliminary Injunction on May 26, 1989. They allege that following the issuance of the Court's order on April 26, 1989, someone under the direction of Defendant entered their Ft. Gaines property.[2]
A trial on both adversary proceedings was held on June 23, 1989. At the conclusion of the trial, the Court invited all parties to submit briefs on the matters in issue. This opinion only addresses the limited issues of ownership of the riverbed, ownership of the personal property on the Lumpkin property, and ownership of the Camp Lightweight property. The Court reserves its decision concerning Kal-O-Mine and Lumpkin Sand's demands for actual damages, punitive damages, and other remedies. The Court, having considered the arguments and briefs of counsel and the evidence presented at trial, now publishes its findings of fact and conclusions of law.
FINDINGS OF FACT
Mr. John William Cooper conveyed a tract of land in Muscogee County, Georgia, to Defendant[3] by deed dated June 1, 1961 (the "Cooper Deed"). The deed described the land as containing 679.58-acres, more or less, lying in one body and composed of six contiguous tracts. Tracts one through five are near or bounded by the Chattahoochee River. Tract six is the riverbed of the Chattahoochee River, which bounds some of the other tracts described in the deed. The riverbed described in Tract six extends to the Georgia-Alabama State line. On January 5, 1986, Defendant entered into an agreement with Kal-O-Mine Resources, Inc.[4] to convey the land described in the Cooper Deed to Kal-O-Mine in exchange for three million shares of Kal-O-Mine common lettered stock. Defendant conveyed Tracts one through five of this land to Kal-O-Mine by deed dated January 23, 1986 (the "Camp Deed"). The deed describes the land as containing 579.66 acres,[5]*532 more or less, lying in one body and composed of five contiguous tracts. The land, in part, is bounded by the Chattahoochee River on three sides. The Camp Deed neither included nor specifically excluded the riverbed from the conveyance.
Kal-O-Mine conveyed the Camp Deed property to Lumpkin Sand by deed dated December 29, 1986. Kal-O-Mine owns one hundred percent of the stock of Lumpkin Sand. Located on this land (the "Lumpkin property") are a dredge, several trucks, various pieces of equipment, and scrap iron. These items are not listed in the deed. No bill of sale or other document of title was executed covering these items.
Camp Lightweight's amended plan of reorganization was signed by Defendant as president of Camp Lightweight. The disclosure statement was also signed by Defendant.[6] Kal-O-Mine executed an agreement on January 5, 1986[7] to acquire one hundred percent ownership and control of Camp Lightweight.[8] Under Camp Lightweight's amended plan of reorganization confirmed by the Court, Kal-O-Mine is to retain one hundred percent ownership following reorganization. The plan states that Kal-O-Mine has completed a registration statement for a $2.5 million preferential stock offering, the proceeds of which are committed to investment into and reorganization of Camp Lightweight. Title to the assets of Camp Lightweight is to be assigned and transferred to Kal-O-Mine on the distribution date. The plan also states that Kal-O-Mine has contracted with Defendant to continue his employment to manage the day-to-day, nonfinancial operation of Camp Lightweight under the ownership, direction, and complete supervision of Kal-O-Mine.
Kal-O-Mine offered Defendant an employment contract. Defendant made several changes in the contract and returned it to Kal-O-Mine. Defendant's changes included striking the provisions that he would not be responsible for financial management of Lumpkin Sand and that he could be discharged for disloyalty or inattention to duties.
CONCLUSIONS OF LAW
The two adversary proceedings before the Court concern the ownership of real and personal property in two separate but related bankruptcy cases. The Court first will address the property involved in the Lumpkin Sand bankruptcy case. This property is located in Muscogee County, Georgia. The Court then will address the property involved in the Camp Lightweight bankruptcy case. This property is located in Clay County, Georgia.
I. Ownership of the Riverbed Adjacent to the Lumpkin Property.
Lumpkin Sand and Defendant both claim ownership to the riverbed and the minerals in and under the riverbed (the "riverbed") adjoining the Lumpkin property.[9] Defendant claims title under a deed from John William Cooper dated June 1, 1961 (the "Cooper Deed"). The riverbed is described in Tract six of the Cooper Deed. Defendant contends that he never conveyed the riverbed to Kal-O-Mine.
Kal-O-Mine claims to have held title to the riverbed under a deed from Defendant to Kal-O-Mine dated January 23, 1986 (the "Camp Deed"). Kal-O-Mine claims it conveyed title to the riverbed to Lumpkin Sand[10] by deed dated December 29, 1986. *533 Lumpkin Sand thus claims title to the riverbed.
Resolution of title to real property acquired by deed hinges on state law. Kal-O-Mine argues that, by construction of law, the Camp Deed conveyed the riverbed. Kal-O-Mine also argues that the parties intended that the riverbed be conveyed. Kal-O-Mine and Lumpkin Sand argue that title passed to Lumpkin Sand when Kal-O-Mine executed the deed on December 29, 1986. Defendant argues that the parties did not intend that the Camp Deed convey the riverbed. The Court will analyze ownership of the riverbed both by construction of the deed and by intent of the parties.
(a) Construction of the Deed
The general rule concerning the rights of abutting land owners in navigable rivers is stated in section 44-8-5(b) of the Official Code of Georgia,[11] which provides: "(b) The rights of the owner of lands which are adjacent to navigable streams extend to the low-water mark in the bed of the stream." O.C.G.A. § 44-8-5(b) (1982). "[B]ut state grants prior to the Code of 1863 have been construed as conveying title to the adjoining riverbed by mere reference to the river as one of the boundaries of the grant." G. Pindar, Georgia Real Estate Law § 6-10 (1986) (citation omitted). The parties stipulated that the section of the Chattahoochee River covering the riverbed was navigable at all times relevant to this issue.
The Camp Deed describes the property conveyed as being bounded, in part, on three sides by the Chattahoochee River. There is no clear indication of intent on the face of the deed to reserve the riverbed from the conveyance. Neither Lumpkin Sand nor Defendant has cited a Georgia case which explicitly holds that a private grant of land bounded by a navigable river either does or does not convey title to the adjacent riverbed.
Courts in other jurisdictions have held, almost exclusively, that the use of the phrase "bounded by" conveys title to a riverbed, unless there is a clear indication of an intent by the grantor to reserve title to the riverbed. See generally 12 Am. Jur.2d Boundaries § 21 (1964) (Grants by private persons of land bounded upon navigable waters are presumed, in the absence of anything to the contrary indicated in the conveyance, to be intended to convey all land owned by the grantor); Annotation, Deeds: Description of Lands Conveyed by Reference to River or Stream as Carrying to Thread or Center or Only to Bank ThereofModern Status, 78 A.L.R.3d 604, 607 (1977) (It is generally presumed that a grantee acquires whatever land under a watercourse was owned by grantor, in the absence of language expressly or impliedly reserving from the operation of the deed some portion of the grantor's land.); Annotation, Specific Description with Reference to Water, in Conveyance of Riparian Land, as Marking the Extent of Grantee's Ownership of the Submerged Land and the Shore, 74 ALR 597, 600-01 (1931) (Descriptions running the boundary by a river have generally been regarded as extending to embrace the land to the thread of the water. In states where the beds of navigable waters are subject to private ownership, there seems to be no reason why the rules applied to conveyance of the beds' nonnavigable waters should not be applied.); (Bradford v. United States, 651 F.2d 700, 706 (10th Cir.1981) (Absent a clear indication of contrary intent, a grant conveys title to the bed of the stream.); Choctaw and Chickasaw Nations v. Seay, 235 F.2d 30, 35 (10th Cir.), cert. denied, 352 U.S. 917, 77 S.Ct. 216, 1 L.Ed.2d 123 (1956) (A grant of land bounded on a nonnavigable river by a grantor who owns to the center or thread of the stream conveys the land under the stream, unless the terms of the grant and the attendant circumstances clearly denote an intention to stop at the edge or margin of the river.); Fruin-Colnon Corp. v. Vogt, 500 F.Supp. 606, 612 (S.D.Ill.1980) (Riparian land owners hold title to the middle of the main channel of the Mississippi River in Illinois. It is not necessary that the deed recite title to the bed but rather title rests *534 automatically, absent a clear statement to the contrary.); People v. System Properties, Inc., 2 N.Y.2d 330, 160 N.Y.S.2d 859, 141 N.E.2d 429 (1957) (A grant runs to the middle of a river when the granted land in terms touches the water and when there is no express inclusion or exclusion of the bed.); White v. Knickerbocker Ice Co., 254 N.Y. 152, 172 N.E. 452 (1930) (A description which runs the boundary by the river carries title to the center absent a clear and express restriction of the title to the upland.); Smith v. Bartlett, 180 N.Y. 360, 73 N.E. 63 (1905) ("When a deed describes lands so bounded by a river, which is navigable in fact, the rule prima facie is that the deed conveys as far as the grantor owns.") (Quoting 4th American and English Encyclopedia of Law 823).
This Court recognizes that the theory underlying the rule of the common law concerning grants bounded by nonnavigable rivers is, in some respects, distinguishable from the practical aspects of navigable rivers.[12] Other courts, however, have not used this distinction to reach different results for navigable rivers. Several Georgia cases indicate how the Georgia courts would rule.
In Young v. Harrison,[13] the Georgia Supreme Court was asked to consider riparian rights in the Chattahoochee River near Eufaula. The court noted that the bed of the Chattahoochee at Eufaula is private property subject to the servitude of the public interest by a passage upon it.[14] The court stated that, by construction of law, when the proprietor of land owns the margin, that he also owns the bed over which the river passes, even though, by terms, it is bounded on the margin.[15] Six years later, the Georgia Supreme Court clarified this opinion.[16] The court said that its ruling in Young held that grants of land bounded by the Chattahoochee convey title to the opposite bank of the river.[17] The grant, thus, conveyed title to the entire riverbed.
In Jones v. The Water Lot Co. of Columbus,[18] the Georgia Supreme Court held that a state grant bounded by the Chattahoochee River, by construction of law, reaches to the opposite shores, unless there are expressions in the terms of the grant, taken in connection with the situation and condition of the land granted, which clearly indicate the intentions of the state to stop at the margin of the river.[19]
In Moses v. The Eagle and Phoenix Manufacturing Co.,[20] the question before the Georgia Supreme Court was whether, by the terms in a deed, a grantor had conveyed all his interest in the bed of the Chattahoochee River in Columbus. The grantor owned the riverbed to the western shore of the Chattahoochee. The deed, however, stated that the western boundary of the property conveyed was a point twenty-five feet west of the eastern bank in the *535 bed of the river.[21] The court found that because the boundary was fixed in the deed at a definite point, the deed did not convey grantor's interest in the riverbed between the fixed point and the west bank.[22] This is consistent with rulings from other jurisdictions holding that the grantor can expressly reserve part of the riverbed for himself.
In Florida Gravel Co. v. Capital City Sand and Gravel Co.,[23] the Georgia Supreme Court was again concerned with ownership of the bed of the Chattahoochee River. In Florida Gravel Co., the court stated:
In a large number of States the courts, following the letter of the English doctrine, hold, without qualification, that a grant or conveyance of land bounded by a navigable non-tidal river, in the absence of anything in the grant or deed to show a contrary intention, is presumed to carry title to the thread of the stream. This ruling is based on the theory that it could not be anticipated that a grantor would desire to retain title to the bed of a stream between the shore and the center line thereof, when he had conveyed the abutting upper lands.
170 Ga. at 858, 154 S.E. at 257. The court noted, however, that in many jurisdictions title to the bed of a navigable river remains with the state. The court stated that it saw no reason to change or modify its previous rulings concerning private ownership of a riverbed under navigable rivers. This decision reaffirms that a grant bounded by a navigable river conveys title to the riverbed.
Defendant conveyed a tract of land bounded by the Chattahoochee River on three sides. The deed does not express an intent to reserve the riverbed from the operation of the deed. This Court finds that, by construction of law, the Camp Deed conveyed Defendant's title to the riverbed to Kal-O-Mine. Thus, Kal-O-Mine deeded the riverbed to Lumpkin Sand when it executed a deed to Lumpkin Sand on December 29, 1986.
(b) Intent to Convey the Riverbed
The Court will now address a second theory urged by Kal-O-Mine and Lumpkin Sand. Kal-O-Mine argues that the parties intended that Defendant convey the riverbed. Craig Gunter, former president of Kal-O-Mine, testified that he was personally involved in the negotiations involving Kal-O-Mine acquiring the Lumpkin property. Mr. Gunter testified he understood that everything which Defendant owned, including the riverbed, was to be conveyed to Kal-O-Mine. He testified that the riverbed had a value similar to or greater than the adjacent land. Mr. Gunter, however, acknowledged that the riverbed was shown as a separate tract (Tract six) in the Cooper deed.
Defendant argues that he did not intend to convey the riverbed to Kal-O-Mine. Defendant argues that the fact that the Camp Deed conveyed only five of the six tracts which Defendant received under the Cooper Deed clearly indicates an intent by him to keep the riverbed for himself. Defendant testified that he discussed the riverbed with Mr. Ed Kalinoski, deceased, then chairman of Kal-O-Mine, and that Kal-O-Mine knew he was keeping the riverbed.
The Agreement executed by Defendant and Kal-O-Mine eighteen days prior to the execution of the Camp Deed clearly shows that the riverbed (Tract six), was to be conveyed to Kal-O-Mine. Defendant and Kal-O-Mine both, however, argue that prior agreements merged with the Camp deed, and thus, the terms of the deed became controlling.
The Georgia Court of Appeals in San Joi, Inc. v. Peek[24] stated the merger rule as follows:
The general rule regarding the merger of the contract for the sale of realty into *536 the executed deed has long been settled law. "Where in a contract for the sale of land the parties executed a preliminary sales contract and subsequently reduced the contract to a finality evidenced by deed, the terms of the preliminary contract were merged into the deed, and terms or conditions or recitals contained in the preliminary sales contract which are not included in the deed will be considered as eliminated, abandoned, or discarded." (citations omitted).
140 Ga.App. at 398, 231 S.E.2d at 146.
Most Georgia cases apply the strict rule of merger. In Fields v. Davies,[25] the Georgia Supreme Court noted that in the absence of actual fraud, a deed is considered to be a complete relinquishment of all conflicting claims in the contract for sale.[26] Nor will equity reform a deed to conform with the provisions in the contract where there is no misplaced confidence, misrepresentation, or other fraudulent act.[27] The Court concludes that the Agreement merged with the Camp Deed and will not consider the provisions of the Agreement in determining the intent of the parties.
Lumpkin Sand and Defendant disagree concerning the intent of the parties regarding conveyance of the riverbed. Deeds are to be construed in accordance with the intentions of the parties and effect must be given to every part of the description where practicable. Conyers v. Fulton County, 117 Ga.App. 649, 161 S.E.2d 347, 349 (1968), cert. denied. See also Leavell v. State Highway Department, 121 Ga. App. 112, 173 S.E.2d 124, 126 (1970) (The cardinal rule for the construction of a deed is to ascertain the intention of the parties.). Deeds must be construed most favorably to the grantee. Harmon v. First National Bank of Columbus, 50 Ga.App. 3, 6, 176 S.E. 833 (1934).
The facts show that Defendant conveyed certain property to Kal-O-Mine by deed dated January 23, 1986 (the Camp Deed). After observing the demeanor of the witnesses and the evidence presented, the Court believes that the parties intended that Defendant convey both the land and the riverbed to Kal-O-Mine. The Court believes that Kal-O-Mine was to acquire a workable sand and gravel operation. The riverbed was part of the operation. Defendant has not presented any documents which expressly show a mutually agreed upon intent not to convey the riverbed.
II. Personal Property Located on the Lumpkin Property
Located upon the Lumpkin property are a dredge (discussed separately), several trucks, various pieces of equipment and several pieces of iron (hereinafter collectively referred to as "personalty"). Lumpkin Sand claims ownership, stating that the dredge was a fixture and thus passed with the realty. Lumpkin Sand also argues that the parties intended that the dredge and personalty would be conveyed. Defendant denies these allegations and claims ownership of the dredge and personalty.
Under Georgia law a deed conveying land conveys all structures permanently affixed to the land which constitute a part of the realty. Trust Company Bank of Middle Georgia, N.A. v. Huckabee Auto Co. (In re Huckabee Auto Co.), 58 B.R. 826, 829-30 (Bankr.M.D.Ga.1986) (citations omitted). Section 44-1-6 of the Official Code of Georgia[28] describes a fixture as follows:
(a) Anything which is intended to remain permanently in its place even if it is not actually attached to the land is a fixture which constitutes a part of the realty and passes with it.
(b) Machinery which is not actually attached to the realty but is movable at pleasure is not a part of the realty.
*537 (c) Anything detached from the realty becomes personalty instantly upon being detached.
O.C.G.A. § 44-1-6 (1982). All fixtures whether actually or constructionally annexed to the realty pass by a conveyance of the freehold, absence an agreement to the contrary. See Brigham v. Overstreet, 128 Ga. 447, 57 S.E. 484 (1907); Wolff v. Sampson, 123 Ga. 400, 51 S.E. 335 (1905).
The United States Court of Appeals for the Eleventh Circuit recently discussed the factors Georgia courts use in determining whether an article is real or personal property. In Walker v. Washington (In re Washington),[29]the court stated:
Georgia courts have used three factors in analyzing whether an object is personalty or realty. Homac, Inc. v. Fort Wayne Mortgage Co., 577 F.Supp. 1065, 1069 (N.D.Ga.1983). First, the Court looks to the degree to which the object has become integrated with or attached to the land. Under Georgia law, if an article cannot be removed from the land without suffering "essential injury," it is considered a fixture. Id., citing Wade v. Johnston, 25 Ga. 331, 336 (1858).
Second, a court must consider the intention of the parties with regard to the status of the object. In re Janmar, Inc., 4 B.R. 4, 9 (N.D.Ga.1979). An item will remain personalty if the parties so contract, even if the item is permanently affixed to realty.
Third, the Court determines whether there is unity of title between the personalty and the realty at the time the object allegedly became part of the land:
When the ownership of the land is in one person and the thing affixed to it is in another, and in its nature it is capable of severance without injury to the former, the fixture can not, in contemplation of law, become a part of the land, but must necessarily remain distinct property to be used and dealt with as personal estate.
Homac, 577 F.Supp. at 1070, citing Holland Furnace Co. v. Lowe, 172 Ga. 815, 159 S.E. 277 (1931).
837 F.2d at 456-57.
In Goger v. United States (In re Janmar, Inc.),[30] the court stated:
"Whether an article of personalty connected with or attached to realty becomes a part of the realty, and therefore such a fixture that it cannot be removed therefrom, depends upon the circumstances under which the article was placed upon the realty, the uses to which it is adapted, and the parties who are at issue as to whether such an article is realty or detachable personalty." Wolff v. Sampson, 123 Ga. 400, 402, 51 S.E. 335-336 (1905); Consolidated Warehouse Co. v. Smith, 55 Ga.App. 216, 189 S.E. 724 (1937). It is also the law in Georgia that this determination is a question of fact. Babson Credit Plan v. Cordele Production Credit Ass'n, 146 Ga.App. 266, 246 S.E.2d 354 (1978).
4 B.R. 4, 9 (Bankr.N.D.Ga.1979).
(a) The Dredge
The facts show that the dredge is a large piece of equipment which floats on pontoons in an enclosed artificial pond. Lumpkin Sand estimates the dredge to be thirty feet long by fifteen feet wide. Defendant states that it probably weights thirty to forty-five tons. A series of twelve-inch pipes attached to the dredge span across the lake and are embedded in a concrete structure on the shore. To remove the dredge from the pond, it would have to be lifted by a crane to the shore, cut into three pieces by an acetylene torch, and put on trucks. This process would take about two months. The dredge is used to pump sand and gravel up from the pond floor so that it can be processed for sale. The dredge is a primary piece of equipment in the mining operation.
Defendant testified that he designed and had the dredge built. He also testified that he had moved the dredgeby using a bulldozer. *538 Defendant says that he did not intend to abandon the dredge.
In Colorado Gold Dredging Co. v. Stearns-Roger Manufacturing Co.,[31] the court held that a dredge similar to the one in this case was part of the realty. The dredge floated in an artificial pond and removed sand, gravel, and rocks from the pond. The court noted that a fixture does not have to be affixed to the land. The court stated that the dredge was intended for permanently working the deposit and that had the dredge itself been actually affixed to the land, that the use for which it was intended would not have been possible.
This Court concludes that the dredge is a fixture and that ownership passed to Kal-O-Mine under the Camp Deed. Kal-O-Mine then conveyed the dredge to Lumpkin Sand when it executed a deed to Lumpkin Sand on December 29, 1986.
(b) Equipment, Scrap Iron, and Trucks (Personalty)
Several old trucks and various pieces of equipment and scrap iron used in the mining of sand and gravel remain on the Lumpkin property. Six to eight-inch diameter trees are growing through some of this equipment. Some of the equipment needs repair or is no longer repairable. Many pieces appear to have been on the property for a long time. Defendant did not remove the personalty before he executed the Camp Deed. The personalty is not included in either the contract for sale, the deed, or any other written document. Mr. Steve Miller, current president of Kal-O-Mine, admitted at trial that the personalty is not a fixture. Lumpkin Sand admits that it has no bill of sale, deed or other documents showing that the personalty was conveyed to it.
Defendant argues in his post-trial brief that section 11-2-201(1) of the Official Code of Georgia[32] requires the sale of the personalty in question to be in writing. That section provides:
(1) Except as otherwise provided in this Code section a contract for the sale of goods for the price of $500.00 or more is not enforceable by way of action or defense unless there is some writing sufficient to indicate that a contract for sale has been made between the parties and signed by the party against whom enforcement is sought or by his authorized agent or broker. A writing is not insufficient because it omits or incorrectly states a term agreed upon but the contract is not enforceable under this paragraph beyond the quantity of goods shown in such writing.
O.C.G.A. § 11-2-201(1) (1982). There are no written documents which show the personalty on the Lumpkin property has been conveyed to Kal-O-Mine or Lumpkin Sand. The facts indicate that the value of the personalty exceeds $500.
Defendant filed his answer on May 26, 1989. He failed to assert the statute of frauds as a defense. The statute of frauds[33] is an affirmative defense under both the Federal Rules of Civil Procedure[34] and the Georgia Civil Practice Act.[35] The failure to plead an affirmative defense results in the waiver of that defense and its exclusion from the case. See Troxler v. Owens-Illinois, Inc., 717 F.2d 530, 532 (11th Cir.1983). An unalleged affirmative defense cannot be proven under a general denial. 5 C. Wright and A. Miller, Federal Practice and Procedure § 1278 (1969 & Supp.1989). Nor did Defendant raise the statute of frauds defense at trial. Defendant did question Kal-O-Mine's agent concerning whether Kal-O-Mine had any written documents showing a sale of the personalty. The Court, however, does not believe Defendant's statements and questions at trial to be an express or implied *539 consent by the parties such that Defendant's answers were amended to include the statute of frauds as a defense.[36] The admission by Kal-O-Mine that it had no written documents hardly constitutes consent for Defendant to raise an affirmative defense in a post-trial brief. The purpose of the requirement that affirmative defenses be pleaded is to prevent surprise and to give the opposing party fair notice of what he must meet as a defense. See Phillips v. State Farm Mutual Auto Ins. Co., 121 Ga.App. 342, 346, 173 S.E.2d 723, 726 (1970); See also United McGill Corp. v. Gerngross Corp., 689 F.2d 52, 54 (3rd Cir. 1982); Hall v. First National Bank, 145 Ga.App. 267, 269, 243 S.E.2d 569, 571 (1978). To allow Defendant to raise the statute of frauds defense for the first time in his post-trial brief would be contrary to the purpose of the pleading requirements. This Court therefore holds that Defendant failed to properly plead the statute of frauds and waived it as a defense.
Even if Defendant had properly pled the statute of frauds, the facts show that the contract is enforceable notwithstanding the absence of any written documents. A buyer's receipt and acceptance of goods removes an oral agreement between the parties from the writing requirements of the statute of frauds due to part performance of the contract. Section 11-2-201(3)(c) of the Official Code of Georgia[37] provides: "(3) A contract which does not satisfy the requirements of subsection (1) of this Code section but which is valid in other respects is enforceable: . . . (c) With respect to goods for which payment has been made and accepted or which have been received and accepted." O.C.G.A. § 11-2-201(3)(c) (1982). Receipt of goods means taking physical possession of them. O.C.G.A. § 11-2-103(1)(c) (1982). Acceptance of goods is effected as follows:
(1) Acceptance of goods occurs when the buyer:
(a) After a reasonable opportunity to inspect the goods signifies to the seller that the goods are conforming or that he will take or retain them in spite of their nonconformity; or
(b) Fails to make an effective rejection (subsection (1) of Code Section 11-2-602), but such acceptance does not occur until the buyer has had a reasonable opportunity to inspect them; or
(c) Does any act inconsistent with the seller's ownership; but if such act is wrongful as against the seller it is an acceptance only if ratified by him.
O.C.G.A. § 11-2-606(1) (1982). By express terms of the U.C.C. statute of frauds, a contract need not be in writing to be enforceable with respect to goods "which have been received and accepted." Seminole Peanut Co. v. Goodson, 176 Ga.App. 42, 335 S.E.2d 157, 159 (1985). See also Bicknell v. Joyce Sportswear Co., 173 Ga. App. 897, 328 S.E.2d 564, 565 (1985); Jem Patents, Inc. v. Frost, 156 Ga.App. 311, 274 S.E.2d 707 (1980).
It is uncontroverted that Lumpkin Sand has physical possession of the personalty and has had possession since being conveyed the Lumpkin property by Kal-O-Mine. The personalty is on the Lumpkin property which is owned by Lumpkin Sand. Thus, Lumpkin Sand has received the personalty. Under section 11-2-606(1)(b), Kal-O-Mine and Lumpkin Sand have accepted the personalty because, having had a reasonable opportunity to inspect the personalty, they have not rejected it. The Court finds that the statute of frauds does not apply to this contract because the personalty has been received and accepted.
*540 "To constitute a valid contract, there must be parties able to contract, a consideration moving to the contract, the assent of the parties to the terms of the contract, and a subject matter upon which the contract can operate." O.C.G.A. § 13-3-1 (1982). Both Kal-O-Mine and Defendant had legal capacity to enter into a valid contract. The Court must consider whether there was an assent to the terms of the contract and a consideration. The first question concerns whether there was a meeting of the minds concerning what Kal-O-Mine was buying and what Defendant was selling. See generally Associated Mutuals, Inc. v. Pope Lumber Co., 200 Ga. 487, 37 S.E.2d 393, 398 (1946) (Parties must assent to all terms in same sense); Taylor Lumber Co. v. Clark Lumber Co., 33 Ga.App. 815, 127 S.E. 905 (1925) (Meeting of minds of parties is necessary).
Kal-O-Mine and Lumpkin Sand argue that Kal-O-Mine bought everything which Defendant owned. This included the land, riverbed, minerals, dredge, equipment and trucks. Their witnesses testified that when they inspected the property with Defendant after execution of the Camp Deed, that their understanding was that Kal-O-Mine owned everything on it. Defendant never expressed any intent to remove any personalty. When Defendant went to various banks to help Kal-O-Mine obtain financing, he never told the banks that the personalty belonged to him and not Lumpkin Sand.
Defendant states that he and Ed Kalinoski, deceased former chairman of Kal-O-Mine, agreed that Kal-O-Mine would buy the land but that Defendant would keep the personalty. Defendant testified that he did not remove the personalty for two reasons. First, he was attempting to enter into an employment contract with Kal-O-Mine and it would be inconsistent for him to remove the personalty while seeking employment. Second, Defendant's son, Wilson M. Camp, III, and Mr. Pat Kalinoski[38] leased the Lumpkin property from Kal-O-Mine in May 1986. They planned to operate a sand and gravel operation and would need the personalty to do so. Finally, Defendant argues that the personalty on the Lumpkin property belongs to Camp Concrete Industries, Inc. The Court is not persuaded by Defendant's argument on this issue because it is not supported by other evidence.
Having observed the demeanor of the witnesses and the evidence presented, the Court believes that the parties intended that Defendant convey to Kal-O-Mine a workable sand and gravel operation. Kal-O-Mine had very limited experience in the sand and gravel business. It is reasonable that it would need, and expected the conveyance to include, the land, the riverbed, minerals, the equipment, dredge, and trucks. Defendant received three million shares of stock in Kal-O-Mine in consideration for the transfer. Because the Court is persuaded that the parties intended that Kal-O-Mine acquire a workable sand and gravel operation, it is persuaded that ownership of the personalty passed to Kal-O-Mine and then to Lumpkin Sand. The Court holds that Lumpkin Sand owns the personalty (equipment, trucks, scrap iron) and other personal property located on the Lumpkin property.
III. Ownership of the Camp Lightweight, Inc. Property
The Court now turns to the Camp Lightweight case. Kal-O-Mine contends that it is the owner of the property formerly owned by Camp Lightweight pursuant to the confirmed Chapter 11 plan of Camp Lightweight. Defendant claims that he is still the owner because the distribution date of the confirmed plan has not been reached.
Camp Lightweight filed an Amended Plan of Reorganization on June 23, 1986. A modification of the Amended Plan of Reorganization was filed on August 19, 1986. The Court entered an order confirming the amended plan as modified on August 19, 1986. All parties to this matter are bound by the provisions of the confirmed *541 plan. Section 1141(a) of the Bankruptcy Code[39] provides:
(a) Except as provided in subsection (d)(2) and (d)(3) of this section, the provisions of a confirmed plan bind the debtor, any entity issuing securities under the plan, any entity acquiring property under the plan, and any creditor, equity security holder, or general partner in, the debtor, whether or not the claim or interest of such creditor, equity security holder, or general partner is impaired under the plan and whether or not such creditor, equity security holder, or general partner has accepted the plan.
11 U.S.C.A. § 1141(a) (West Supp.1989). See In re Auto Dealers Services, Inc., 89 B.R. 233, 235 (Bankr.M.D.Fla.1988); In re White Farm Equipment Co., 38 B.R. 718, 724 (Bankr.N.D.Ohio 1984).
The confirmed plan provides that title to the Camp Lightweight assets will be transferred to Kal-O-Mine on the distribution date. Section 5.02 of the confirmed plan provides as follows:
5.02 Title Transfer: Title to the assets of the debtor shall be assigned and transferred to the successor on the distribution date. A condition to this plan is the assignment to Kal-O-Mine of title and rights in all property, equipment or equipment leases held by the debtor, and any related property and equipment held by certain third parties or entities.
Section 1.10 of the confirmed plan defines Distribution Date as follows:
1.10 DISTRIBUTION DATE shall mean the date upon which the Order of Confirmation is no longer subject to appeal or certiorari proceeding, on which date no such appeal or certiorari proceeding is then pending and on which date all of the conditions to the effectiveness of the Plan expressly set forth in the Plan have been satisfied fully, or effectively waived.
In summary, title to Camp Lightweight's assets will be transferred to Kal-O-Mine when all the conditions to the effectiveness of the plan had been satisfied fully.[40]
The plan was to be financed as follows:
5.01 Reorganization: To finance this plan, the debtor has entered and proposes as part of the plan to enter the following contracts, subject to approval as part of this plan:
Kal-O-Mine Industries, Inc., a publicly traded Colorado corporation executed an agreement on January 5, 1986 to acquire 100% ownership and control of Camp Lightweight, Inc., debtor in possession for purposes of reorganizing the company and will retain 100% ownership following reorganization. Kal-O-Mine has completed a registration statement for $2.5 million preferred stock offering, Series B, the proceeds from which are committed to investment into and reorganization of the debtor pursuant to this plan. The plan and the $2.5 million in funding are committed to commencing and achieving profitable operation of the Camp Lightweight aggregate facility and to realize substantially greater operating concern values, returns and liquidation preferences for the creditors than they would receive in liquidation.
The confirmed plan provides:
5.04 Use of Borrowed Funds: All funds derived by reason of the pledge, encumbrance, or hypothecation of the present assets of the debter [sic] in possession shall be used for operating capital or other purposes directly benefiting the business operations or the estate of the debtor in possession or the successor to the debtor in possession for the benefit of the lightweight aggregate plant in Clay County, Georgia. This provision will be effective for the six years next following the entry of the order of confirmation.
Kal-O-Mine argues that consummation of the plan has been delayed because of Defendant's continued claims of ownership and other efforts to frustrate consummation of the confirmed plan. Kal-O-Mine's witnesses testified that they have attempted *542 to obtain financing for the plan since the plan was confirmed in August 1986 but their efforts have been stalled by title problems. Kal-O-Mine demonstrated that at least fifteen entities have checked the title to the property in question. Kal-O-Mine has demonstrated that no one is willing to loan money until the title issue is resolved.
The amended plan created eight classes of claims. Kal-O-Mine submits that it has complied with the plan concerning treatment of claims in Classes Three, Four, Five, Seven, and Eight. The Class Five claimant repossessed certain equipment, thus satisfying its claim. Classes Three, Four, and Seven claimants were issued preferred stock, which has been converted to common stock. In addition, the unsecured portion of Class Two was issued preferred stock which was later converted to common stock. Class Eight was to receive nothing under the plan.[41]
Kal-O-Mine submits that the following payments remain to be made under the plan:
Approximate
Class Amount
One $ 30,000
Two (Secured Portion) 459,000[42]
Six 30,000
_________
Total $519,000
Kal-O-Mine asserts that after these payments are made, absolutely nothing would remain to be paid under the plan.
Mr. Gary J. Graham, president of Graham and Associates, a private investment banking firm, testified that he was contacted about one year ago by Kal-O-Mine to help obtain financing. Mr. Graham testified that he has extensive experience in obtaining financing, especially in the mining industry. Mr. Graham testified that he has been unable to provide funding primarily because of title problems concerning the Lumpkin and Camp Lightweight properties. He testified, however, that he can provide $2.5 million in financing if the title problems can be resolved. Mr. Graham testified that $1.1 million of this amount will be a personal contribution. Finally, he testified that he believes the proposed operations, properly structured and collateralized, would be sufficient to service the loan he proposes to make.
Mr. Kenneth Tribby, director of Kal-O-Mine, testified that Kal-O-Mine has a commitment for an approximately $2 million loan from a bank. Part of this loan would be used to pay off liens to Trust Company Bank, the Bank of Eufaula, and Mr. Leon Camp. Part of the loan would also be used to finance start up of both the Lumpkin and Camp Lightweight operations. Mr. Tribby testified that if the Lumpkin and Camp Lightweight properties are not operated and, instead end up in Chapter 7 liquidation, that very few of the creditors in these two Chapter 11 cases would receive anything. The Court is persuaded this is a correct conclusion.
Defendant contends that title to the Camp Lightweight property never passed to Kal-O-Mine because the distribution date has not arrived. Defendant argues that Kal-O-Mine has paid out very little of the cash required under the plan and that all Kal-O-Mine has done is issue stock, which cost Kal-O-Mine nothing. Defendant further argues that under the confirmed plan, financing was to come from the sale of preferred stock rather than from the borrowing of money.
Following confirmation, compliance with the plan becomes the business agenda of the postconfirmation entity which is required to make payments as provided for in the plan. In re Jartran, Inc., 76 B.R. 123, 125 (Bankr.N.D.Ill.1987). Since confirmation, Kal-O-Mine has sought *543 financing for the plan. It has been unable to obtain financing because of title questions to the Lumpkin and Camp Lightweight properties. Kal-O-Mine has a loan commitment from a bank for $2 million. An investment banker has demonstrated that he can provide $2.5 million, including $1.1 million of his personal assets, when the title issues are resolved. This Court believes that section 5.04 of the confirmed plan contemplates that Debtor would seek and use borrowed funds. The Court notes the circuity of the position being asserted. Mr. Graham has money for the financing but cannot provide it until the title issues are resolved. Kal-O-Mine wants to comply with the plan by paying the remaining creditors, but cannot until Mr. Graham provides the money. Defendant says he still owns title to the properties because Kal-O-Mine has not complied with the plan and, thus, the distribution date has not been reached. It is, however, Defendant's conduct that has prevented the financing from being completed.
Section 5.01 of the confirmed plan states that on January 5, 1986, Kal-O-Mine agreed to acquire one hundred percent ownership and control of Camp Lightweight for the purpose of reorganizing it. The section continues stating that Kal-O-Mine will retain one hundred percent ownership of Debtor following reorganization. Retain means: "To continue to hold, have, use, reorganize, etc., and to keep." Black's Law Dictionary 1183 (5th ed. 1979). This language shows that the plan contemplated that ownership and control of Camp Lightweight would pass to Kal-O-Mine. Kal-O-Mine, under the terms of the confirmed plan, is to retain that ownership.
Kal-O-Mine has possession of Defendant's stock certificate for Camp Lightweight.[43] The Court does not believe that Defendant would have surrendered his stock certificate to Kal-O-Mine unless he knew that Kal-O-Mine was in fact the owner of Camp Lightweight.
Kal-O-Mine has arranged financing sufficient to pay the remaining three classes of claims. Upon payment of Classes One, Two, and Six, which are to be paid from the financing, the confirmed plan will be fully consummated. Defendant's claims to title have prevented Kal-O-Mine from obtaining financing. The evidence shows that creditors will receive more under the plan than they would receive in liquidation. This Court will not allow Defendant to hinder Kal-O-Mine's acquisition of needed funding by asserting claims of title, and at the same time, complain that Kal-O-Mine has not complied with the plan. The Court concludes that Kal-O-Mine owns title to the Camp Lightweight property as a result of Camp Lightweight's Chapter 11 reorganization.
Defendant also claims that Kal-O-Mine is obligated to enter into an employment agreement with him under the confirmed plan. Section 5.03 of the confirmed plan states:
5.03 Management Contract: Kal-O-Mine Industries, Inc. has contracted with Mr. Wilson Camp (the founder, past owner and president of the debtor) to continue his employment to manage the day-to-day operations (but not the financial responsibility) of the debtor's facility upon reorganization under the ownership, direction and complete supervision of Kal-O-Mine.
The plan specifically states that Defendant will not have financial responsibility for Camp Lightweight's operations. The plan was signed by Defendant, as president of Camp Lightweight. The evidence shows that Kal-O-Mine sent one or more draft employment agreements to Defendant. Defendant changed several provisions in the draft agreements. Defendant wanted to be president rather than manager of Camp Lightweight and wanted to retain financial responsibility of Camp Lightweight. Kal-O-Mine declined to accept these changes. The Court notes that Defendant also struck the requirement in the draft agreements that he remain loyal to Kal-O-Mine. The Court is persuaded that Kal-O-Mine has met its obligation under *544 the plan to make a good faith offer of employment to Defendant.
An order in accordance with this opinion is attached hereto.
ORDER
Based upon the attached and foregoing findings of fact and conclusions of law; it is
ORDERED that Kal-O-Mine Industries, Inc. hereby is determined to be the owner of all real and personal property and equipment leases owned by Camp Lightweight, Inc.; and it is further
ORDERED that Lumpkin Sand and Gravel, Inc. hereby is determined to be the owner of the riverbed adjoining that 579.66-acre tract of land in Muscogee County, Georgia, which was conveyed to Kal-O-Mine Resources, Inc. by Wilson M. Camp, II, (the "Lumpkin property") to the extent the riverbed may be privately owned; and it is further
ORDERED that Lumpkin Sand and Gravel, Inc. hereby is determined to be the owner of all fixtures and personal property located on the Lumpkin property; and it is further
ORDERED that this order be entered on the dockets on the date set out below.
SO ORDERED.
NOTES
[1] The Court granted Defendant an extension of time to file his answer.
[2] The Ft. Gaines property is located in Clay County, Georgia, and will be referred to in the opinion as the Camp Lightweight property.
[3] Wilson M. Camp, the grantee in the Cooper Deed, is the same person as Wilson M. Camp, II, Defendant.
[4] Kal-O-Mine Resources, Inc. is the predecessor of Kal-O-Mine Resources Industries, Inc. The complaint names Kal-O-Mine Industries, Inc. as Plaintiff. All three names refer to the same corporation. The Court will simply refer to the corporation as "Kal-O-Mine" unless a distinction among the names is important.
[5] Defendant conveyed 99.92 acres of Tract Two to Camp Concrete Industries, Inc. by deed dated July 24, 1981. Defendant subsequently conveyed the same 99.92 acres to Kal-O-Mine Resources, Inc. by quitclaim deed dated January 23, 1986. Ownership of this tract is not at issue in this adversary proceeding.
[6] The first and second addendum to the disclosure statement and the modification to the confirmed plan were not signed by Defendant.
[7] Camp Lightweight's petition under Chapter 11 was filed on March 22, 1985.
[8] The shareholders of Camp Lightweight, Inc. changed the name of the corporation to Claylite, Inc. on May 15, 1986. The Court will simply refer to the corporation as "Camp Lightweight" unless a distinction between the names is important.
[9] The Court's opinion is limited to ownership rights in the riverbed as between the parties. Neither party has provided the Court with original or certified copies of deeds and grants to prove that either party actually owns the riverbed. The Court is judicially ignorant, therefore, of the contents of those deeds and grants.
[10] As previously stated, Kal-O-Mine owns one hundred percent of the stock in Lumpkin Sand.
[11] O.C.G.A. § 44-8-5(b) (1982).
[12] See United States v. Champlin Refining Co., 156 F.2d 769 (10th Cir.1946), aff'd 331 U.S. 788, 67 S.Ct. 1346, 91 L.Ed. 1818 (1947).
Under the rules of the common law, unless a contrary intention appears or is clearly inferable from the terms of the grant, the grantee of land, bounded by a nonnavigable stream or river, acquires title to the land to the center or thread of the water, on the theory that the grantor will not be presumed to have reserved a strip of land covered by water which will be of no practical value to him.
Id. at 774 (citing Oklahoma v. Texas, 258 U.S. 574, 42 S.Ct. 406, 66 L.Ed. 771 (1922); United States v. Elliott, 131 F.2d 720, 723 (10th Cir. 1942)). The grantor of land adjoining a navigable river, however, would still, as a member of the public, have a right of passage over the entire river. He would, thus, still have access to the riverbed. See generally Parker v. Durham, 258 Ga. 140, 365 S.E.2d 411, 413 (1988) (The public has a right of passage on a navigable river).
[13] 6 Ga. 130 (1849).
[14] This characterization is consistent with a 1988 holding by the Georgia Supreme Court concerning navigable rivers. See Parker v. Durham, 258 Ga. 140, 365 S.E.2d 411, 413 (1988).
[15] 6 Ga. at 141.
[16] See Jones v. The Water Lot Co. of Columbus, 18 Ga. 539 (1855).
[17] Id. at 541.
[18] 18 Ga. 539 (1855).
[19] Id. at 541.
[20] 62 Ga. 455 (1879).
[21] Id. at 459-60. The property conveyed extended into the riverbed but did not convey all of the riverbed which grantor owned.
[22] Id. at 461.
[23] 170 Ga. 855, 154 S.E. 255 (1930).
[24] 140 Ga.App. 397, 231 S.E.2d 145 (1976).
[25] 235 Ga. 87, 218 S.E.2d 828 (1975).
[26] Id., 218 S.E.2d at 830.
[27] See O.C.G.A. § 23-2-29 (1982), which states: "If a party, by reasonable diligence, could have had knowledge of the truth, equity shall not grant relief; nor shall the ignorance of a fact known to the opposite party justify an interference if there has been no misplaced confidence, misrepresentation, or other fraudulent act." Id. See also Martin v. Heard, 239 Ga. 816, 238 S.E.2d 899, 900 (1977).
[28] O.C.G.A. § 44-1-6 (1982).
[29] 837 F.2d 455 (11th Cir.1988).
[30] 4 B.R. 4 (Bankr.N.D.Ga.1979).
[31] 60 Colo. 412, 153 P. 765 (1916).
[32] O.C.G.A. § 11-2-201(1) (1982).
[33] The title of O.C.G.A. § 11-2-201 (1982) is "Formal Requirements; statute of frauds."
[34] See Fed.R.Civ.P. 8(c). The provisions of Federal Rules of Civil Procedure 8 applies in adversary proceedings in bankruptcy courts. See R. Bankr.P. 7008(a).
[35] See O.C.G.A. § 9-11-8(c) (1982).
[36] Fed.R.Civ.P. 15(b) provides, in part: "When issues not raised by the pleadings are tried by express or implied consent of the parties, they shall be treated in all respects as if they had been raised in the pleadings." Id. Contra American Nat. Bank of Jacksonville v. Federal Dep. Ins. Corp., 710 F.2d 1528, 1537-39 (11th Cir.1983) (Mere advancement of a notion that affirmative defense existed does not imply an implied consent to litigate); Glass Containers Corp. v. Miller Brewing Co., 643 F.2d 308, 312 (5th Cir. Unit A April 22, 1981) (In reviewing an assertion that an issue has been tried by implied consent, the record must be carefully examined. The court has no obligation to introduce issues inferentially suggested by incidental evidence in the record.)
[37] O.C.G.A. § 11-2-201(3)(c) (1982).
[38] Pat Kalinoski is the son of Ed Kalinoski, deceased former chairman of the board of Kal-O-Mine.
[39] 11 U.S.C.A. § 1141(a) (West Supp.1989).
[40] The date upon which the order of confirmation could be appealed has long since expired.
[41] Kal-O-Mine has demonstrated that Defendant, a Class Eight claimant, was issued 1,000,000 shares of stock in error.
[42] Kal-O-Mine has demonstrated that $459,000 is owed to the Trust Company Bank as trustee for the bond holders. Kal-O-Mine has also shown that this is the same obligation reflected in the Lumpkin Sand and Gravel case and that payment would satisfy Trust Company Bank in each case.
[43] The Court notes that Defendant has not signed the back of the stock certificate.
|
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abstract: 'Many-qubit entanglement is crucial for quantum information processing although its exploitation is hindered by the detrimental effects of the environment surrounding the many-qubit system. It is thus of importance to study the dynamics of general multipartite nonclassical correlation, including but not restricted to entanglement, under noise. We did this study for four-qubit GHZ state under most common noises in an experiment and found that nonclassical correlation is more robust than entanglement except when it is imposed to dephasing channel. Quantum discord presents a sudden transition in its dynamics for Pauli-X and Pauli-Y noises as well as Bell-diagonal states interacting with dephasing reservoirs and it decays monotonically for Pauli-Z and isotropic noises.'
author:
- 'P. Espoukeh'
- 'R. Rahimi'
- 'S. Salimi'
- 'P. Pedram'
title: '**Dynamics of Entanglement and Nonclassical Correlation for Four-Qubit GHZ State**'
---
Introduction
============
It is assumed that entanglement can be useful in quantum computing [@1], quantum cryptography [@4] and quantum information processing such as superdense coding [@6] and quantum teleportation [@8]. In practical applications, there are quantum tasks with no entanglement but representing quantum advantages over classical counterparts [@10; @11; @13]. This indicates that entanglement is not the only feature of quantum correlation and we need to study correlations in a more general concept. This statement is further more correct once it is an experimental implementation of quantum computing or quantum information processing. In any experiment in the field, entanglement is generally difficult to be achieved, but nonclassical correlation is comparably less challenging. Due to this fact, and considering the additional fact that entanglement in larger Hilbert spaces is not well-known yet, understanding the dynamics of nonclassical correlation, generally, and entanglement, specifically, is of importance specially from practical point of view.
Experiments are nowadays elaborated such that they can, at least in some physical systems such as NMR [@15] and EPR/ENDOR [@16], achieve controls on larger numbers of quits. Therefore, it is getting of practical importance to study the characteristics and behaviour of larger networks of quits and determine the corresponding dynamics of the correlated states under noises that are more common in the physical systems of the study.
Quantum discord is one of the measures of nonclassical correlations [@17]. Its definition is based on the difference between two classically equivalent forms of mutual information. It has been shown that quantum discord is very useful to describe correlations involved in quantum systems [@19]. Nonclassical correlation and entanglement can have in principal different behaviours. For example, in some temperature ranges, quantum discord of a two-qubit one-dimensional XYZ Heisenberg chain in thermal equilibrium increases with temperature while entanglement decreases with temperature and even it goes to zero [@20]. Datta et al. [@13] showed that entanglement in DQC1 is negligibly small, however DQC1 includes nonzero discord. Thus, the notion of quantum speed up is related to nonclassical correlation rather than to entanglement [@21].
Implementations of quantum computing and quantum information processing are ultimate goals for studies and researches in the field thus there have been continuously extensive efforts in the context of performing experiments relating to quantum technologies. One immediate consideration that is imposed right after starting plans for experimental practices is how to deal with decoherence of quantum systems. Decoherence is generally critical for any physical system that is determined for experiments, but in the context of quantum protocols this issue becomes one of the most challenging steps. Decoherence of quantum systems are due to unavoidable interactions with the environment and it is led to the degradation of quantum correlations and limitations on using nonclassical correlation and more importantly quantum entanglement in practical applications.
Studies on quantum channels are usually divided into two categories: Markovian [@24; @26] and non-Markovian [@19; @27; @27-5]. Investigations of nonclassical correlations under Markovian environments show that nonclassical correlation is more robust than entanglement. Consequently, implementations of quantum algorithms that rely on nonclassical correlation, and not an absolute entanglement, are less fragile [@28]. Studies on non-Markovian errors show that since there is no occurrence of sudden death of quantum discord in spite of the entanglement sudden death, the description is more practical in the case of nonclassical correlation [@19].
Time evolutions of nonclassical correlation and entanglement in bipartite systems coupled to external environments have been extensively studied [@32]. However, this concept is yet not very well resolved for higher dimensions. Quantifications of nonclassical correlation and entanglement for multi-partite systems are not yet generally d known, in addition and consequently determinations of their behavior in presence of environmental noises are far from being clear. In the case of tripartite systems there have been some results [@35; @38-1] but for larger spaces the sources are very few [@39; @40; @40-1] and the existing papers only study the entanglement of the states not nonclassical correlations in terms of e.g. quantum discord and their behavior under noise. From the previous studies, we have learned that nonclassical correlation and entanglement are preserved in three-qubit GHZ state under noise, but correlations are eliminated in the case of a W-state [@38].
In this paper, we study nonclassical correlation and entanglement of four-qubit Greenberger-Horne-Zeilinger (GHZ) state that is initially prepared in a pure state described as $|\mathrm{GHZ}_4\rangle=\frac{1}{\sqrt{2}}\left(|0000\rangle+|1111\rangle\right)$. The time evolutions are studied for the $|\mathrm{GHZ}_4\rangle$ state under experimentally common noises, Pauli-X (bit-flip), Pauli-Y (bit-phase-flip), Pauli-Z (phase-flip) and isotropic (depolarizing) noises. For each type of noise, the time evolution of the state is given by the solution of the master equation in the Lindblad form. The entanglement evolution of the mixed state is described by using the lower bound for multi-qubit concurrence proposed by Li et al. [@41]. Nonclassical correlation of the mixed four-qubit GHZ state is described by the global quantum discord that is introduced by Rulli *et al.* [@42] which uses a systematic extension of bipartite quantum discord.
This paper is organized as follows. In the next section, we briefly explain the measures that we use for quantifying entanglement and nonclassical correlation of $|\mathrm{GHZ}_4\rangle$ state. In Sec. \[sec3\], we obtain time evolutions of entanglement and nonclassical correlation for the initially prepared $|\mathrm{GHZ}_4\rangle$ state but imposed to Pauli and isotropic noises. In Sec. \[sec4\], we present the conclusions.
Entanglement and nonclassical correlation of $|\mathrm{GHZ}_4\rangle$ State {#sec2}
===========================================================================
There is not any general approach in quantifying entanglement for multi-partite states. However, as a practical method, one can make use of entanglement measures for bipartite states, in which characterizing entanglement is simpler, and extend them to all states by convex roof [@43]. This approach is generally difficult to be performed analytically. Here, in order to characterize entanglement of $|\mathrm{GHZ}_4\rangle$ state, we apply the lower bound for the multi-qubit concurrence proposed by Li et al. [@41] which is based on the bipartite concurrences of the multi-qubit system corresponding to all possible bipartite cuts of the $N$-qubit system.
For a pure $N$-qubit state, the concurrence is defined as follows $$C_N(|\psi\rangle ) =\sqrt{1-\frac{1}{N}\sum_{i=1}^N \mbox{Tr} \rho_i^ 2}$$ where $\rho_i=\mbox{Tr}(|\psi\rangle\langle\psi|)$ is the reduced density matrix of the $i$-th qubit after tracing out other $N-1$ qubits. The concurrence for mixed $N$-qubit states can be generalized as follows $$C_N(\rho ) =\mbox{min} \sum_i p_i C_N(|\psi_i\rangle ),$$ in which the minimum is over the pure-state ensemble that specifies $\rho$, namely, $\rho =\sum_i p_i |\psi_i\rangle\langle\psi_i| $. Note, that there is no analytical solution to optimize the concurrence of a multi-qubit system except for two-qubit systems and a special case of three-qubit state. Recently, Li et al. [@41] presented a lower bound to this measure which is simpler to calculate $$\label{lowerbound}
C_N(\rho) \geq \tau_N(\rho)\equiv\sqrt{\frac{1}{N}\sum_{n=1}^N\sum_{k=1}^K (C_k^n)^2}.$$ This bound contains $N$ bipartite concurrences $C^n$ that correspond to the possible bipartite cuts of the multi-qubit system. In order to calculate each bipartite concurrence $C^n$, one needs to evaluate a sum of $K= 2^{N-2} (2^{N-1} - 1)$ terms $C_k$ that are given by $$C^n_k =\mathrm{max}\{0, \lambda_k^1 - \lambda_k^2 - \lambda_k^3 -\lambda_k^4\}.$$ Here, $\lambda_k^i$’s ($i = 1..4$) are the square roots of the four non-vanishing eigenvalues of the matrix $\rho \tilde\rho_k^n$ in decreasing order and $\tilde\rho_k^n=S_k^n\rho^*S_k^n$ in which $\rho^*$ is the complex conjugate of $\rho$ and $S_k^n =L_k^n
\otimes L_0, k = 1, ...,K$. Moreover, $L_0$ is the generator of the group $SO(2)$ and $L_k^n$’s are the generators of the group $SO(2^{N-1})$.
Consider the density matrix of a composed system $AB$ being denoted by $\rho$. $\rho^A=\mathrm{Tr}_B(\rho)$ and $\rho^B=\mathrm{Tr}_A(\rho)$ are the reduced density matrices for subsystems $A$ and $B$, respectively. Quantum discord for this system, according to the definition of Ollivier and Zurek, is given by $$D(\rho)=I(\rho)- C(\rho),$$ where $I(\rho)=S(\rho^A) + S(\rho^B) - S(\rho)$ is the quantum mutual information that is a well-known measure of the total correlation and $S(\rho)=-\mathrm{Tr}(\rho \log_{2}\rho)$ is the von-Neumann entropy. In addition, $$C(\rho)=S(\rho^a)- \mathrm{min}_{\{\Pi_k\}}S(\rho|\{\Pi_k\})$$ is a measure of classical correlations in which the conditional entropy is defined as $S(\rho|\{\Pi_k\})=\sum_kp_kS(\rho_k)$ where $\rho_k=\frac{1}{p_k}(I^a\otimes\Pi_k^b)\rho(I^a\otimes\Pi_k^b)$ is the conditional density operator, $p_k=\mathrm{Tr}[(I^A\otimes\Pi_k^B)\rho]$, and the minimum is taken over the set of projective measurements $\{\Pi_k\}$. This form of quantum discord is appropriate for bipartite systems and for multi-qubit states we resort to a proper generalization of it.
There are various approaches to generalize quantum discord for multipartite states [@44; @46; @47]. Here, in order to evaluate quantum discord for a four-qubit system, we apply the global quantum discord which is introduced by Rulli *et al.*. It uses a systematic extension of bipartite quantum discord [@42]. The global quantum discord $D(\rho_{A_1...A_N})$ for a multipartite state $\rho_{A_1...A_N}$ is then defined as $$\begin{aligned}
\label{gqd}
D(\rho_{A_1...A_N})= \mathrm{min}_{\{\Pi_k\}}[S(\rho_{A_1...A_N}\|
\Phi(\rho_{A_1...A_N})) -\sum_{j=1}^N
S(\rho_{A_j}\|\Phi_j(\rho_{Aj}))],\end{aligned}$$ where $S(\rho_{A_1...A_N}\| \Phi(\rho_{A_1...A_N}))$ is the relative entropy and $$\begin{aligned}
\Phi_j(\rho_{A_j})&=&\sum_{i}\Pi_{A_j}^{i}\rho_{A_j}\Pi_{A_j}^{i},\\
\Phi(\rho_{A_1...A_N})&=&\sum_k\Pi_k\rho_{A_1...A_N}\Pi_k,\\
\Pi_k&=&\Pi_{A_1}^{j_1}\otimes...\otimes\Pi_{A_N}^{j_N} ,\end{aligned}$$ and $k$ denotes the index string $(j_1...j_N)$.
In order to define local projective measurements, we select a set of von-Neumann measurements as $$\begin{aligned}
\Pi_{A_j}^1={\left(
\begin{matrix}
\cos^2( \frac{\theta_j}{2} ) & e^{i\phi_j} \cos( \frac{\theta_j}{2} ) \sin( \frac{\theta_j}{2} )\\
e^{-i\phi_j} \cos( \frac{\theta_j}{2} ) \sin( \frac{\theta_j}{2} ) & \sin^2( \frac{\theta_j}{2} )
\end{matrix}\right)}\end{aligned}$$ and $$\begin{aligned}
\Pi_{A_j}^2=\left(
\begin{matrix}\sin^2( \frac{\theta_j}{2} ) & -e^{-i\phi_j} \cos( \frac{\theta_j}{2} ) \sin( \frac{\theta_j}{2} )\\
e^{i\phi_j} \cos( \frac{\theta_j}{2} ) \sin( \frac{\theta_j}{2} ) & \cos^2( \frac{\theta_j}{2} )
\end{matrix}\right)\end{aligned}$$ where $\theta_j\in[0,\pi)$ and $\phi_j\in[0,2\pi)$. By varying the angles $\theta_j$ and $\phi_j$, for $j=1..4$, one can find the measurement basis that minimizes Eq. (\[gqd\]).
Time Evolution of $|\mathrm{GHZ}_4\rangle$ State Under Noise {#sec3}
============================================================
Time evolution of a quantum system under noise is given by the master equation in the Lindblad form [@48] $$\label{Lindblad}
\frac{\partial \rho}{\partial t} = -\frac{i}{\hbar} [H_S, \rho] +\sum_{i, \alpha} \left( \mathcal{L}_{i,\alpha} \rho \mathcal{L}_{i,\alpha}^{\dagger} -
\frac{1}{2} \left\{ \mathcal{L}_{i,\alpha}^{\dagger} \mathcal{L}_{i,\alpha}, \rho\right\} \right),$$ where $\mathcal{L}_{i,\alpha}= \sqrt{\kappa_{i,\alpha}}
\sigma^{(i)}_{\alpha}$ is the Lindblad operator that describes the noise and acts on the $i$th qubit. $\kappa_{i,\alpha}$ is the decoherence rate and $\sigma^{(i)}_{\alpha}$ are the Pauli spin matrices for the $i$th qubit with $\alpha=x$ for Pauli-X, $\alpha = y$ for Pauli-Y and $\alpha = z$ for Pauli-Z noise. Also, $H_S$ is the Hamiltonian of the system. Solutions to the above equation under various noises for four-qubit GHZ state is recently presented in Ref. [@49]. The idea is to write the density matrix for infinitesimal time interval $t=\delta
t$ by using the Lindblad equation as $$\begin{aligned}
\label{del}
\rho(\delta t)&=& \rho(0)+\left[ \sum_{i, \alpha} \left(\mathcal{L}_{i,\alpha}
\rho(0) \mathcal{L}_{i,\alpha}^{\dagger} \right) - \frac{1}{2}
\left\{\mathcal{L}_{i,\alpha}^{\dagger} \mathcal{L}_{i,\alpha}, \rho(0) \right\}
\right]\delta t,\end{aligned}$$ where $\rho(0)= |\mbox{GHZ}_4\rangle\langle\mbox{GHZ}_4|$. Then, by using a proper ansatz, the solutions can be obtained for all time [@49].
Under different noises, if each qubit interacts locally with the environment then the dynamics of nonclassical correlation and entanglement can be extracted from the above formulation, specifically for an initially prepared four quit GHZ state.
Pauli-X noise
-------------
The density matrix of four quit GHZ state under the Pauli-X error is the solution of the Lindblad equation [@49], as follows $$\begin{aligned}
\label{x}
\rho^{\rm X}= { \left(
\begin{smallmatrix}
\alpha & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & \alpha \\
0 & \beta & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & \beta & 0 \\
0 & 0 & \beta & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & \beta & 0 & 0 \\
0 & 0 & 0 & \gamma & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & \gamma & 0 & 0 & 0 \\
0 & 0 & 0 & 0 & \beta & 0 & 0 & 0 & 0 & 0 & 0 & \beta & 0 & 0 & 0 & 0 \\
0 & 0 & 0 & 0 & 0 & \gamma & 0 & 0 & 0 & 0 & \gamma & 0 & 0 & 0 & 0 & 0 \\
0 & 0 & 0 & 0 & 0 & 0 & \gamma & 0 & 0 & \gamma & 0 & 0 & 0 & 0 & 0 & 0 \\
0 & 0 & 0 & 0 & 0 & 0 & 0 & \beta & \beta & 0 & 0 & 0 & 0 & 0 & 0 & 0 \\
0 & 0 & 0 & 0 & 0 & 0 & 0 & \beta & \beta & 0 & 0 & 0 & 0 & 0 & 0 & 0 \\
0 & 0 & 0 & 0 & 0 & 0 & \gamma & 0 & 0 & \gamma & 0 & 0 & 0 & 0 & 0 & 0 \\
0 & 0 & 0 & 0 & 0 & \gamma & 0 & 0 & 0 & 0 & \gamma & 0 & 0 & 0 & 0 & 0 \\
0 & 0 & 0 & 0 & \beta & 0 & 0 & 0 & 0 & 0 & 0 & \beta & 0 & 0 & 0 & 0 \\
0 & 0 & 0 & \gamma & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & \gamma & 0 & 0 & 0 \\
0 & 0 & \beta & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & \beta & 0 & 0 \\
0 & \beta & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & \beta & 0 \\
\alpha & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & \alpha
\end{smallmatrix} \right),}\end{aligned}$$ where $$\begin{aligned}
\left\{
\begin{array}{l}
\alpha =\frac{1}{16} \left(1 + 6 e^{-4 \kappa t} + e^{-8 \kappa t}\right), \\
\beta =\frac{1}{16}\left(1 - e^{-8 \kappa t}\right),\\
\gamma=\frac{1}{16} \left(1 - 2 e^{-4 \kappa t} + e^{-8 \kappa t}\right),
\end{array} \right.\end{aligned}$$ and $\kappa$ is the decoherence parameter. For this mixed state, the lower bound Eq. (\[lowerbound\]) to the four-qubit concurrence gives $$\label{entx}
\tau(\rho^{\rm X}) = \mathrm{max} \left\{0, \frac{\sqrt{2}}{4}\left(e^{-8 \kappa t} + 6 e^{-4 \kappa t} - 3\right)\right\},$$ which is an exponentially decaying function of time. The plot of this lower bound (Fig. \[fig1\]) shows that the entanglement of the four-qubit GHZ state vanishes after some finite time for the bit-flip channel. However, using the positive partial transpose criteria [@43], we find it out that the density matrix of (\[x\]) is separable only for $t\rightarrow\infty$. This indicates that the introduced lower bound does not display proper long-time entanglement for this state.
![\[fig1\] The lower bound for the four-qubit concurrence for an initial $|\mathrm{GHZ}_4\rangle$ state, transmitted through Pauli-X, Pauli-Y, Pauli-Z and isotropic channels as function of $\kappa t$.](fig1.eps){width="10cm"}
In order to obtain nonclassical correlation, we need to evaluate Eq. (\[gqd\]) by first finding the reduced density matrix of $i$th subsystem which is obtained by tracing out other three qubits that reads $$\rho^{\rm X}_{A_1}=\rho^{\rm X}_{A_2}=\rho^{\rm X}_{A_3}=\rho^{\rm X}_{A_4}=\left(\alpha + 4 \beta + 3 \gamma\right)\textbf{1}.$$ Since $\rho^{\rm X}_{A_j}$ is proportional to the unity operator, $\Phi_j(\rho_{A_j})=\sum_{i}\Pi_{A_j}^{i}\rho_{A_j}\Pi_{A_j}^{i}$ is unaffected under any projective measurements, therefore, $\Phi_j(\rho^{\rm X}_{A_j})=\rho^{\rm X}_{A_j}$ and the second term in Eq. (\[gqd\]) vanishes. To evaluate the first term, we need to find the measurement bases that minimize quantum discord. Calculations show that quantum discord suddenly changes during the dynamics of the system, namely, the measurement bases change from $\sigma_z$ ($\theta=0$) to $\sigma_x$ ($\theta=\pi/2$), so we find $$\begin{aligned}
S(\Phi({\rho^{\rm X}}))&=& 4-\frac{(1 - e^{-8 \kappa t})}{2}\log_2
(1 - e^{-8 \kappa t})\nonumber \\
&&-\frac{1}{8}[ (1+ 6 e^{-4 \kappa t}+ e^{-8 \kappa t})\log_2 (1+ 6 e^{-4 \kappa t}+ e^{-8 \kappa t})\nonumber \\
&&+ 3(1- 2 e^{-4 \kappa t}+ e^{-8 \kappa t})\log_2 (1- 2 e^{-4\kappa
t}+ e^{-8 \kappa t})].\end{aligned}$$ for $0<\kappa t<0.137$ and $$S(\Phi({\rho^{\rm X}})) = 3,$$ for $\kappa t>0.137$. Also, $$\begin{aligned}
S({\rho^{\rm X}})&=&3 -\frac{(1 - e^{-8 \kappa t})}{2}\log_2 (1 -
e^{-8 \kappa t})\nonumber \\
&&-\frac{1}{8}[ (1+ 6 e^{-4 \kappa t}+ e^{-8 \kappa t})\log_2 (1+ 6 e^{-4 \kappa t}+ e^{-8 \kappa t})\nonumber \\
&&+ 3(1- 2 e^{-4 \kappa t}+ e^{-8 \kappa t})\log_2 (1- 2 e^{-4
\kappa t}+ e^{-8 \kappa t})].\end{aligned}$$ Finally, we obtain $$\label{dx1}
D({\rho^{\rm X}})=1,$$ for $0<\kappa t<0.137$ and $$\begin{aligned}
\label{dx2}
D({\rho^{\rm X}})&=& \frac{(1 - e^{-8 \kappa t})}{2}\log_2 (1 -
e^{-8 \kappa t})\nonumber \\
&&+\frac{1}{8}[ (1+ 6 e^{-4 \kappa t}+ e^{-8 \kappa t})\log_2 (1+ 6 e^{-4 \kappa t}+ e^{-8 \kappa t})\nonumber \\
&&+ 3(1- 2 e^{-4 \kappa t}+ e^{-8 \kappa t})\log_2 (1- 2 e^{-4
\kappa t}+ e^{-8 \kappa t})],\end{aligned}$$ for $\kappa t>0.137$. Therefore, the quantum discord is constant for $0<\kappa t<0.137$, however, it experiences a sudden transition in its dynamics at $\kappa t=0.137$ and monotonically decays for $\kappa t>0.137$. This peculiar behavior of quantum discord is known as the sudden change of the quantum discord which is also observed for two qubit systems [@51; @53-2], linked to the universal freezing of quantum correlations [@53-5].
Pauli-Y noise
-------------
Now, we investigate the time evolution of nonclassical correlation and entanglement for $|\mathrm{GHZ}_4\rangle$ state under Pauli-Y error. The density matrix for this system is given by [@49] $$\begin{aligned}
{\rho^{\rm Y}}= { \left(
\begin{smallmatrix}
\alpha & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & \alpha \\
0 & \beta & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & -\beta & 0 \\
0 & 0 & \beta & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 &- \beta & 0 & 0 \\
0 & 0 & 0 & \gamma & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 &- \gamma & 0 & 0 & 0 \\
0 & 0 & 0 & 0 & \beta & 0 & 0 & 0 & 0 & 0 & 0 & -\beta & 0 & 0 & 0 & 0 \\
0 & 0 & 0 & 0 & 0 & \gamma & 0 & 0 & 0 & 0 & \gamma & 0 & 0 & 0 & 0 & 0 \\
0 & 0 & 0 & 0 & 0 & 0 & \gamma & 0 & 0 & \gamma & 0 & 0 & 0 & 0 & 0 & 0 \\
0 & 0 & 0 & 0 & 0 & 0 & 0 & \beta & -\beta & 0 & 0 & 0 & 0 & 0 & 0 & 0 \\
0 & 0 & 0 & 0 & 0 & 0 & 0 &- \beta & \beta & 0 & 0 & 0 & 0 & 0 & 0 & 0 \\
0 & 0 & 0 & 0 & 0 & 0 & \gamma & 0 & 0 & \gamma & 0 & 0 & 0 & 0 & 0 & 0 \\
0 & 0 & 0 & 0 & 0 & \gamma & 0 & 0 & 0 & 0 & \gamma & 0 & 0 & 0 & 0 & 0 \\
0 & 0 & 0 & 0 & -\beta & 0 & 0 & 0 & 0 & 0 & 0 & \beta & 0 & 0 & 0 & 0 \\
0 & 0 & 0 & \gamma & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & \gamma & 0 & 0 & 0 \\
0 & 0 &- \beta & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & \beta & 0 & 0 \\
0 & -\beta & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & \beta & 0 \\
\alpha & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & \alpha
\end{smallmatrix} \right).}\end{aligned}$$ For this case, the lower bound to the concurrence is similar to Eq. (\[entx\]), i.e., $\tau({\rho^{\rm Y}}) = \mathrm{max}
\left\{0, \frac{\sqrt{2}}{4} \left(e^{-8 \kappa t} + 6 e^{-4 \kappa
t} - 3\right)\right\}$. Also, similar to Pauli-X noise, we observe a sudden change in quantum discord at $\kappa t=0.137$. Indeed, for $\kappa t<0.137$ the optimal local measurements are given by $\Pi_{A_j}^i=| i\rangle\langle i|$ and since $\Phi_j(\rho^{\rm
Y}_{A_j})=\rho^{\rm Y}_{A_j}$ and $S(\Phi({\rho^{\rm
Y}}))-S({\rho^{\rm Y}})=1$, we find $$\label{dy}
D({\rho^{\rm Y}})=1.$$ But, for $\kappa t>0.137$, $\sigma_y$ is the basis which minimizes quantum discord, so we have $S(\Phi({\rho^{\rm Y}}))=3$ and $S({\rho^{\rm Y}})=S({\rho^{\rm X}})$. Therefore, $D({\rho^{\rm
Y}})$ coincides with Eq. (\[dx2\]).
Pauli-Z noise
-------------
For the next case, consider Pauli-Z error where its corresponding density matrix takes the following form [@49] $$\begin{aligned}
\label{z}
{\rho^{\rm Z}} = \frac{1}{2} \left(|0\rangle^{\otimes 4} \langle 0
|^{\otimes 4} + |1\rangle ^{\otimes 4}\langle 1|^{\otimes 4}\right)
+ \frac{1}{2} e^{-8\kappa t} \left(|0\rangle ^{\otimes 4} \langle 1| ^{\otimes 4}+ |1\rangle ^{\otimes 4}\langle 0 |^{\otimes 4} \right),\end{aligned}$$ that results in the lower bound $$\label{entz}
\tau({\rho^{\rm Z}}) = \sqrt{2}\, e^{-8 \kappa t}.$$ As it is shown in Fig. \[fig1\], nonclassical correlation and entanglement of this state decrease more slowly with respect to the previous noise models. For this case, the reduced density matrices become $$\rho^{\rm Z}_{A_1}=\rho^{\rm Z}_{A_2}=\rho^{\rm Z}_{A_3}=\rho^{\rm Z}_{A_4}=\frac{\textbf{1}}{2},$$ which results in $\Phi_j(\rho^{\rm Z}_{A_j})=\rho_{A_j}$, therefore the second term of Eq. (\[gqd\]) vanishes. The optimization procedure of $\theta$ and $\phi$ for each qubit shows that the optimized projective measurements are the bases of $\sigma_z$. Then we find $S(\Phi({\rho^{\rm Z}}))=1$ and the von-Neumann entropy becomes $$\begin{aligned}
S({\rho^{\rm Z}})= 1-\frac{1}{2}(1 - e^{-8 \kappa t})\log_2 (1-
e^{-8 \kappa t}) +\frac{1}{2}(1 + e^{-8 \kappa t})\log_2 (1 + e^{-8
\kappa t}).\end{aligned}$$ Therefore, we have $$\begin{aligned}
\label{dz}
D({\rho^{\rm Z}})=\frac{1}{2}(1 - e^{-8 \kappa t})\log_2 (1 - e^{-8
\kappa t}) +(1 + e^{-8 \kappa t})\log_2 (1 + e^{-8 \kappa t}).\end{aligned}$$ This result shows that the Pauli-Z error causes dissipative behavior on nonclassical correlation for $|\mathrm{GHZ}_4\rangle$ state. Decoherence behavior in terms of $\kappa t$ is depicted in Fig. \[fig2\].
Isotropic noise
---------------
To this end, consider $|\mathrm{GHZ}_4\rangle$ state under isotropic noise. It should be noted that for this case, the Lindblad equation depends on all three Pauli operators (see Ref. 29). Thus, the density matrix as the solution of the master equation is described by [@49] $$\begin{aligned}
\label{rod}
{\rho^{\rm D}}= { \left(
\begin{smallmatrix}
\tilde\alpha_+ & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 &\tilde \alpha_- \\
0 & \tilde\beta & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 \\
0 & 0 & \tilde\beta & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 &0 & 0 & 0 \\
0 & 0 & 0 & \tilde\gamma & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 &0 & 0 & 0 & 0 \\
0 & 0 & 0 & 0 & \tilde\beta & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 \\
0 & 0 & 0 & 0 & 0 & \tilde\gamma & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 \\
0 & 0 & 0 & 0 & 0 & 0 & \tilde\gamma & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 \\
0 & 0 & 0 & 0 & 0 & 0 & 0 & \tilde\beta & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 \\
0 & 0 & 0 & 0 & 0 & 0 & 0 &0 & \tilde\beta & 0 & 0 & 0 & 0 & 0 & 0 & 0 \\
0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & \tilde\gamma & 0 & 0 & 0 & 0 & 0 & 0 \\
0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & \tilde\gamma & 0 & 0 & 0 & 0 & 0 \\
0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & \tilde\beta & 0 & 0 & 0 & 0 \\
0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & \tilde\gamma & 0 & 0 & 0 \\
0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & \tilde\beta & 0 & 0 \\
0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & \tilde\beta & 0 \\
\tilde\alpha_- & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & 0 & \tilde\alpha_+
\end{smallmatrix} \right),}\end{aligned}$$ where $$\begin{aligned}
\left\{
\begin{array}{l}
\tilde\alpha_+ =\frac{1}{16}\Big( 1 + 6 e^{-8 \kappa t} + e^{-16 \kappa t}\Big),\\
\tilde\beta =\frac{1}{16}\Big( 1 - e^{-16 \kappa t}\Big),\\
\tilde\gamma = \frac{1}{16}\Big(1 - 2 e^{-8 \kappa t} + e^{-16 \kappa t}\Big),\\
\tilde\alpha_- = \frac{1}{2} e^{-16 \kappa t}.
\end{array}\right.\end{aligned}$$ Now, the lower bound (\[lowerbound\]) to the concurrence reads $$\label{entd}
\tau_({\rho^{\rm D}}) = \mathrm{max} \left\{0, \frac{\sqrt{2}}{8}\left(9 e^{-16 \kappa t} + 6 e^{-8 \kappa t} - 7\right)\right\},$$ This lower bound shows strong dissipation of entanglement in presence of isotropic error. It should be noted that for this density matrix, similar to the Pauli-X and Pauli-Y errors, according to the positive partial trace criteria, expression (\[entd\]) is only valid for $t<t_0$.
The reduced density matrices become $$\rho^{\rm D}_{A_1}=\rho^{\rm D}_{A_2}=\rho^{\rm D}_{A_3}=\rho^{\rm D}_{A_4}=\left(\alpha + 4 \beta + 3 \gamma\right)\textbf{1}.$$ So, Eq. (\[gqd\]) reduces to $$\label{gqdd}
D(\rho^{\rm D}_{A_1...A_N})= \mathrm{min}_{\{\Pi_k\}}S(\rho^{\rm D}_{A_1...A_N}\| \Phi(\rho^{\rm D}_{A_1...A_N})).$$ Calculations show that the optimized local projective measurements are $\Pi_{A_j}^i=| i\rangle\langle i|$. Thus, we have $$\begin{aligned}
S({\rho^{\rm D}})&=& 4-\frac{(1 - e^{-16 \kappa t})}{2}\log_2 (1 -e^{-16 \kappa t})\nonumber \\
&&-\frac{3}{8}(1-2 e^{-8 \kappa t}+ e^{-16 \kappa t})\log_2 (1-2 e^{-8 \kappa t}+ e^{-16 \kappa t})\nonumber \\
&&- \frac{1}{16}(1+6 e^{-8 \kappa t}-7 e^{-16 \kappa t})\log_2 (1+6e^{-8 \kappa t}-7 e^{-16 \kappa t}) \nonumber \\
&& +\frac{1}{16}(1+6 e^{-8 \kappa t}+ 9e^{-16
\kappa t})\log_2 (1+6 e^{-8 \kappa t}+ 9e^{-16 \kappa
t}),\hspace{1cm}\label{sd1}\end{aligned}$$ and $$\begin{aligned}
S(\Phi({\rho^{\rm D}}))&=& 4-\frac{(1 - e^{-16 \kappa t})}{2}\log_2(1 - e^{-16 \kappa t})\nonumber \\
&&-\frac{3}{8}(1-2 e^{-8 \kappa t}+ e^{-16 \kappa t})\log_2 (1-2 e^{-8 \kappa t}+ e^{-16 \kappa t})\nonumber \\
&& -\frac{1}{8}(1+6 e^{-8 \kappa t}+ e^{-16 \kappa t})\log_2 (1+6
e^{-8 \kappa t}+ e^{-16 \kappa t}).\label{sd2}\end{aligned}$$ By inserting Eqs. (\[sd1\]) and (\[sd2\]) in Eq. (\[gqdd\]) then $$\begin{aligned}
D({\rho^{\rm D}})&=& - \frac{1}{8}(1+6 e^{-8 \kappa t}+ e^{-16\kappa t}) \log_2 (1+6 e^{-8 \kappa t}+ e^{-16 \kappa t})\nonumber \\
&&+\frac{1}{16}(1+6 e^{-8 \kappa t}-7 e^{-16 \kappa t})\log_2 (1+6 e^{-8 \kappa t}-7 e^{-16 \kappa t})\nonumber \\
&&+\frac{1}{16}(1+6 e^{-8 \kappa t}+ 9e^{-16 \kappa t})\log_2 (1+6 e^{-8 \kappa
t}+ 9e^{-16 \kappa t})].\label{dd}\end{aligned}$$ The time evolution of quantum discord for this case is plotted in Fig. \[fig2\]. As the figure shows, the isotropic error results in a more decrease in quantum discord in comparison to Pauli-Z channel.
![\[fig2\] Quantum discord for the four-qubit system with the initial $|\mathrm{GHZ}_4\rangle$ state transmitted under Pauli-X, Pauli-Y, Pauli-Z, and isotropic errors as a function of $\kappa t$.](fig2.eps){width="10cm"}
Conclusions {#sec4}
===========
In this paper, we investigated the dynamics of nonclassical correlation and entanglement for the initial $|\mathrm{GHZ}_4\rangle$ state under interactions with several independent Markovian environments. These noises include Pauli-X, Pauli-Y, Pauli-Z and the isotropic errors. In order to describe the time evolution of entanglement, we utilized the lower bound (\[lowerbound\]) as an approximation for the convex roof of the four-qubit concurrence. The results showed that entanglement is more robust in transmission under the Pauli-Z error compared to Pauli-X, Pauli-Y and isotropic errors. For Pauli-X, Pauli-Y, and isotropic errors the lower bound vanishes in a finite time (sudden death phenomenon). However, from the positive partial transpose separability criteria [@43], we conclude that these states are separable only for $t\rightarrow\infty$. Thus, the lower bound only describes the behavior of the entanglement for $t<t_0$ where the lower bound vanishes at $t_0$. This is due to the fact that the accuracy of the lower bound over convex roof seems to depend on the rank of the corresponding density matrix [@36]. Indeed, the numerical calculation of the convex roof is a quite difficult task which requires an optimization over too many (proportional to $r^3$ where $r$ is the rank of the density matrix) free parameters [@36].
In order to obtain the time evolution of nonclassical correlation, we used the global quantum discord as a measure to calculate nonclassical correlations in multipartite states. We found that quantum discord is not affected by Pauli-X and Pauli-Y noises for $\kappa t<0.137$ whereas it decreases monotonically for $\kappa
t>0.137$. This transition of quantum discord is due to the transition of measurement bases which minimize the quantum discord. Also, quantum discord decays in the presence of Pauli-Z and isotropic noises in terms of the dimensionless scaled time $\kappa t$. In comparison, quantum discord of $|\mathrm{GHZ}_3\rangle$ state is more robust than $|\mathrm{GHZ}_4\rangle$ against decoherence for all noises under study [@54]. Moreover, except the case of Pauli-Z error, quantum discord is more robust than entanglement for the initially prepared $|\mathrm{GHZ}_4\rangle$ state.
RR is supported by CIFAR, Industry Canada and NSERC.
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|
Founders at Work
Founders at Work: Stories of Startups' Early Days (2007) is a book written by Jessica Livingston composed of interviews she did with the founders of famous technology companies concerning what happened in their early years.
Interviews
Max Levchin - PayPal
Sabeer Bhatia - Hotmail
Steve Wozniak - Apple Computer
Joe Kraus - Excite
Dan Bricklin - Software Arts
Mitch Kapor - Lotus
Ray Ozzie - Iris Associates, Groove Networks
Evan Williams - Pyra Labs (Blogger.com)
Tim Brady - Yahoo
Mike Lazaridis - Research in Motion
Arthur van Hoff - Marimba
Paul Buchheit - Gmail
Steve Perlman - WebTV
Mike Ramsay - TiVo
Paul Graham - Viaweb
Joshua Schachter - del.icio.us
Mark Fletcher - ONElist, Bloglines
Craig Newmark - craigslist
Caterina Fake - Flickr
Brewster Kahle - WAIS, Internet Archive, Alexa Internet
Charles Geschke - Adobe
Ann Winblad - Open Systems, Hummer Winblad
David Heinemeier Hansson - 37signals
Philip Greenspun - ArsDigita
Joel Spolsky - Fog Creek Software
Steve Kaufer - TripAdvisor
James Hong - HOT or NOT
James Currier - Tickle
Blake Ross - Creator of Firefox
Mena Trott - Six Apart
Bob Davis - Lycos
Ron Gruner - Alliant Computer, Shareholder.com
Reception
Chris Anderson, editor-in-chief of Wired Magazine stated "this book offers both wisdom and engaging insights straight from the source."
The Motley Fool says "The stories are fascinating, filled with many valuable lessons."
Silicon India list it at the top of its list Five Books that Every Entrepreneur Must Read
References
External links
Category:2007 non-fiction books
Category:Business books
Category:Books of interviews |
IL10 inversely correlates with the percentage of CD8⁺ cells in MDS patients.
The role of the immune system in myelodysplastic syndrome (MDS) progression has been widely accepted, although mechanisms underlying this immune dysfunction are not clear. CD4(+) and CD8(+) lymphocyte profiles in the peripheral blood of MDS patients were evaluated and correlated with clinical characteristics, the expression of FOXP3 and the anti-inflammatory cytokines IL10, TGFβ1 and CTLA4. IL10 expression inversely correlated with the percentage of CD8(+) cells and was higher in high-risk MDS. Our findings provide further evidence for the role of T cell-mediated IL10 production in MDS and strengthen the idea of distinct cytokine profiles in low and high-risk MDS. |
All relevant data are within the paper.
Introduction {#sec001}
============
Systemic lupus erythematosus (SLE) is an autoimmune disease that typically presents in women. It is characterized by heterogeneous clinical manifestations, including production of various autoantibodies and disease flares, alternating with remissions. The etiology behind development of SLE is complex and involves both genetic predispositions and environmental factors, particularly infections with human herpes viruses (HHVs). \[[@pone.0193244.ref001]--[@pone.0193244.ref008]\]
HHVs comprise eight viruses including Epstein-Barr virus (EBV, HHV4), cytomegalovirus (CMV, HHV5), and human herpes virus 6 (HHV6). They are dsDNA viruses and ubiquitous infectious agents infecting the majority of the world's population. They have a latent state, from which they occasionally reactivate and establish a productive cycle \[[@pone.0193244.ref009]--[@pone.0193244.ref011]\]. The tropism varies greatly among the viruses. Latent infections are established mainly in resting B-cells regarding EBV, and mainly in monocytes and hematopoietic stem cells regarding CMV, and in monocytes regarding HHV6 \[[@pone.0193244.ref012]--[@pone.0193244.ref014]\]. The immune system is capable of keeping a tight control of the HHV infections in immune competent individuals, and cell-mediated immunity is fundamental in this regard.
The association between SLE and EBV infection is by far the most studied and shows reduced control of the EBV infection, with elevated seroprevalence and elevated titers of EBV antibodies against lytic cycle antigens, decreased T-cell responses against EBV, and increased viral load in SLE patients compared to healthy controls (HCs) \[[@pone.0193244.ref008], [@pone.0193244.ref015]--[@pone.0193244.ref019]\].
The association between SLE and CMV infection has also previously been investigated and has shown increased percentages of SLE patients positive for CMV DNA \[[@pone.0193244.ref020], [@pone.0193244.ref021]\]. Studies on CMV-directed antibodies in SLE patients have shown increased titers of IgG and IgA antibodies against CMVpp52, which is an early lytic cycle antigen necessary for lytic viral replication \[[@pone.0193244.ref022]\]. Furthermore, elevated percentages of IgM and IgG antibodies to unspecified CMV antigens have been observed in SLE patients compared to HCs \[[@pone.0193244.ref020], [@pone.0193244.ref023]--[@pone.0193244.ref025]\]. Using HLA/CMVpp65-peptide tetramers, Larsen et al. showed a normal amount of CMVpp65-specific CD8+ T-cells in SLE patients with normal cytokine responses to CMV stimulation and no increased viral load \[[@pone.0193244.ref026]\]. Kang et al. merely showed a tendency of a reduced CMV-directed T-cell response, when whole blood samples were stimulated with CMV antigens \[[@pone.0193244.ref027]\].
Only a few studies have examined HHV6 infection in SLE patients. Rasmussen et al. showed no difference between SLE patients and HCs in antibody (IgM, IgG and IgA) titres against HHV6p41 (which is a HHV6 early lytic antigen) \[[@pone.0193244.ref022]\]. However, two other studies have shown an association between SLE and active HHV6 infection \[[@pone.0193244.ref028], [@pone.0193244.ref029]\].
The current study is a continuation of our previously published results on EBV-directed immune responses in SLE patients \[[@pone.0193244.ref018], [@pone.0193244.ref030]\] but with focus on CMV and HHV6. We sought to determine if our previously observed results on reduced T-cell response and cytokine response pattern upon EBV antigens stimulation \[[@pone.0193244.ref018], [@pone.0193244.ref030]\] is a general defect in the immune responses against HHVs in SLE patients. Thus, we investigated the T-cell response to CMV and the cytokine response pattern induced by stimulation with CMV and HHV6 antigens. CMVpp52 and HHV6p41 were chosen as stimulatory antigens as they are lytic cycle antigens and functional homologues to the previously investigated stimulatory agent EBV-EA/D (EBV early antigen diffuse), and also the antibody response against these two antigens have previously been determined \[[@pone.0193244.ref022]\]. In a 4-color flow cytometric assay the T-cell response to CMVpp52 was measured using CD69 as an early marker for activation and interferon(IFN)γ-production in the individual T-cells as a marker for the anti-viral response. These results on CMVpp52-responding T-cells were compared with the CMVpp52 antibody status. Furthermore, in a separate experimental setup, T-cell-related cytokines (IFNγ, interleukin(IL)12, IL17), and also, one inflammatory (tumor necrosis factor(TNF)α) and one anti-inflammatory (IL10) cytokine induced upon stimulation with CMVpp52 and HHV6p41 were measured by Luminex technology.
Materials and methods {#sec002}
=====================
SLE patients and healthy controls {#sec003}
---------------------------------
Two different setups were applied in the current study using two different SLE patient/HC cohorts. In both cases were heparinized whole blood samples from SLE patients collected at Copenhagen Lupus & Vasculitis Clinic, Centre for Rheumatology and Spine Disease, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark, and blood samples from apparently HCs were collected from volunteers at Statens Serum Institut, Copenhagen, Denmark. All patients fulfilled internationally accepted classification criteria for SLE \[[@pone.0193244.ref031]\].
During flow cytometric analyses of EBV-induced activation of T-cells in SLE patients \[[@pone.0193244.ref018]\], the CMVpp52-induced T-cell response was additionally investigated by flow cytometry in a subset of the cohort comprising 17 age- and sex-matched pairs of the included SLE patients and HCs. The characteristics of these 17 SLE/HC-pairs are outlined in [Table 1](#pone.0193244.t001){ref-type="table"}, left column.
10.1371/journal.pone.0193244.t001
###### Characteristics of SLE patients and HCs in the two studies.
{#pone.0193244.t001g}
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Study:\ Study:\
Flow cytometric T-cell analysis Cytokine quantification by luminex
---------------------------------------- ----------------------------------------- ------------------------------------ ---------
No. of individuals 17 17
Mean age (years) (range) 40.7 (21--81) 42,6 (23--61)
Females 94% 100%
Disease manifestations:
Nephritis 29% 12%
Vasculitis 0% 0%
Arthritis 29% 6%
Rash 18% 18%
Alopecia 0% 0%
Myositis 0% 0%
Mucosal ulcers 0% 0%
Serositis 6% 6%
Leucopenia 12% 0%
Thrombocytopenia 18% 0%
Visual disturbance 0% 0%
Fever 18% 0%
Mean SLEDAI score (range) 6.7 (0--22) 3.2 (0--12)
dsDNA antibody positive 47% 65%
Rheumafactor positive
IgA 12% 29%
IgM 0% 24%
Low C3 or C4 level 71% 35%
Mean C-reactive protein (mg/L) (range) 5.7 (1--22) 6.4 (1--38)
Medication:
Prednisolone (median dose, mg) 65% (5) 24% (0)
Azathioprine (median dose, mg) 29% (0) 18% (0)
Mycophenolate mofetil (median dose, mg) 24% (0) 18% (0)
Methotrexate (median dose, mg) 12% (0) 6% (0)
Hydroxychloroquine (median dose, mg) 59% (200) 47% (0)
Anticoagulant 35% 47%
Antihypertension 24% 35%
**HCs cohort 1** **HCs cohort 2**
No. of individuals 17 17
Mean age (years) (range) 37.3 (25--59) 42.9 (28--64)
Females 94% 100%
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In addition, another cohort of 22 included SLE patients and age- and sex-matched HCs (with no overlap to the 17 SLE patient/HC-pairs investigated above) was investigated in the current study for CMVpp52-induced cytokine induction (and HHV6p41-induced cytokine induction in a subset of eight SLE patient/HC-pairs). Five of the included 22 SLE patients were found to suffer from lymphopenia (\<1.00\*10^9^/L) and were excluded in order to assess the issue without an effect on results due to low levels of T-cells. The characteristics of these 17 investigated SLE/HC-pairs are shown in [Table 1](#pone.0193244.t001){ref-type="table"}, right column.
Ethics statement {#sec004}
----------------
The studies were approved by the Scientific Ethical Committee of the Capital Region of Denmark (no. HA-2007-0114 and no. H-15009640, for the two cohorts, respectively). Written informed consent was obtained from all participants before inclusion.
Ex vivo stimulation of whole blood samples with antigens {#sec005}
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Two *ex vivo* stimulation setups were employed during the studies. One for flow cytometric T-cell analyses and another for quantification of antigen-induced cytokines by Luminex technology.
The *ex vivo* stimulations of whole blood samples for flow cytometric T-cell analyses were made simultaneously with the stimulations in a previous study \[[@pone.0193244.ref018]\]. Heparinized whole blood samples were incubated at 37°C for 24 hours with recombinant CMVpp52 (5 μg/ml, *Escherichia coli* (*E-coli*)-derived, CMV-214, Prospec Protein Specialist, Ness-Ziona, Israel) and with staphylococcal enterotoxin B (SEB) and phosphate-buffered saline (PBS) as positive and negative controls, respectively. Eight hours subsequent to stimulation, Brefeldin A (10 μg/ml, Sigma-Aldrich, St- Louis, Missouri, USA) was added to inhibit cytokine secretion from activated cells. Stimulation was terminated after 24 hours by addition of 20 mM EDTA (100 μl/ml), and samples immediately employed for staining and subsequent flow cytometric T-cell analysis (see below).
The *ex vivo* stimulations of whole blood samples for quantification of induced cytokines by Luminex technology were executed correspondingly as above, but without the addition of the secretion inhibitor. In addition, stimulation was also performed using recombinant HHV6p41 (5 μg/ml, *E-coli*-derived MyBiosource, San Diego, CA, USA) and also an extra negative control was included by stimulation with *E*.*coli*-derived β-galactosidase (5 μg/ml, Sigma-Aldrich, St. Louis Missouri, USA). The latter to ensure that the stimulation of cytokine production was not due to the fact that the CMVpp52 and HHV6p41 antigens are produced in *E*.*coli* and possibly contaminated with lipopolysaccharide (LPS). Subsequent to stimulation, 100 μl stimulated whole blood was spotted, dried and stored at -20°C as dried blood spot samples (DBSS) on filter paper until all patients and HCs were included in the study and then used for cytokine quantification by Luminex technology (see below).
To facilitate comparability between results on SLE patients and HCs, each age- and sex-matched SLE/HC-pair had the same lag-time before stimulation in both experimental setups. The lag-time was defined as the period of time from blood collection until beginning of stimulation. In setup 1 with stimulations for flow cytometric T-cell analysis, the lag-time ranged between 44 and 81 minutes, and in setup 2 with stimulations for quantification of induced cytokines by Luminex technology, the lag-time ranged between 50 and 171 minutes.
Flow cytometric T-cell analysis {#sec006}
-------------------------------
The staining and detection of activated (CD69-positive) and IFNγ-producing T-cells in the stimulated whole blood samples (here with CMVpp52, SEB and PBS) was described previously \[[@pone.0193244.ref018]\]. In short, erythrocytes were initially lysed and next the lymphocytes were permeabilised. After washing, the lymphocytes were stained with a mixture of allophycocyanin (APC)-conjugated anti-CD3, cyanine 5.5 peridinin chlorophyll (PerCP-Cy5.5)-conjugated anti-CD8, phycoerythrin (PE)-conjugated anti-CD69, and fluorescein isothiocyanate (FITC)-conjugated anti-IFNγ (20 μl in total, BD Biosciences, San Jose, CA, USA). In addition, another SEB-stimulated sample from each individual was stained with an isotype-specific control antibody mix (anti-CD3- APC, anti-CD8-PerCP-Cy5.5, IgG~1~-PE, and IgG~2a~-FITC, BD Biosciences, San Jose, CA, USA) to assess the staining and also the non-specific staining and to check for autofluorescence. After staining, washing and fixation, the flow cytometric analyses were done on a FACScalibur flow cytometer and CELLQuest software (BD Biosciences, San Jose, CA, USA). CaliBRITE beads (BD Biosciences, San Jose, CA, USA) were used to accomplish fluorescence compensations. Data was analyzed by the use of FLOW JO software (Tree Star, San Carlos, CA, USA).
Data for a large number of CD3-positive events (100000) was acquired on the flow cytometer in order to ensure that even low percentages of activated cells account for a considerable number of cells.
The gating strategy and a representative example of the flow cytometry data are presented in [Fig 1](#pone.0193244.g001){ref-type="fig"} and correspond to a previously described procedure \[[@pone.0193244.ref018]\] with examination of subpopulations of activated (CD69-positive) and IFNγ-producing T-cells (CD3-positive).
{#pone.0193244.g001}
For each measurement of SEB- and CMVpp52-stimulated samples, the result obtained from the negative control sample with PBS stimulation was subtracted. A sample was considered positive for activated T-cells if the percentage of CD69-positive T-cells was higher than 0.98% (cut-off value determined by the mean value of all measurements), and was considered to have a high number of activated T-cells if the percentage of CD69-positive T-cells was higher than 4.09% (high cut-off value determined by mean + 2xSD).
Cytokine quantification by multiplexed Luminex assay {#sec007}
----------------------------------------------------
The concentrations of five cytokines (IFNγ, IL10, IL12, IL17, and TNFα) secreted upon stimulation with CMVpp52, HHV6p41, SEB, PBS, and β-galactosidase were analyzed with an in-house assay by multiplexed Luminex xMAP technology (Luminex Corp, TX, USA) as previously described \[[@pone.0193244.ref030], [@pone.0193244.ref032]\].
In short, two 3 mm diameter disks were punched from each DBSS of stimulated whole blood and then extracted. Next, the extracted samples were incubated with capture antibody-conjugated beads. After washing, the samples were incubated first with corresponding biotinylated detection antibodies and then with streptavidin-PE. After additional washing, samples were analyzed on the Luminex 100^TM^ platform (Luminex Corp, TX, USA).
In addition to the standard assay conditions, heterophillic blocking reagent plus (HBR+) (3KC545 Scantibodies Laboratory, Inc., Santee, CA, USA) was added to samples (from both SLE and HC) and conjugate in a concentration of 400 μg/ml to avoid false positive results due to rheumatoid factors/heterophilic antibodies.
The working ranges were 8--4000 pg/ml for IL12 and IL17; and 156--80000 pg/ml for IL10, TNFα, and IFNγ. All samples from each SLE/HC-pair were always analyzed on the same plate, and each plate contained a high and a low positive control together with the standard curve. The standard curves were fitted with a five-parameter logistic equation (Logistic-5PL) using BioPlex^TM^ Manager 6.1 (Bio-Rad Laboratories, CA, USA).
Detection of antibodies in plasma by ELISA {#sec008}
------------------------------------------
Specific CMVpp52-directed antibodies were detected in plasma from included individuals (the 17 SLE patients and 17 HCs included for flow cytometric T-cell analysis) by the use of an ELISA setup previously employed \[[@pone.0193244.ref022]\]. Briefly, Nunc polysorp microtitre plates (Thermo Fisher Scientific, Denmark) were coated with CMVpp52 (1 **μg**/ml, *Escherichia coli* (*E-coli*)-derived, CMV-214, Prospec Protein Specialist, Ness-Ziona, Israel) in carbonate buffer (50 mM sodium carbonate, pH 9.6) over night at 4°C. After washing, plates were blocked for 30 minutes in TTN buffer (0.05 M Tris, 1% Tween20, 0.3 M NaCl, pH 7.5). Plasma samples were diluted 1:100/1:100/1:50 for detection of CMVpp52-directed IgM/IgG/IgA antibodies, respectively. Diluted samples were added in duplicates to both coated and non-coated wells. After washing, the plates were incubated with alkaline phosphatase (AP)-conjugated goat anti-human IgM, IgG or IgA (Sigma-Aldrich, St. Louis, MO, USA) (1:2000). Plates were developed after extensive washing by adding ρ-nitrophenol phosphate (ρ-NPP) (Sigma-Aldrich, St. Louis, MO, USA) in substrate buffer (1M diethanolamine, 9.5 mM MgCl~2~, pH 9.8) (1 mg/ml). Plates were read by a Versamax microplate reader (Molecular Devices, Sunnyvale, CA, USA) with a wavelength of 405 nm and a reference wavelength of 650 nm.
The absorbance values from the non-coated wells were subtracted from the absorbance values from the coated wells and all net absorbance values were then normalized to standard curves derived from a two fold serial dilution of serum pools. A plasma sample was considered positive for CMVpp52-antibodies if the antibody binding was higher than cut-off values (0.5, 0.64 and 0.5 arbitrary binding units regarding CMVpp52-directed IgM, IgG and IgA, respectively).
Total CMV antibodies were determined as previously described using a cellular CMV lysate as antigen and cellular lysate without CMV as control \[[@pone.0193244.ref033], [@pone.0193244.ref034]\].
Statistical analyses {#sec009}
--------------------
Statistical analyses were made in GraphPad Prism software 5 (GraphPad Prism Software Inc, San Diego, CA, USA). Comparison between SLE patients' and HCs' T-cell responses (CD69-positives and intracellular IFNγ) measured by flow cytometry, and also cytokine responses measured by Luminex technology were performed using Wilcoxon matched-pairs test. Spearman's correlation test was used for correlation analyses. Fisher's exact test was used for comparisons on SLE patients and HCs divided in positives and negatives for CMVpp52-responding T-cells and CMVpp52-directed antibodies, respectively. p-values below 0.05 were considered significant and indicated on Figs and tables with \*, \*\*, or \*\*\* for p-values less than 0.05, 0.01, or 0.001, respectively.
To be able to compare the current results to previously published results on flow cytometric analyses of EBV-responding T-cells \[[@pone.0193244.ref018]\] and EBV-induced cytokines quantified by Luminex technology \[[@pone.0193244.ref030]\], results are presented here as in the preceding papers with mean±SEM for flow cytometric T-cell analyses data, and median with interquartile range for Luminex technology quantitative cytokine data.
Results {#sec010}
=======
In order to investigate the CMV-directed immune response in SLE patients and compare it to the normal response in HCs, the CMVpp52-directed T-cell response was characterized, and its relation to the CMVpp52 antibody status was evaluated. Furthermore, CMVpp52- and also HHV6p41-induced cytokines were examined.
Reduced T-cell response in SLE patients upon CMV stimulation {#sec011}
------------------------------------------------------------
A 4-color flow cytometric T-cell analysis was performed to characterize T-cells upon stimulation of whole blood samples from 17 SLE patients and 17 HCs with the lytic cycle CMV antigen pp52, in order to investigate whether the previously established reduced T-cell response to EBV antigens \[[@pone.0193244.ref018]\] also applies to the CMV-directed T-cell response.
Activated T-cells, and T-cells that produced IFNγ, upon CMVpp52 stimulation were determined and control stimulation values with PBS were subtracted. [Fig 2](#pone.0193244.g002){ref-type="fig"} illustrates the percentages of T-cells (CD3-positives) from SLE patients and HCs that express CD69 on their surface (activated T-cells) ([Fig 2A](#pone.0193244.g002){ref-type="fig"}), and/or were producing intracellular IFNγ ([Fig 2B](#pone.0193244.g002){ref-type="fig"}) in response to CMVpp52 stimulation. Results show a statistically significant reduced percentage of CMVpp52-responding T-cells in SLE patients compared to HCs. The SLE patients experienced a weaker CD69 expression on the surface with statistically significant fewer T-cells, both CD8+ and CD8-, becoming activated (p = 0.001, 0.004, and 0.0004, regarding total, CD8+, and CD8-, CD69-expressing T-cells upon CMVpp52 stimulation) ([Fig 2A](#pone.0193244.g002){ref-type="fig"}). In addition, the SLE patients experienced statistically significant reduced percentages of T-cells, both CD8+ and CD8-, producing IFNγ upon CMVpp52 stimulation compared to HCs (p = 0.0007, 0.003, and 0.0009, regarding CD69, CD8+, and CD8-, IFNγ-producing T-cells upon CMVpp52 stimulation), however, with low percentages of IFNγ-producing T-cells in both SLE patients and HCs ([Fig 2B](#pone.0193244.g002){ref-type="fig"}).
{#pone.0193244.g002}
As observed in the previous study on EBV antigen-responding T-cells \[[@pone.0193244.ref018]\], no statistically significant differences between SLE patients and HCs were observed upon stimulation with the superantigen SEB. However, with an exception of IFNγ-producing CD8- T-cells, with SLE patients having a significant (p = 0.033) lower percentage of IFNγ-producing CD8- T-cells compared to HCs upon SEB stimulation. However, these percentages of IFNγ-producing T-cells are all very low (especially for CD8- T-cells), and should be interpreted cautiously regarding all stimulations.
Comparisons of the results in [Fig 2](#pone.0193244.g002){ref-type="fig"} on CMVpp52-responding T-cells and previous results on EBV-responding T-cells are illustrated in [Fig 3](#pone.0193244.g003){ref-type="fig"} and show a strong correlation to both EBNA1-responding T-cells (r = 0.933, p\<0.0001), and EA/D-responding T-cells (r = 0.917, p\<0.0001), indicating an association between the viral responses, which was valid for both SLE patients and HCs.
{#pone.0193244.g003}
No correlation was observed between CMVpp52-responding T-cells and disease activity (determined by the SLEDAI score) or intake of immunosuppressant medication of the SLE patients.
Outline of T-cell responses and antibody responses against CMV {#sec012}
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The antibody status against CMVpp52 was determined by indirect ELISA in plasma from unstimulated blood samples from the SLE patients and HCs also included in the flow cytometric assay above. The results are listed in [Table 2](#pone.0193244.t002){ref-type="table"} and [Table 3](#pone.0193244.t003){ref-type="table"}. In the previous investigations on EBV-directed immune responses \[[@pone.0193244.ref018]\], a clear inverse relation between EBV-responding T-cells and EBV-directed antibodies was revealed, and it was investigated if the same pattern emerged for the CMV-directed immune response.
10.1371/journal.pone.0193244.t002
###### CMVpp52 antibodies and CMVpp52-specific T-cells in SLE patients and healthy controls.
{#pone.0193244.t002g}
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CMVpp52-specific\ CMVpp52 antibodies
(CD69) T-cells
--------- -------------------------------------- --------- ------------------------ -- ------------- ---------- ----------
SLE-07
SLE-09
SLE-10
SLE-15
SLE-18
SLE-20
SLE-08
SLE-19
SLE-06
SLE-26
SLE-13
SLE-12
SLE-252
SLE-17
SLE-14
SLE-27
SLE-28
HC-07
HC-09
HC-10
HC-15
HC-18
HC-20
HC-08
HC-19
HC-06
HC-26
HC-13
HC-12
HC-252
HC-17
HC-14
HC-27
HC-28
**Color code**
**CMVpp52-specific (CD69+) T-cells** **CMVpp52 antibodies**
\>4.09% \>0.98% \<0.98% \>2\*cutoff \>cutoff \<cutoff
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10.1371/journal.pone.0193244.t003
###### Overview of CMVpp52 antibody status and CMVpp52-specific T-cells in SLE patients and healthy controls.
{#pone.0193244.t003g}
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CMVpp52-specific\ CMVpp52 antibodies
(CD69) T-cells
--------------------------------------------- ------------------- -------------------- ---------- ------ ------ ------
SLE patients (n = 17), % 24 12 18 35 35 59
Healthy controls (n = 17), % 100 82 88 18 47 29
Comparison by Fisher's exact test, p-values \<0.0001 \<0.0001 \<0.0001 0.44 0.73 0.17
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In [Table 2](#pone.0193244.t002){ref-type="table"}, an outline of results on both CMVpp52-responding T-cells (CD69-expressing T-cells upon stimulation) and CMVpp52-directed antibodies for each included individual are presented with color codes. The colors dark green, medium green, and light green represent positive for high numbers of activated T-cells (above the high cut off value), positive for activated T-cells (above the cut off value), and negative for activated T-cells (below the cut off value), respectively, regarding T-cell responses. Regarding antibody status, the colors represent positive for high titres of antibodies (above 2\*cut off value), positive for antibodies (above the cut off value), and negative for antibodies (below the cut off value), respectively. SLE patients are listed with increasing disease activity in [Table 2](#pone.0193244.t002){ref-type="table"} (determined by the SLEDAI scores) (and the HCs are listed according to their matched SLE patients).
[Table 2](#pone.0193244.t002){ref-type="table"} clearly outlines the lower CMVpp52-directed T-cell response in the SLE patients compared to the HCs shown above ([Fig 2A](#pone.0193244.g002){ref-type="fig"}) but on the individual level. Furthermore, it shows a tendency of higher titres of CMVpp52-directed antibodies in SLE patients compared to HCs, though no statistical test was employed. However, the increasing disease activity do not seem to have an impact on the CMVpp52-directed immune responses in the SLE patients (which the above rejected correlation test between T-cell responses and SLEDAI scores also showed).
The pattern with the inverse relation previously demonstrated for the EBV-directed response with HCs having high percentages of virus-responding T-cells and few antibodies, and SLE patients having very few T-cells but high titres of antibodies \[[@pone.0193244.ref018]\], is also indicated for the CMVpp52-directed response in [Table 2](#pone.0193244.t002){ref-type="table"}. However, to a lesser extent than demonstrated with the EBV-directed response.
[Table 3](#pone.0193244.t003){ref-type="table"} provides an overview of percentages of SLE patients and HCs positive for CMVpp52-responding T-cells (with CD69-expressing T-cells above the cut off value upon CMVpp52-stimulation) and CMVpp52-directed antibodies (titres above cut off values). Results on CMVpp52 antibody status show that higher percentages of SLE patients were positive for IgG and IgA with positivity percentages of 35% and 59% compared to 18% and 29% of HCs, respectively ([Table 3](#pone.0193244.t003){ref-type="table"}). Contrarily, a slightly lower positivity percentage of IgM CMVpp52-directed antibodies was observed in SLE patients (35%) compared to HCs (47%) ([Table 3](#pone.0193244.t003){ref-type="table"}). However, Fisher's exact test showed no significant differences in antibody-positivity between SLE patients and HCs. The strong differentiation between SLE patients and HCs in percentages of CMVpp52-responding T-cells regarding both total number of CD69-expressing T-cells, and CD8+ and CD8- T-cells expressing CD69, was further outlined in [Table 3](#pone.0193244.t003){ref-type="table"}. All 17 HCs were found positive for CMVpp52-responding T-cells compared to only 4 (24%) of the 17 SLE patients. Fisher's exact test showed significant differences in positivity of CMVpp52-responding T-cells between SLE patients and HCs (p\<0.0001), regarding both total, CD8+, and CD8- T-cells, respectively, as expected confirming results in [Fig 2](#pone.0193244.g002){ref-type="fig"}.
All of the 17 HCs and 14 of the 17 SLE patients showed either CMVpp52-directed antibodies and/or CMVpp52-responding T-cells, indicating positive CMV immune status. The last three SLE patients (negative in our initial analyses), were all found to have positive CMV serology measuring the total CMV antibody titer. Thus, the above presented results do not reflect a distortion in previous CMV infection among the SLE patients and HCs.
CMV- and HHV6-induced cytokine responses {#sec013}
----------------------------------------
The cytokine responses (IFNγ, IL12, IL17, TNFα, and IL10) against CMV and HHV6 were characterized in SLE patients and compared to HCs by quantifying cytokines secreted upon stimulation with the early lytic cycle antigens CMVpp52 and HHV6p41. As previously applied (with results on EBV-induced cytokines \[[@pone.0193244.ref030]\]) in order to assess the issue without an effect on results due to lymphopenia (which is common in SLE patients), only SLE patients with normal lymphocyte levels (\>1.00\*10^9^ /L) were compared to their corresponding matched HC in the following results.
Unlike previous results on EBV antigen-induced cytokines, no difference in any of the quantified secreted cytokines were observed between SLE patients and HCs upon CMVpp52-stimulation ([Table 4](#pone.0193244.t004){ref-type="table"}). Both SLE patients and HCs had a significant induction of all cytokines (except IL17 in SLE patients) by stimulation with CMVpp52 compared to PBS stimulation and thus to normal levels.
10.1371/journal.pone.0193244.t004
###### Cytokine responses in SLE patients and HCs upon HHV-stimulation.
Median concentration (pg/ml) \[interquartile range\].
{#pone.0193244.t004g}
CMVpp52-induced cytokines HHV6p41-induced cytokines
------ --------------------------- --------------------------- ------ ------------------------ ------------------------ ------------
IFNγ 3736 \[1946--6564\] 1239 \[303--5121\] 0.27 2387 \[410--12979\] 78 \[78--2266\] 0.22
IL12 306 \[182--352\] 252 \[137--337\] 0.91 299 \[222--390\] 223 \[24--324\] **0.03\***
IL17 242 \[42--452\] 209 \[4--377\] 0.27 291 \[38--374\] 327 \[58--352\] 0.84
TNFα 18229 \[14661--24486\] 21042 \[13413--24918\] 0.78 20569 \[13523--20838\] 16928 \[11486--24458\] 0.55
IL10 21902 \[21149--25792\] 21738 \[17923--24500\] 0.30 19391 \[17613--22042\] 19400 \[16510--20439\] 0.64
All cytokine responses were compared using Wilcoxon matched-pairs test
The same pattern was observed after stimulation with HHV6p41 (however only eight SLE/HC-pairs were investigated making results less conclusive) with nearly no difference in cytokine concentrations between SLE patients and HCs ([Table 4](#pone.0193244.t004){ref-type="table"}). Only IL12 induction was significantly different between the groups, but looking at the similar medians ([Table 4](#pone.0193244.t004){ref-type="table"}) this difference is probably negligible.
No differences were observed between SLE patients and HCs upon PBS stimulation (served as basic levels of cytokines) in any of the 5 quantified cytokines as also demonstrated in the previous study.
Actually, even though no differences between SLE patients and HCs were observed in cytokine secretions upon β-galactosidase stimulation (which served as a control for antigens produced in *E*.*coli*), an induction was observed in IL10 secretion upon stimulation with β-galactosidase compared to PBS stimulation in both SLE patients (p = 0.008) and HCs (p = 0.03). This might make the results on CMVpp52- and HHV6p41-induced cytokines inconclusive, as the antigens are also produced in *E*.*coli*. However, the induction of IL10 was significantly higher in HHV-stimulated samples compared to β-galactosidase-stimulated samples. This result, together with the fact that the β-galactosidase induction is similar between SLE patients and HCs, indicates that the results on a normal CMVpp52- and HHV6p41-induced cytokine response in SLE patients should be valid.
Statistically significantly reduced secretion of IFNγ, IL17, and TNFα was observed in SLE patients compared to HCs upon stimulation with the superantigen SEB ([Table 5](#pone.0193244.t005){ref-type="table"}). Due to exclusion of SLE patients with lymphopenia, these results might be an effect of dysfunctional leukocytes in SLE patients.
10.1371/journal.pone.0193244.t005
###### Cytokine responses in SLE patients and HCs upon SEB-stimulation.
Median concentration (pg/ml) \[interquartile range\].
{#pone.0193244.t005g}
SEB-induced cytokines PBS-induced cytokines (basic levels)
------ ------------------------ -------------------------------------- --------------- -------------------- --------------------- ------
IFNγ 28950 \[23178--42766\] 16547 \[11904--25201\] **0.003\*\*** 78 \[78--200\] 78 \[78--78\] 0.31
IL12 264 \[183--356\] 230 \[177--336\] 0.43 67 \[4--180\] 95 \[4--168\] 0.90
IL17 2384 \[1465--4000\] 1922 \[1475--2152\] **0.04\*** 4 \[4--238\] 4 \[4--310\] 0.49
TNFα 16326 \[11355--18373\] 10166 \[6139--12807\] **0.001\*\*** 78 \[78--489\] 78 \[78--78\] 0.69
IL10 9457 \[5658--12373\] 7920 \[5327--10582\] 0.37 1544 \[787--3913\] 1920 \[1151--3456\] 0.92
All cytokine responses were compared using Wilcoxon matched-pairs test
In order to check if the above presented results on CMV-directed cytokine-responses is due to a distortion between SLE patients and HCs in CMV immune status, total CMV antibody titers were also measured in the individuals. Actually, results showed that three of the 17 SLE patients and four of the 17 HCs in this cohort 2 were negative for CMV serology. Exclusion of the data from these individuals revealed no differende in outcome with still no significant differences in cytokine responses between SLE patients and HCs. This indicates that the above presented results do not reflect a distortion in previous CMV infection among SLE patients and HCs.
Discussion {#sec014}
==========
In this study, we have presented an outline of immune responses to the early lytic CMV antigen, CMVpp52, in SLE patients. This comprised results on percentages of CMVpp52-reponding T-cells by flow cytometry and comparison to CMVpp52 antibody status measured by ELISA, and also CMVpp52-induced cytokine response patterns quantified by multiplexed Luminex technology. Furthermore, cytokine responses to its functional homologue for HHV6, HHV6p41, were briefly studied.
We sought to clarify if the previously determined reduced T-cell response and cytokine response pattern in SLE patients upon EBV antigens stimulations \[[@pone.0193244.ref018], [@pone.0193244.ref030]\] is specific for EBV, or if SLE patients have a general immune defect regarding responses to more HHVs. EBV-EA/D, CMVpp52, and HHV6p41 are all early antigens of their respective HHVs, and serves as DNA polymerase processivity factors and are essential for the productive cycle of the viruses \[[@pone.0193244.ref035]--[@pone.0193244.ref038]\]. Investigations of immune responses against these functional homologues of three HHVs in SLE patients make direct comparisons possible in the evaluation of the immune defects in SLE patients and whether it comprises all three HHVs or is specific for EBV responses.
Overall, results were diverse with decreased percentages of responding T-cells upon CMVpp52-stimulation but with normal cytokine response patterns to both CMVpp52 and HHV6p41 in SLE patients compared to HCs.
Regarding, flow cytometric results investigating activation of the individual cells, the CMVpp52 response seemed decreased with statistically significantly fewer T-cells becoming activated in SLE patients compared to HCs, even though a rather small sample size was employed (n = 17). These findings correlated with earlier results on EBV-responding T-cells, but did not correlate with disease activity of the SLE patients. Furthermore, a higher positivity of IgG and IgA antibodies against CMVpp52 were detected in SLE patients.
This observed reduced CMV-specific T-cell response is somewhat contradictory to previous observations in SLE patients \[[@pone.0193244.ref026], [@pone.0193244.ref027]\]. Larsen et al. applied MHCI tetramers with CMVpp65 peptides, and PBMCs from SLE patients (n = 21) and HCs (n = 15), and showed normal amounts of CD8 CMVpp65-specific T-cells in SLE patients with normal cytokine responses upon CMV stimulation \[[@pone.0193244.ref026]\]. Kang et al. stimulated whole blood samples for six hours with unspecified CMV antigens and only found a tendency of a reduced CMV-directed T-cell response in SLE patients (n = 17) compared to HCs (n = 9) \[[@pone.0193244.ref027]\]. In the current study, the percentages of functional CD8+ and CD8- lytic antigen CMVpp52-responding T-cells was found reduced in SLE patients, which is opposite of results by Larsen et al and Kang et al. However, the differences might be due to the use of different CMV antigens (pp65 as opposed to pp52) and also differences in experimental setups (PBMCs and MHCI tetramers as opposed to whole blood samples with various stimulation times), and cohorts which are all relatively small and might represent different subgroups of patients.
Our current results on reduced percentages of CMVpp52-responding T-cells are possibly a consequence of limited or defective CMVpp52-specific T-cells. As discussed previously with the reduced percentages of EBV-responding T-cells, a possible reason is hyperactivation and subsequent exhaustion of HHV-specific T-cells in SLE patients upon continuous exposure to HHV antigens following frequent and recurrent HHV reactivation, a theory also proposed by Larsen et al. \[[@pone.0193244.ref018], [@pone.0193244.ref026]\].
However, due to the chosen methodology comprising whole blood stimulation, another possibility is that the decreased T-cell activation observed in SLE patients is not due to intrinsic T-cell defects, but rather indirect effects on T-cell activation, since T-cell activation is complex with multiple influential factors. Previous studies on SLE patients show altered cytokine levels in the circulation \[[@pone.0193244.ref039]--[@pone.0193244.ref041]\] giving rise to an altered, and perhaps suboptimal environment for T-cell activation in SLE patients compared to HCs. The most characteristic observation in this regard is the IFN signature in SLE patients with increased levels of type I IFNs, especially IFNα \[[@pone.0193244.ref042]\], which is actually known to reduce the T-cell response during chronic infections and inflammation \[[@pone.0193244.ref043]\]. Another indirect effect, possibly leading to decreased T-cell activation is poor antigen presentation, which is of special importance in current experimental setup using whole blood samples and stimulation with exogenous antigens. Previous studies have pointed to defects in antigen presentation in SLE patients \[[@pone.0193244.ref044], [@pone.0193244.ref045]\], which would influence the T-cell activation. Since Larsen et al. found normal levels of CMV-specific T-cells in SLE patients with normal effector responses using CMV-MHCI tetramers \[[@pone.0193244.ref026]\], our results on decreased T-cell activation upon CMVpp52 stimulation possibly reflect poor antigen presentation in the SLE patients.
As previously discussed, a general limitation and challenge in the current study is the experimental approach, and the process of activation of CD8 T-cells upon stimulation with an exogenous antigen. Previous studies suggest a cross-presentation pathway of exogenous antigens \[[@pone.0193244.ref046]--[@pone.0193244.ref049]\] or neighboring bystander activation but the exact reason for the observed activation of CD8 T-cells is not clear. Nonetheless, this experimental setup makes it difficult to evaluate the exact mechanisms of the immune stimulation including antigen processing and the T-cell response. Thus, the interpretation of the underlying reasons for the data presented in this study is difficult to assess.
The previously shown pattern of an inverse relation for the EBV-directed immune response with SLE patients having low percentages of EBV-responding T-cells and high amounts of antibodies, and the reverse for HCs \[[@pone.0193244.ref018]\], was also proposed in the current study for the CMVpp52-directed immune response, however, to a much lesser extent. As previously discussed, it could be speculated that the deficient T-cell response to HHVs (and thereby probably a deficient control of HHV infections), may cause a shift in the immune reaction towards a humoral response in order to compensate for the lacking cell-mediated response. Another reason might be reduced HHV antigen removal subsequent to recurrent reactivations. Irrespective of the function, the observed higher positivity percentages of IgG and IgA antibodies against CMVpp52 in SLE patients further indicates a defect in the CMV-directed immune response, which also was previously shown by Rasmussen et al. with elevated titres of CMVpp52-directed antibodies in another SLE cohort \[[@pone.0193244.ref022]\]. A future study on cell-associated CMV loads in SLE patients would clarify if the immune reaction against CMV is exhausted in SLE patients and the T-cell control of CMV is dysfunctional and therefore results in CMV reactivations and increased viral load. This would also explain the increased lytic cycle antigen CMVpp52-directed antibody titres in SLE patients.
As no correlation was observed between lytic early antigen CMVpp52-responding T-cells and disease activity of the SLE patients, (which previously was demonstrated with the EBV functional homologue lytic early antigen EBV-EA/D-responding T-cells \[[@pone.0193244.ref018]\]), the reduced CMVpp52-responding T-cells might not be involved in the exacerbation of SLE to the same extent as we previously have proposed for the reduced EBV-responding T-cells. However, interestingly, the results on CMVpp52-responding T-cells correlated with the earlier results on EBNA1- and EBV-EA/D-responding T-cells \[[@pone.0193244.ref018]\], which suggested some relation of the viral immune responses. Results propose a similar reaction (or lack of) to the HHV infections in the individuals. These results indicate that the poor control of one virus is reflected in poor control of other HHVs and possibly other viral infections.
The second setup on Luminex-quantified cytokines induced by CMVpp52 (and also HHV6p41) were contradictive to the observed reduced percentages of CMVpp52-responding T-cells by flow cytometry.
Our previous results on cytokines induced by EBV antigens showed that the SLE patients had significantly lower cytokine secretions than HCs regarding numerous T-cell- and/or NK-cell-related cytokines \[[@pone.0193244.ref030]\]. But here we showed that this presumably is specific for the response to EBV antigens, as stimulation with both CMVpp52 or HHV6p41 induced a normal cytokine response pattern in SLE patients regarding both T-cell response-related cytokines (IL12, IFNγ, (IL17)) and also both inflammatory (TNFα, IL17) and anti-inflammatory (IL10) cytokines. However, the small sample size investigated in this study and the chosen methodology comprising whole blood stimulation (and possibly poor antigen-presentation to follow) designate that these results should be interpreted lightly.
The normal basic levels of cytokines in SLE patients (as also seen in the previous study, \[[@pone.0193244.ref030]\]) indicated that the SLE patients without lymphopenia actually have a normal distribution of cytokines without aberrant exaggerated immune stimulation. As previously stated, this ensures that any differences in induction of cytokines upon CMVpp52 and HHV6p41 stimulation are not due to differences in basic levels between the groups.
Stimulation with the negative control, *E*.*coli*-derived β-galactosidase actually induced production of IL10 compared to stimulation with PBS in both SLE patients and HCs, but the induction was significantly lower than by stimulation with HHV antigens, and furthermore, it was similar between the groups. These results are probably not a general effect of LPS from the *E*.*coli* production as not all quantified cytokines were induced precipitously upon β-galactosidase stimulation.
The significant difference between SLE patients and HCs observed upon stimulation with the superantigen SEB, regarding IFNγ, IL17, and TNFα may indicate that leukocytes are generally dysfunctional in the SLE patients, also in those without lymphopenia, and unable to respond properly to the stimuli. The dysfunctional leukocytes presumably comprise macrophages and Th17 cells not able to uphold the inflammatory response to SEB, and perhaps also T-cells and/or NK-cells unable to activate the cell-mediated immune response. Low cytokine responses to SEB in SLE patients were also demonstrated in the previous cytokine secretion study regarding EBV \[[@pone.0193244.ref030]\]. Contrary to this though, is that this was not suggested by the flow cytometric analysis of CMVpp52-responding T-cells where SEB stimulation showed normal responses in SLE patients.
Overall, the contradictive nature of the current results on CMVpp52-directed immune responses in SLE patients with decreased activity of T-cells in the flow cytometric analysis but with normal cytokine-induction measured by Luminex technology could have several reasons. One might be the fact that different SLE patient and HC cohorts were employed in the two setups (with a difference in mean disease activities between the cohorts), or the fact that flow cytometric results are normalized as we are investigating percentages of T-cells, and cytokine results are actual values and not normalized to number of cells or other factors. Another reason might be that the clear dysfunctional immune responses against EBV observed in multiple studies on SLE patients do not apply to the same degree regarding the immune responses against CMV or HHV6. This might be due to the variant but overlapping tropisms of EBV, CMV and HHV6, and thereby differences in infected cells involvement in SLE according to the individual patient's immune profiles. Elevated titres of antibodies to EBV-EA/D and CMVpp52 but not to HHV6p41 have previously been reported in SLE patients by Rasmusssen et al. \[[@pone.0193244.ref022]\]. Perhaps, the main viral contributing agent to the development or exacerbation of SLE in genetically predisposed individuals is the uncontrolled EBV infection, and to a lesser extent CMV infection and probably with no involvement of HHV6 infection. In fact it cannot be ruled out that the observed reduced CMV-induced T-cell activation is an effect of poor antigen presentation in SLE patients.
[^1]: **Competing Interests:**The authors have declared that no competing interests exist.
|
Australia's first Muslim woman to sit in federal parliament has revealed her ex-husband used Islam to stop her getting a divorce.
Anne Aly, the Labor member for the Perth seat of Cowan, said her husband abused her during the 1990s and refused to accept her request for divorce by citing Sharia law.
'I remained married to a man that was being abusive in an abusive relationship for longer than I should have,' she said.
Australia's first Muslim woman to sit in federal parliament (pictured) has revealed her ex-husband used Islam to stop her getting a divorce
'When I did finally get the courage to divorce my husband, as soon as I did start talking about divorce he suddenly found a use for religion and brought up that I couldn't get a civil divorce from him, that I would need to get a Sharia divorce.'
Dr Aly, 51, told the ABC's The Drum program it took her five years to secure a civil divorce.
The Egyptian-born mother-of-two met her husband in Egypt after finishing high school. The pair were living in Perth when he allegedly abused her.
Dr Aly, a former counter-terrorism academic, was commenting on an ABC investigation which found Islamic imams are often unsympathetic to Muslim women caught in violent marriages.
'We need to start listening to the real, lived experiences of women who are forced to stay married to men who are abusive towards them because they cannot have access to a divorce,' she said.
Anne Aly (pictured), Labor MP for Cowan in Western Australia, said her husband abused her during the 1990s and refused to accept her request for a divorce
The Labor backbencher said Islamic imams were too focused on keeping marriages together, even in cases of domestic violence.
'I've had one imam brag to me that he has a 97 per cent success rate at keeping relationships together, regardless of whether they're happy marriages or abusive marriages,' Dr Aly said.
Dr Aly previously told MPs that she had to raise her children with just $400 a fortnight after leaving her violent husband aged 25.
'I haven't forgotten what it's like to stand at the shopping centre counter and return half your shopping because you simply can't afford it that week,' Ms Aly said in parliament in March last year.
'I haven't forgotten what it's like to delve through my purse and pick up coins just to be able to afford essentials like milk and bread.'
|
The Q at Parkside
(for those for whom the Parkside Q is their hometrain)
News and Nonsense from the Brooklyn neighborhood of Lefferts and environs, or more specifically a neighborhood once known as Melrose Park. Sometimes called Lefferts Gardens. Or Prospect-Lefferts Gardens. Or PLG. Or North Flatbush. Or Caledonia (west of Ocean). Or West Pigtown. Across From Park Slope. Under Crown Heights. Near Drummer's Grove. The Side of the Park With the McDonalds. Jackie Robinson Town. Home of Lefferts Manor. West Wingate. Near Kings County Hospital. Or if you're coming from the airport in taxi, maybe just Flatbush is best.
Monday, February 28, 2011
While waiting for the useless walk light at the absurdly dangerous corner of Ocean and Parkside, I noticed the above poster. I spent the rest of the day thinking about it, reading about it. With so much ugly discourse in our country over immigration, and so much economic adversity in our midst, and health care merely a dream for millions...you gotta wonder whether America is really the best destination for those looking for a better life. The more I read, the more I realize that Canada beckons like a giant neon chunk o' tundra.
Living here in Caledonia, you can't swing a dead cat without hitting an "illegal." Or more delicately, we keep the immigration lawyers in diapers. For me, frankly, it's one of the blessings of living here. And how fitting for a Canadian immigrant headhunter like JMED to reach out to Flatbush.
The propaganda, in this case, is largely true. From the Living In Canada website:
For several years now, Canada has been accepting around quarter of a million new Permanent Residents each year. For people with skills, work experience and a good standard of English or French, qualifying for residence is not a huge barrier. Once accepted, you can take pleasure from the fact that you will be free to live permanently in a country consistently rated by the UN as the world's best country to live in.
Furthermore, Canada is the world's second biggest country, rich in natural resources. Despite the abundance of natural wealth, real estate in most Canadian locations is cheap compared with other developed countries. Add to this the fact that Canada's 34 million residents enjoy virtually unlimited recreational opportunities and you might be forgiven for thinking you have found paradise.
Wednesday, February 23, 2011
This little shopping strip on Bedford 'tween Parkside and Clarkson has always struck me as undervalued. The buildings themselves are pretty cute, and the rents have got to be nearly half of Flatbush. Something could nicely compliment Gandhi, the Indian restaurant we choose when the idea of cooking makes us want to poop in our shoes. Get a load of this:
I for one won't miss the chicken/ice cream/feelawful place. Can't say I ever visited the Dry Cleaners. Luckily, the Wet Cleaners is still packing 'em in noon and night and will likely stay put, meaning a business that caters to people in-between loads could be JUST the ticket. Actually, Mike's Pizza seems to do well in that regard. Maybe a detergent store?
As you can see I'm clearly not cut out for the entrepreneurial life. But if you or someone you know is looking for space and has an idea that doesn't need the intense street traffic of Flatbush...this could be just the spot.
Saturday, February 19, 2011
Our neighbors Keith and Beth led the charge for this sign. They split for California, but their dream of a honkless Clarkson lives on. This sign went up without fanfare not long ago. Needless to say, there's been no audible change.
Has anyone ever actually been written up for honking? And why $350? Why not $3,500? Or $350 per honk? I figure the money should go to the neighbors anyway, not the City. It could be deducted automatically from the offender's EZ-Pass, straight into the Clarkson FlatBed Block Association coffers. With that kinda dough our block party could put Dave Chappelle to shame.
I must say that I do look forward to the day when some selfish gridlocked motorist lays on the horn a couple dozen times and I can walk up to his Olds, rap on the glass and point to this sign. Or maybe I'll think better of it.
Friday, February 18, 2011
On my way back from the excellent dentist Carole Germain, of Care Dental on Nostrand near Lenox, I stopped to admire the derring-do of neighbor Kitty and her fearless school of driving on Clarkson tween Bed and Rog:
Frankly I might be more inclined to tell nervous drivers not to drive at all. For their sake and for ours. And what exactly is meant by "easy parking?"
T'was surely a fabulous day - by comparison of course. It was actually a day of mush and wet trash, but it was easy to look past the filth and revel in the relative balm.
This special scene at the curb directly out from the Pioneer "canners" took my breath away. Later in the day it was dutifully scrubbed, but to me this picture captures the moment when Caledonian winter made a U-turn towards Parkside spring.
Thursday, February 17, 2011
Don't know what it is in these Caledonian waters. But I just got an email from Rench of Gangstagrass, a duo that adds to our neighborhood's reputation as the home of genre-splicing crossover music.
With just a day left, you can add your jingoistic vote to Deli Magazine's Artist of the Month calculation. For simplicity's sake, I say go to the Gangstagrass website and listen to a tune before voting. Would you sign a contract without reading it? I thought not. But don't dally. The poll ends tomorrow night.
DISCLAIMER: The Q wouldn't bother recommending anything if there weren't a solid reason to check it out. I ain't no shill and I don't boost for the sake of boosting. These Gangstagrass guys are serious contenders for most ridiculous combination of musical forms - and when it works, it works. Rench's slinky country slide guitar playing clinch's the deal. Not the Rolling Stones, maybe. But a pretty decent showing for "the keepin' it real" side of the park. Rench is at Bedford and Lenox, and yes, that qualifies him as neighbor. Throw rocks at his window and tell him the Q sent ya.
Wednesday, February 16, 2011
Perhaps you've been approached by one of the gentleman preying on your sympathies at our beloved Q at Parkside. One of them, a painfully malnourished drug addict posing as an AIDS stricken father, is particularly galling. If you're not hip to the age-old BABY FORMULA SCAM, let me skool you right now.
Dude or Lady comes up to you with big doe eyes and sobs about how they can't feed their babies. Would you buy them some formula? They don't need cash, mind you. Just go into the store and buy some Enfamil (e.g.) - the powdered formula. Looks kinda like this:
You might be surprised to learn that the canister goes for about $15. But by now, you're hooked. You wouldn't let those babies starve, would you? If you're in deep, you might end up buying a couple.
Turns out formula has a quick cash turnaround on the street, and believe it or not, often gets illegally purchased by some of the less reputable bodegas and markets. Your "father of three" could be smokin' a rock before you get home to catch the latest episode Glee. Actually, he's probably watching it too. Except he's watching it high on crack.
Formula itself is a bit of a scam, of course. Most indigent moms would be MUCH better off breastfeeding - financially, emotionally and developmentally. (Plus, breasts take up much less space in one's kitchen cabinets.) The above picture shows Enfamil's LIPIL brand, the latest "breakthrough" in formula - more breastmilk-like than ever before. (I jest of course; there are many valid reasons to use formula - I ain't no La Leche League Bullyman. Heck, I enjoy a tall glass of formula myself from time to time - goes nice with a plate of teething biscuits.)
I'm fondly remembering my favorite NYC scam I ever encountered. About 20 years ago, I lived on Flatbush at Sixth Avenue - above the since-relocated Royal Video Store. A guy came up to me claiming he had a gig on Long Island, and could I help him get a train ticket so he could make the show. Before I had time to fashion a response, he starts telling me about his band - Spyro Gyra, and how the gig is real important because his son, whose mother hasn't let him see in years, will be there in the front row. It's gonna be a tearful reunion! The story was so far-fetched it HAD to be true, right? I told him to wait downstairs while I went up to grab my wallet. He started to follow me in, and I had to physically restrain him from gaining entry. At that point I caught the glazed manic look in his eyes and came to my senses. At this point, he started asking if he could "borrow" my Sony Walkman to work on a sax part. I persuasively sent him on his smooth-jazzin' way.
Years later, my girlfriend (cum wife) would tell me a story about a man she met outside a rehearsal space. She and her fellow dancer took pity on a guy trying to get home. At first they were suspicious, but he won their trust by telling them he was a musician, trying to get to a gig with his band...Spyro Gyra.
Friday, February 11, 2011
Why go to law school, when you can make easy cash dishing out bogus legal advice to hapless illegal immigrants?
A store on Bedford Avenue near Clarkson called Profimax (sounds like an impotence drug) and another down by Church called Rincher's Bookstore apparently preyed on Haitians following the earthquake. A merciful law designed to help Haitians gain visas following the disaster brought a lot of folks out of the shadows seeking legal work papers. Neighbor Fred Pinard runs Profimax, and duped folks into believing he had the expertise needed to file the paperwork, charging them hundreds of bucks EVEN though many of the immigrants would have qualified to have the fees waived. There's a special place in hell, Fred...
Newly elected AG Eric Schneiderman boasts in the Daily News: "We will continue working aggressively to root out fraud wherever it exists, and that includes bringing those who prey on the immigrant community to justice,"
Great going Eric. And if the past couple of years is any indication, we'll be seeing your name on the ballot for Governor soon enough. Nice to hear some common sense coming out of an elected official about immigrants.
Schneiderman's nanny, housekeeper and gardener could not be reached for comment.
Wednesday, February 9, 2011
Lest we forget our farming roots, the above portrait of the still-standing Erasmus Hall high school on Flatbush 'neath Church shows off its rural environs. To any of you who have peaked inside the gates of the currents Erasmus campus, you've seen the decaying original schoolhouse inside.
The Wall Street Journal reports that some funding has finally been pried loose to get some serious rehab going. It's not nearly enough, but it's a start. I just want to add my voice to the chorus of those saying...WTF? This is the second oldest continuously standing secondary school in the country. It doesn't get much more historic than this. Why isn't this a friggin' museum like Valley Forge or tourist attraction like the Corn Palace of South Dakota?
I mean, you could gather a bunch of wax mannequins of the historic alumni - set them at tables in incongruous groupings. I know you've already heard about some of celebrated Erasmus graduates, but it's impressive when you look at a big ol' list, this one cherry-picked by yours truly.
Some potential tableaux: "Doc" and Special Ed sharing a Courvoisier. Marky Ramone jamming with Neil Diamond. Bobby Fischer playing Mr. Kotter in a game of checkers. Barbra Streisand. I said, Barbra Streisand.
Sunday, February 6, 2011
The fire department battled a blaze this afternoon on Woodruff (#95) just west of Ocean. Sadly, neighbor Martin Johnson, 60, lost his life. Though the 4th floor fire was contained quickly, it wasn't quick enough.
Condolences to the family. Let this be a reminder to us all that when that fire truck barrels down Flatbush, lights flashing and horn blaring -- it ain't no party, disco, or foolin' around.
Friday, February 4, 2011
I was beginning to feel like Paula from that classic movie Gas Light. Newcomers to the neighborhood think I'm nuts for referring to us as Caledonia. But no, Gregory, I'm NOT crazy. Get a load of this:
The "official" street map as you come out of the Q at Parkside station clearly shows a hospital called Caledonia nary three blocks west. Granted, the same map tells of a mysterious "D" train stopping within, and for lovers of talkies there's an RKO movie theater right off the Church Avenue stop. I'm also fond of the way the B16 loop-de-loops round Parkside and St. Paul's Place. They don't even mention the playground at the Parade Grounds. And I'm pretty sure that giant red circle graffiti has been removed. I wonder how many items must become anachronistic for the MTA to redraw the map?
In the meantime, big sale down at the Pioneer. Must be part of their ongoing Anniversary celebration.
Tuesday, February 1, 2011
These signs are EVERYWHERE in our neighborhood. Once you notice the misspelling, you'll always notice them. The number belongs to an Askarinam Realty, which as you'd imagine, doesn't even handle rentals in most of the buildings with this sign.
Still, you gotta wonder how many of these things were printed before someone noticed. I've tried many times over the years to learn to say the word without a vowel between the p and the t. Not so easy, is it? |
B-town’s hot hunk, Rampal, will be seen having a scandalous affair with Kareena Kapoor in Madhur Bhandarkar’s next, Heroine
We’ve just heard some interesting goss from the sets of Madhur Bhandarkar’s Heroine, and we are itching to let this cat out of the bag. The suave villain of Bollywood will be seen having a fling with Kareena Kapoor (who plays the character of a glamorous star). Arjun Rampal confirms the rumour in an interview to a daily, “Well, he is a married superstar and yes, he is having an affair with this very attractive actress.”
Now, we are sure that a lot of our married male stars will squirm at this controversial portrayal! But we are sure that Bhandarkar, who loves to make bold films, is not scared of pushing the envelope. And going by what our birdie on the sets of the film has to say, there are going to be some intimate scenes between Arjun and Kareena! The dishy dude neither agrees nor denies the story, but that’s definitely not going to stop us from speculating, is it? Bebo, who had sworn not to do any intimate and kissing scenes, we hear, has made an exception for this ambitious project. Now, will this steamy affair make the audience squirm in their seats? That totally depends on how Bhandarkar manages to bring out the chemistry between these two actors. Honestly, going by what we’ve seen of them in Karan Johar‘s We Are Family, wethinks they make for a very cold couple. What do you think, Bollywoodlifers? |
Introduction {#Sec1}
============
Metabolic reprogramming has been readily accepted as part of the revised hallmarks of cancer where tumour cells are able to modulate their metabolic pathways to support their unremitting proliferation.^[@CR1]^ Amino-acid transport systems are essential for the growth of cancer cells, not only because they provide amino acids required for protein synthesis but also they activate mammalian target of rapamycin complex 1 (mTORC1), which in turn regulates protein translation and cell growth.^[@CR2],\ [@CR3]^ There is also growing evidence that crosstalk can occur among oncogenes and/or tumour suppressor genes and altering the cancer cell metabolism, including the direct regulation of the solute carrier (SLC) family 3 member 2 (SLC3A2) by the oncogene *MYC*.^[@CR4]^
Recently, membrane transporters have attracted great attention for their crucial roles in cancer proliferation and survival. SLC3A2, also known as CD98hc, is a transmembrane protein, which primarily acts as a chaperone that heterodimerises with a group of amino-acid transporters (e.g., SLC7A5 and SLC7A11) for their functional expression in the plasma membrane.^[@CR5],\ [@CR6]^ SLC3A2 also has a biological role in favouring cancer growth, as it associates and regulates the function of β1 integrins and its overexpression leads to amplification of integrin-dependent signals, which involves extracellular matrix remodelling resulting in promoting tumourigenesis and cell proliferation.^[@CR7],\ [@CR8]^
SLC3A2 is highly expressed in various cancer types, including gastric cancer,^[@CR9]^ osteosarcoma,^[@CR10]^ renal cell carcinoma^[@CR11]^ and biliary tract cancer.^[@CR12]^ Previous studies of SLC3A2 in human breast cancer (BC) showed its prognostic significance but in a limited number of cases.^[@CR13],\ [@CR14]^ To our knowledge there is no prognostic analysis, which involves the impact of SLC3A2 overexpression in large cohorts, including the different BC molecular subtypes.
In this study, we aimed to assess *SLC3A2* gene copy number (CN) and mRNA expression alongside protein expression in large and well-characterised annotated cohorts of BC to determine its clinicopathological and prognostic value with emphasis on the different molecular classes.
Materials and methods {#Sec2}
=====================
*SLC3A2* genomic profiling {#Sec3}
--------------------------
A cohort of 1980 invasive BC in the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC)^[@CR15]^ was used to evaluate *SLC3A2* gene CN aberrations and gene expression. In the METABRIC study, DNA/RNA was isolated from fresh frozen samples and transcriptional profiling was obtained using the Illumina HT-12v3 platforms. Data were pre-processed and normalised as described previously.^[@CR15]^ In this cohort, patients who were oestrogen receptor-positive (ER+) and/or lymph node (LN)-negative did not receive adjuvant chemotherapy, whereas ER− and LN+ patients were offered adjuvant chemotherapy. None of the patients were treated with anti-HER2-targeted therapy. Dichotomisation of *SLC3A2* mRNA expression was determined using the median value as the cutoff point. The association between the *SLC3A2* mRNA expression and clinicopathological parameters, molecular subtypes and patient outcome was investigated.
The online dataset, Breast Cancer Gene Expression Miner v4.0 (<http://bcgenex.centregauducheau.fr>), was used for external validation of SLC3A2 mRNA expression.
SLC3A2 protein expression {#Sec4}
-------------------------
Immunhisotchemistry for SLC3A2 was performed using a well-characterised cohort of early-stage primary operable invasive BC patients aged ≤70 years. Patients presented at Nottingham City Hospital between 1989 and 2006. Patients were managed based on a uniform protocol. Clinical history, tumour characteristics, information on therapy and outcomes are prospectively maintained. Outcome data included development and time to distant metastasis (DM) and BC-specific survival (BCSS).
The clinicopathological parameters for the Nottingham and METABRIC series are summarised in (Supplementary Table [1](#MOESM1){ref-type="media"}).
Western blotting {#Sec5}
----------------
The antibody specificity of anti-SLC3A2 (HPA017980, Sigma-Aldrich, UK) was validated using western blotting in MDA-MB-231 BC lysate (American Type Culture Collection; Rockville, MD, USA) as previously described.^[@CR16]^ A single band for SLC3A2 was visualised at the correct predicted size (80 kDa; Fig. [1a](#Fig1){ref-type="fig"}).Fig. 1Western blotting results for **a** SLC3A2 expression in MDA-MB-231 breast cancer cell lysates and SLC3A2 protein expression in invasive breast cancer cores. **b** Positive IHC expression, **c** negative IHC expression
Tissue arrays and immunohistochemistry {#Sec6}
--------------------------------------
Tumour samples, 0.6 mm cores, were arrayed as previously described.^[@CR17]^ Immunohistochemical staining was performed on 4 μm tissue micoarray (TMA) sections using Novolink polymer detection system (Leica Biosystems, RE7150-K) as previously described.^[@CR16]^
Stained TMA sections were scanned using high-resolution digital images (NanoZoomer; Hamamatsu Photonics, Welwyn Garden City, UK), at ×20 magnification. Evaluation of staining for SLC3A2 was based on a semiquantitative assessment of cores' digital images using a modified histochemical score (*H*-score), which includes an assessment of both the intensity and the percentage of stained cells.^[@CR18]^ Staining intensity was assessed as follows 0, negative; 1, weak; 2, medium; 3, strong and the percentage of the positively stained tumour cells was estimated subjectively. The final *H*-score was calculated multiplying the percentage of positive cells (0--100) by the intensity (0--3), producing a total range of 0--300. Dichotomisation of protein expression was determined using the median value as the cutoff point.
Immunhistochemical staining and dichotomisation of the other biomarkers included in this study were as per previous publications^[@CR17],\ [@CR19]--[@CR27]^ (Supplementary table [2](#MOESM1){ref-type="media"}). ER and PgR positivity was defined as ≥1% staining. Immunoreactivity of HER2 was scored using standard HercepTest guidelines (Dako). Chromogenic in situ hybridisation (CISH) was used to quantify *HER2* gene amplification in borderline cases using the HER2 FISH pharmDx™ plus HER2 CISH pharmDx™ kit (Dako) and was assessed according to the American Society of Clinical Oncology guidelines. BC molecular subtypes were defined, based on tumour immunohistochemical profile and the Elston-Ellis^[@CR28]^ mitotic score as: ER+/HER2− low proliferation (mitotic score 1) and ER+/HER2− high proliferation (mitotic score 2 and 3); HER2-positive class: HER2+ regardless of ER status; triple-negative (TN): ER−, PgR− and HER2−.^[@CR29]^
Statistical analysis {#Sec7}
--------------------
Statistical analysis was performed using SPSS 22.0 statistical software (SPSS Inc., Chicago, IL, USA). Spearman's correlation coefficient was carried out to examine the association between continuous variables. The Chi-square test was performed for inter-relationships between categorical variables. Survival curves were analysed by Kaplan--Meier with log rank test using BC-specific death censoring cases who were lost to follow-up or died of other causes. Cox's proportional hazard method was performed for multivariate analysis to identify the independent prognostic/predictive factors and the proportional hazard assumption was tested with Schoenfeld residuals test to avoid violation of the assumption. The statistical test for heterogeneity was applied to assess the difference between the subtypes. *p*-values were adjusted using Bonferroni correction for multiple testing, whenever applicable. A *p*-value \< 0.05 was considered significant. The study end points were 5-year BCSS or DM-free survival (DMFS).
This study was approved by the Nottingham Research Ethics Committee 2 under the title 'Development of a molecular genetic classification of breast cancer'. All samples from Nottingham used in this study were pseudo-anonymised and collected prior to 2006 and therefore under the Human Tissue Act informed patient consent was not needed. Release of data was also pseudo-anonymised as per Human Tissue Act regulations.
Results {#Sec8}
=======
SLC3A2 genomic profiling in BC {#Sec9}
------------------------------
High SLC3A2 mRNA expression was observed in 961/1858 (52%) of the METABRIC BC cases. In all, 90 (4.5%) of cases showed *SLC3A2* CN gain, whereas 109 (5.5%) showed a CN loss. A significant association was observed between *SLC3A2* CN variation and *SLC3A2* mRNA expression (*p* \< 0.001, Fig. [2a](#Fig2){ref-type="fig"}). There was a positive association between *SLC3A2* CN gain and its regulator, *MYC*, gain (*p* \< 0.001, Supplementary Table [2](#MOESM1){ref-type="media"}).Fig. 2*SLC3A2* expression and its association with copy number aberrations, clinicopathological parameters and molecular subtypes: **a** *SLC3A2* and gene copy number variations; **b** *SLC3A2* and tumour grade; **c** *SLC3A2* and lymph node stage; **d** *SLC3A2* and NPI; **e** *SLC3A2* and PAM50 subtypes; **f** *SLC3A2* and METABRIC integrative clusters
High *SLC3A2* mRNA expression was significantly associated with higher tumour grade (Fig. [2b](#Fig2){ref-type="fig"}, *p* \< 0.001), positive nodal metastasis (Fig. [1c](#Fig1){ref-type="fig"}, *p* \< 0.001) and poor Nottingham Prognostic Index (NPI; Fig. [2d](#Fig2){ref-type="fig"}, *p* \< 0.001). These associations were confirmed using the Breast Cancer Gene-Expression Miner v4.0 (Supplementary Figure [1](#MOESM1){ref-type="media"}A, [1B](#MOESM1){ref-type="media"}).
The correlation of *SLC3A2* mRNA with other relevant genes were investigated using the METABRIC dataset (Supplementary Table [4](#MOESM1){ref-type="media"}). The genes were selected based on previous publications, being either regulatory genes or those that share or support the SLC3A2 biological function focussing primarily on the amino-acid transport system. There was a relationship between *SLC3A2* and the regulatory genes, *ATF4* (*p* = 0.02) and *MYC* with the latter showing significant correlation across all BC subtypes (*p* \< 0.001). High *SLC3A2* mRNA expression was significantly associated with its heterodimers, the glutamine exchanger, *SLC7A5* and, the glutamate transporter, *SLC7A11* (all *p* = 0.002). Nevertheless, the majority of other glutamine transporters were negatively correlated with the *SLC3A2* expression. A similar association was also observed with glutaminase (GLS) enzyme, which mediates the conversion of glutamine to glutamate (*p* \< 0.001). High *SLC3A2* mRNA expression was associated with those tumours where there were *TP53* mutations (*p* \< 0.001, Table [1](#Tab1){ref-type="table"}).Table 1Expression of SLC3A2 in breast cancer and the expression of other molecular biomarkersSLC3A2 (mRNA)SLC3A2 (protein)Low*n* (%)High*n* (%)*χ*^2^(*p*-value)Adjusted *p*-valueLow*n* (%)High*n* (%)*χ*^2^(*p*-value)Adjusted *p*-valueER Negative182 (40.1)272 (59.9)16.138208 (38.1)338 (61.9)44.97 Positive715 (50.9)689 (49.1)(**0.0003**)**0.0009**1051 (54.3)883 (45.7)(1.9 × 10^−11^)**\<0.0001**PR Negative390 (43.6)504 (56.4)14.943708 (46.4)818 (53.6)28.5 Positive507 (52.6)457 (47.4)(**0.001**)**0.002**466 (58.0)337 (42.0)(9.3 × 10^−8^)**\<0.0001**HER2 Negative799 (49.2)826 (50.8)4.1251090 (51.9)1009 (48.1)16.14 Positive98 (42.1)135 (59.9)(**0.04**)0.0894 (38.4)151 (61.6)(0.00005)**\<0.0001**Triple negative No786 (50.7)765 (49.3)21.641082 (53.0)961 (47.0)23.61 Yes111 (36.2)196 (63.8)(**0.000003**)**\<0.0001**156 (39.6)238 (60.4)(0.000001)**0.0001**TP53 mutations Wild type280 (42.1)385 (57.9)37.41N/A Mutation27 (28.7)67 (71.3)(**3.7** × **10**^**−8**^)**\<0.0001**p53 protein NegativeN/A499 (76.7)152 (23.3)40.299 Positive146 (55.5)269 (29.4)(2.1 × 10^−10^)**\<0.0001***P* values in bold means statistically significant
SLC3A2 protein expression in BC {#Sec10}
-------------------------------
SLC3A2 protein expression was observed, predominantly in the membrane of invasive BC cells, with expression levels varying from absent to high (Fig. [1b, c](#Fig1){ref-type="fig"}). Positive SLC3A2 protein expression (\>15 *H*-score) was observed in 50% of the cases.
Table [2](#Tab2){ref-type="table"} summarises the observed associations with high SLC3A2 protein expression, including larger tumour size (*p* = 0.006), high tumour grade (*p* \< 0.001) and poor NPI (*p* \< 0.001). In addition, high SLC3A2 protein was associated with medullary-like tumours (*p* \< 0.001). Regarding BC metastatic sites, high SLC3A2 protein levels were associated with the development of distant metastases to the brain (*p* \< 0.001) while there was no association with developing DM to the bone or lung.Table 2Clinicopathological associations of SLC3A2 expression in breast cancerSLC3A2 proteinLow*n* (%)High*n* (%)*χ*2(*p*-value)Adjusted *p*-valueTumour size ≥2.0 cm526 (47.7)576 (52.3)7.49 \<2.0 cm736 (53.3)646 (46.7)(0.006)**0.03**Tumour grade 1252 (62.7)150 (37.3) 2543 (56.9)412 (43.1)76.34 3466 (41.4)659 (58.6)(2.6 × 10^−17^)**\<0.0001**Lymph node stage 1794 (51.2)756 (48.8) 2350 (50.1)349 (49.9)0.292 3115 (50.2)114 (49.8)(0.86)1.72Nottingham Prognostic Index (NPI) Good481 (58.9)337 (41.1) Moderate611 (48.2)657 (51.8)36.37 Poor167 (42.5)226 (57.5)(8.01 × 10^−7^)**\<0.0001**IHC subtypes ER+/HER2− low proliferation748 (58.0)542 (42.0) ER+/HER2− high proliferation156 (42.9208 (57.1)66.58 Triple negative153 (39.5)234 (60.5)(2.3 × 10^−14^)**\<0.0001**Histological type Ductal (including mixed)1039 (49.5)1060 (50.5) Lobular141 (62.7)84 (37.3) Medullary9 (25.7)26 (74.3)29.73 Miscellanous9 (50.0)9 (50.0)(0.0002)**0.001** Special type59 (57.3)44 (42.7) HER2+94 (38.4)151 (61.6)Site of distant metastasis Brain No648 (72.6)245 (27.4)17.08 Yes25 (46.3)29 (53.7)(0.00003)**0.0002** Viscera No649 (70.4)273 (29.6)5.065 Yes26 (89.7)3 (10.3)(0.02)0.1 Bone No529 (70.9)217 (29.1)0.041 Yes144 (71.6)57 (28.4)(0.839)2.51 Lung No618 (71.7)244 (28.3)1.837 Yes55 (64.7)30 (35.3)(0.175)0.7*P* values in bold means statistically significant
SLC3A2 protein was significantly expressed with high Ki67 and c-MYC expression (*p* \< 0.001, Supplementary Table [5](#MOESM1){ref-type="media"}). SLC7A5, SLC1A5, GLS and PIK3CA were significantly expressed in breast tumours with high expression of SLC3A2 (*p* \< 0.001), while the low expression was associated with high levels of p-mTORC1 (*p* \< 0.001, Supplementary Table [5](#MOESM1){ref-type="media"}). Moreover, high SLC3A2 protein was positively associated with high nuclear p53 protein expression (*p* \< 0.001, Table [1](#Tab1){ref-type="table"}).
SLC3A2 expression in molecular BC intrinsic subtypes {#Sec11}
----------------------------------------------------
High expression of *SLC3A2* mRNA was significantly associated with hormone receptor-negative (ER− and PR−) tumours (*p* ≤ 0.001, Table [1](#Tab1){ref-type="table"}) but not with HER2+ BC. These results were in concordance with the Breast Cancer Gene-Expression Miner v4.0 (Supplementary Figure [1C-F](#MOESM1){ref-type="media"}). Similarly, SLC3A2 protein expression was associated with negative hormone status and HER2+ tumours (all *p* ≤ 0.001, Table [1](#Tab1){ref-type="table"}) and it was highly expressed in TN compared with non-TN tumours (*p* \< 0.001, Table [1](#Tab1){ref-type="table"}).
When comparing the levels of *SLC3A2* CN and mRNA expression in the intrinsic (PAM50) subtype,^[@CR30]^ high mRNA expression was observed in basal-like, luminal B and HER2+ tumours (Fig. [2e](#Fig2){ref-type="fig"}, *p* \< 0.001), whereas *SLC3A2* CN gain was primarily observed in luminal B subtype and to lesser extent in HER2+ and triple negative breast cancer (TNBC) (*p* \< 0.001, Supplementary Table [3](#MOESM1){ref-type="media"}). In the METABRIC Integrative Clusters, high *SLC3A2* mRNA expression was associated with clusters 1 (luminal B subgroup), 5 (ERBB2-amplified) and 10 (TN/basal-like) with proportions 63%, 61% and 65%, respectively (*p* \< 0.001, Fig. [2f](#Fig2){ref-type="fig"}). Association of *SLC3A2* mRNA with the molecular subtypes was confirmed using the Breast Cancer Gene-Expression Miner v4.0 (Supplementary Figure [1G](#MOESM1){ref-type="media"}).
Expression of SLC3A2 protein in the defined molecular subtypes showed a lower expression in the ER+ low-proliferation tumours compared with the other subtypes (*p* \< 0.001, Table [2](#Tab2){ref-type="table"}).
SLC3A2 expression and patient outcome {#Sec12}
-------------------------------------
High SLC3A2 protein expression, but not mRNA, was associated with poor outcome in terms of shorter BCSS (*p* \< 0.001, Fig. [3a, b](#Fig3){ref-type="fig"}). When investigating within the molecular classes, high expression of SLC3A2 protein was predictive of shorter BCSS in ER+ high-proliferation class (*p* = 0.01, Fig. [3d](#Fig3){ref-type="fig"}), and TN tumours (*p* = 0.04, Fig. [3f](#Fig3){ref-type="fig"}). There was no association between SLC3A2 protein and outcome in HER2+ (Fig. [3e](#Fig3){ref-type="fig"}) and ER+ low-proliferation tumours (Fig. [3c](#Fig3){ref-type="fig"}).Fig. 3SLC3A2 and breast cancer patient outcome. **a** *SLC3A2* vs BCSS in all cases, **b** SLC3A2 vs BCSS in all cases, **c** SLC3A2 vs BCSS of ER+ low-proliferation tumours, **d** SLC3A2 vs BCSS of ER+ high-proliferation tumours, **e** SLC3A2 vs BCSS in HER2+ tumours, **f** SLC3A2 vs BCSS in triple-negative tumours
High SLC3A2 protein expression was associated with shorter DMFS (*p* \< 0.001, Supplementary Figure [2A](#MOESM1){ref-type="media"}) and this was only observed in ER+ high-proliferation and TN tumours (*p* = 0.04, Supplementary Figure [2](#MOESM1){ref-type="media"}C, [2E](#MOESM1){ref-type="media"}) but not with other two subtypes (Supplementary Figure [2](#MOESM1){ref-type="media"}B, [2D](#MOESM1){ref-type="media"}).
In multivariate Cox regression analysis, SLC3A2 protein was a predictor of shorter BCSS (*p* \< 0.001, Table [3](#Tab3){ref-type="table"}) independent of tumour size, grade and stage. The same significant result was remained in the ER+ high-proliferation and TN tumours (*p* = 0.01, Supplementary table [6](#MOESM1){ref-type="media"}) when different subtypes were considered. However, heterogeneity test revealed no evidence of a difference in the observed effects for the three aggressive subtypes, ER+ high proliferation, HER2+ and TN tumours, after adjusting the confounding variables (*p* = 0.91 and 0.90 in BCSS and DMFS, respectively; data not shown).Table 3Univariate and multivariate analysis of prognostic variables and SLC3A2 expression in relation to BCSSSLC3A2 proteinUnivariateMultivariateVariableHazard ratio (95% CI)*p*-valueHazard ratio (95% CI)*p*-valueSLC3A2Low vs high2.17 (1.69--2.79)**1.4 **×** 10**^**−9**^1.83 (1.42--2.36)**0.000003**Size\<2 cm vs ≥2 cm2.89 (2.37--3.53)**1.1** × **10**^**−25**^1.55 (1.19--2.01)**0.001**GradeG1 vs G2 and 34.39 (3.55--5.43)**2.5** × **10**^**−42**^4.04 (3.00--5.43)**2.8 **×** 10**^**−20**^Lymph node stageN1 vs N2 and 32.49 (2.21--2.81)**2.2** × **10**^**−50**^2.11 (1.81--2.47)**4.5 **×** 10**^**−21**^*P* values in bold means statistically significant
Discussion {#Sec13}
==========
BC is a heterogeneous disease^[@CR31]^ and the high level of diversity among the various subtypes is reflected on the clinical behaviour, response to therapy and patient outcome. In addition, different subtypes exhibit a disparity in their metabolic pathways and nutritional needs. ER+/luminal tumours are the most common BC subtypes,^[@CR32],\ [@CR33]^ which are also different it terms of disease prognosis and mortality rates.^[@CR32]^
SLC proteins are related to tumourigenesis and drug resistance in cancer cells^[@CR34]^ and SLC3A2 is characterised by its dual effect to promote cancer cell growth and survival. Besides its role in regulating the function of amino-acid transporter systems, it modulates integrin-induced signal transduction, which derives malignant tumour cells' behaviour, including cell spreading and migration.^[@CR35]^
The present study involved a large BC cohort to reveal the significant association between the high SLC3A2 protein expression and the poor prognostic clinicopathological parameters. Furthermore, high SLC3A2 expression was significantly associated with proliferation. This supports the results of previous studies, which reported that these, SLC3A2 and Ki67, are significantly correlated in non-small-cell lung cancer^[@CR36]^ and hypo-pharyngeal squamous cell carcinoma,^[@CR37]^ confirming that SLC3A2 is critical for proliferation in cancer cells.
Regarding the ER+ BC subtypes, SLC3A2 expression was lower in ER+ tumours that have low proliferation compared with the highly proliferative ER+ tumours, and it was associated with poor patient outcome in the latter class only. This is doubtlessly attributable to their aggressive character as well as their heavier nutrient requirements for cell survival and proliferation.
SLC3A2 protein was also highly expressed in TNBC and HER2+, in concordance with Furuya et al.^[@CR14]^ However, the significant association between SLC3A2 protein expression and patient outcome was only restricted to TNBC. In this regard, it has been shown that over-expression of SLC3A2 is actively involved in the proliferation of vascular smooth muscle cells and is necessary for efficient angiogenesis.^[@CR38],\ [@CR39]^ In this study, ER+ high-proliferation and TN tumours showed the most significant positive correlation between the mRNA expression of SLC3A2 and vascular endothelial growth factor B, which maintains the continuity of angiogenesis and thus implicated for the metastatic process.^[@CR40]^ Although the association between HER2+ tumours and patient outcome was not nominally significant, there was no difference in the effect of this subtype and the other aggressive tumour types.
Generally, the association with patient outcome was observed at the protein, but not the mRNA, level. This can be attributed to the post-translational modification, *N*-glycosylation, of the SLC3A2 protein, which is required to make this protein functioning as it is renowned that the glycosylated SLC3A2 (\~80 kDa) is necessary to form the heterodimeric complex, which further assist the amino-acid transport function.
Previous studies have showed regulation of SLC3A2 by other proteins, including the tumour oncogene *c-Myc*.^[@CR4]^ In the current study, the relationship between SLC3A2 and other regulatory proteins in both mRNA and protein expression was investigated. A positive relationship was observed between SLC3A2 and c-Myc, at both protein and mRNA levels and this correlation was observed in all BC subtypes when tested at the mRNA level. However, it was only significant with the ER+ high-proliferation and TN tumours (p = 0.006 and 0.002), respectively, when investigated at the protein level (data not shown).
The heavy chain of SLC3A2 forms a disulphide bond with the light chain of a group of amino-acid transporters mediating their functions in the plasma membrane. The most prominent is the glutamine exchanger (SLC7A5), which imports the essential amino acids to cancer cells in exchange for intracellular glutamine, the procedure that subsequently activates mTORC1.^[@CR2],\ [@CR3]^ Another protein that heterodimerises with SLC3A2 is the cysteine-glutamate transporter (SLC7A11), which potentiates the cellular antioxidant machinery through assisting the glutathione synthesis.^[@CR41]^ This study revealed the depth of the positive correlation between these amino-acid transporters, specifically for SLC7A5, which remained significant in almost all subtypes, apart from in luminal A tumours. Hence, we investigated the association of SLC3A2 with the downstream signal, mTORC1. However, high SLC3A2 protein expression was associated with lower expression of the mTORC1 phosphorylated at ser (2448), which was included in this study, and this attributed to what was confirmed by Cheng et al. that phosphorylation of mTORC1 at ser (2448), which is stimulated by growth factors, was mutually exclusive with mTORC1 phosphorylated at thr (2446), which is regulated by amino acids.^[@CR42]^
This study further investigated the association of SLC3A2 expression with other glutamine transporters, which provide the substrate, glutamine, required to operate the SLC3A2-SLC7A5 heterodimeric complex. GLS, which converts glutamine to glutamate, is the substrate needed for SC3A2-SLC7A11 function. Although the mRNA showed a negative correlation with most glutamine transporters and GLS, the high SLC3A2 protein expression was associated with the higher levels of the glutamine transporter (SLC1A5), SLC7A5 and GLS, indicating a system of functional coupling between these biomarkers at the protein level.
The role of the tumour microenvironment is well-known with respect to disease development and progression, and SLC3A2 appears to have a role in this, as the SLC3A2 heavy chain binds to the cytoplasmic tail of integrin β1, which in turn mediates extracellular matrix remodelling that controls cell spreading, survival and growth.^[@CR43],\ [@CR44]^ The SLC3A2 interaction with integrin is well studied in renal cancer cell^[@CR35]^ and the current study also confirmed the positive correlation between gene expressions in all BC subtypes.
A recent study reported that SLC3A2 influences osteosarcoma growth through the PI3K/AKt signalling pathway^[@CR10]^ and this could be the case in BC as demonstrated by our finding that high levels of SLC3A2 protein is positively associated with PIK3CA expression. Therefore, it appears that all functions of SLC3A2 in BC were associated with poor prognosis and would not be in favour of patients with aggressive subtypes.
Targeting SLC3A2 efficiently decreases colony formation of osteosarcoma cells^[@CR10]^ and affects renal cancer cell growth in vivo.^[@CR35]^ The consequences of blocking SLC3A2 is therefore warranted in the aggressive highly proliferative BC subtypes.
Conclusion {#Sec14}
==========
This study revealed that SLC3A2 was associated with poor prognostic characteristics and poor survival outcome. Over-expression of SLC3A2 appears to play a role in the proliferation and progression of the highly proliferative ER+, HER2+ and TN subtypes of BC, thus it could act as a potential prognostic marker and therapeutic target. Functional assessment is necessary to reveal the specific role played by this membrane protein in the highly proliferative more aggressive BC subclasses.
Electronic supplementary material
=================================
{#Sec15}
Supplementary tables and figures
Electronic supplementary material
=================================
**Supplementary information** is available for this paper at 10.1038/s41416-018-0038-5.
We thank the Nottingham Health Science Biobank and Breast Cancer Now Tissue Bank for the provision of tissue samples. We thank the University of Nottingham (Nottingham Life Cycle 6 and Cancer Research Priority Area) for funding.
The authors declare no competing interests.
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Q:
Using AdMob Adverts with ListAdapter on Android
I am currently developing an app where the main screen hasn't got an actual view as in setContentView(R.layout.myScreen); is used. Instead it uses an XML file which just details a textview which is assigned to an list adapter and fill with data from the database.
Below is the XML file that is used
<?xml version="1.0" encoding="utf-8"?>
<TextView xmlns:android="http://schemas.android.com/apk/res/android"
xmlns:myapp="http://schemas.android.com/apk/res/com.BoardiesITSolutions.PasswordManager"
android:id="@+id/showLogin"
android:layout_width="fill_parent"
android:layout_height="fill_parent"
android:padding="10dp"
android:textSize="16dp">
</TextView>
And below is the code where data is added to the textview list adapter
public class ShowLogins extends ListActivity {
String LOGINS[] = null;
String company = null;
String longClickCompany;
String companyName = "";
String companyURL = "";
String companyUsername = "";
String companyPassword = "";
Boolean passwordEnabled;
public void onCreate(Bundle savedInstanceState)
{
SharedPreferences settings = getSharedPreferences("prefs", 0);
boolean enablePassword = settings.getBoolean("enablePassword", false);
boolean loggedIn = settings.getBoolean("loggedIn", false);
super.onCreate(savedInstanceState);
if (loggedIn)
{
passwordEnabled = settings.getBoolean("enablePassword", false);
setContentView(R.layout.show_login);
//registerForContextMenu(getListView());
addToArray();
setListAdapter(new ArrayAdapter<String>(this, R.id.showLoginBox, LOGINS));
//ListView lv = getListView();
ListView lv = (ListView)findViewById(R.id.show_list_view);
//View myView = findViewById(R.layout.advert);
//lv.addView(myView);
lv.setTextFilterEnabled(true);
lv.setOnItemLongClickListener(new OnItemLongClickListener() {
@Override
public boolean onItemLongClick(AdapterView<?> parent, View view,
int position, long id) {
longClickCompany = ((TextView) view).getText().toString();
return false;
}
});
lv.setOnItemClickListener(new OnItemClickListener() {
@Override
public void onItemClick(AdapterView<?> parent, View view, int position, long id) {
company = ((TextView) view).getText().toString();
StringTokenizer st = new StringTokenizer(company, "\n");
String companyName = st.nextToken();
String username = st.nextToken();
prepareLoadingWebsite(companyName, username);
}
});
}
else
{
Intent intent = new Intent(ShowLogins.this, SplashScreen.class);
startActivity(intent);
}
}
private void addToArray()
{
int totalRows = 0;
int added = 0;
int arrayField = 0;
SQLiteDatabase myDB = null;
Cursor c = null;
Cursor count = null;
try
{
myDB = this.openOrCreateDatabase("PasswordManager", MODE_PRIVATE, null);
count = myDB.rawQuery("SELECT COUNT(*) FROM PASSWORD", null);
if (count.moveToNext())
{
totalRows = count.getInt(0);
}
LOGINS = new String[totalRows];
c = myDB.rawQuery("SELECT * FROM password ORDER BY pas_company ASC", null);
while(arrayField <=2 && c.moveToPosition(added))
{
LOGINS[added] = c.getString(1) + "\n" + c.getString(3);
added++;
}
if (totalRows == 0)
{
AlertDialog.Builder builder = new AlertDialog.Builder(this);
builder.setMessage("No login records have been found.\n\n Press menu > New login to add a record")
.setCancelable(false)
.setPositiveButton("OK", new DialogInterface.OnClickListener() {
@Override
public void onClick(DialogInterface dialog, int which) {
dialog.cancel();
}
});
AlertDialog alert = builder.create();
alert.show();
}
else
{
setListAdapter(new ArrayAdapter<String>(this, R.layout.show_login, LOGINS));
ListView lv = getListView();
lv.setTextFilterEnabled(true);
}
}
catch (SQLiteException ex)
{
Log.d("Database Error", ex.toString());
}
finally
{
myDB.close();
c.close();
count.close();
}
}
A:
When you use ListActivity you get a content layout specified by the system if you don't specify one yourself. Create your own layout for the activity that looks something like this:
<?xml version="1.0" encoding="utf-8"?>
<LinearLayout xmlns:android="http://schemas.android.com/apk/res/android"
android:layout_width="match_parent"
android:layout_height="match_parent"
android:orientation="vertical">
<ListView android:id="@android:id/list"
android:layout_width="match_parent"
android:layout_height="0dip"
android:layout_weight="1" />
<!-- Ad view goes here with layout_width="match_parent" and layout_height="wrap_content" -->
</LinearLayout>
Set it using setContentView as usual. ListActivity needs a ListView with id @android:id/list that it can find if you're using a custom layout. The height=0, weight=1 configuration of the list will give it all remaining space in the layout after the ad's height is measured.
|
<!DOCTYPE html>
<html>
<head>
<title>Testcase for width attribute of colgroup element (bug 434733)</title>
</head>
<body>
<table border="1">
<colgroup width="400"><col width="20%"/><col/></colgroup>
<tr><td>width is 20%</td><td>width is 400</td></tr>
</table>
</body>
</html>
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The Best Fast And Easy Keto Pancake With Cream Cheese And Coconut Flour Hi keto family, I share with you this best recipe of the... |
Q:
PHP array grouping values
I have an array like below
array(0=>A,1=>A,2=>B,3=>B,4=>C,5=>A,6=>A)
My problem is i need to group the same value with multiple occurrence. For example for the above question I need an array like array('A' => (count1=>2,count2=>2), 'B' => (count1=>2), 'C' => (count1=>1)). How can i loop the array
A:
$data = array(0=>A,1=>A,2=>B,3=>B,4=>C,5=>A,6=>A);
$counters = array();
$prev = NULL;
array_walk(
$data,
function ($entry) use (&$prev, &$counters) {
if ($entry !== $prev) {
$prev = $entry;
$counters[] = 1;
} else {
$counters[count($counters)-1]++;
}
}
);
var_dump($counters);
|
Night of the Living Dead 1968 Insert Card Poster Reproduction
$26.99
Night of the Living Dead 1968 Insert Card Poster Reproduction:
14" X 36"
All reproductions are printed full-size (unless otherwise noted) on a heavy weight acid-free archival stock which provides excellent sharpness, color reproduction and similar weight to the original paper stock. Any defects in the original posters (folds, creases, tears, discoloration, etc.) have been digitally removed or corrected to enhance the image and make for a superb print. |
The ancient City of Hattusa is home to megalithic stones, sphinxes, Lions, a mysterious green stone, laser-like drill-holes somehow performed on andesite blocks, and archeological features eerily similar to those found halfway across the world in South America.
The magnificent ruins of this once great city lie near the city of Boğazkale, Turkey. It served as a capital city for the Hittite Empire in the late Bronze Age.
The city had extensive forests and fertile adjacent fields, although its location had two drawbacks: the rivers in the area were not navigable, which impeded river transport, and the proximity to the barbarous Kaskians. According to historical accounts, the kaskas were a permanent and constant threat to Hattusa.
The Hittites occupied the city; a people shrouded in mystery.
The Hittite empire was not small; it stretched as far as the Bosphorus and what is today’s Syria.
This ancient civilization was a significant super-power of the near East, and their military incursions often provoked other great powers such as the ancient Egyptians.
Experts have excavated several ancient texts in Turkey show an intense diplomatic relationship present in distant times between the Egyptians and the Hittites.
One of the most important discoveries at the site has been the cuneiform royal archives of clay tablets, known as the Bogazköy Archive.
These ancient documents consist of official correspondence and contracts, as well as legal codes. Among them, archaeologists also discovered procedures for a cult ceremony, oracular prophecies and even literature of the ancient Near East.
One of the most important ancient tablets discovered on the site, currently on display at the Istanbul Archaeology Museum, details the terms of a peace settlement after the Battle of Kadesh between the Hittites army and the Egyptians ruled under Ramesses II, in 1259 or 1258 BC.
Curiously, this happens to be the first peace treaty in History, and a copy is on display in the United Nations in New York City considered an example of the earliest known international peace treaties.
Archaeological excavations
The first excavations carried out in the area date back to 1906, when the German Archaeological Institute began to work in the ruins of the city, work that has continued uninterrupted until now in the summer archaeological campaigns.
Researchers shave excavated Numerous clay tablets, written in a multitude of languages, such as Luwian or Akkadian, which are the main source for the study of Hittite culture.
The remains excavated so far correspond mainly to the reign of the last Hittite monarchs who modified many ancient temples in order to show the splendor of their empire, taking advantage of the prosperity of that time and the empire’s military power.
The ‘Ups’ and ‘Downs’ of the city
This ancient city went through turbulent times.
Hattusa was initially founded by a people of non-Indo-European language, Hatti, but during the reign of Anitta (XVIII century BC) it hosted aristocrats rebelling against Anitta and was, therefore, destroyed.
Hattusili I reconstructed the city, and it turned it into his capital, to the detriment of Nesa, until the point of which its own name, Hattusili, is related to the name of the city.
All Hattusili’s successors retained the capital at Hattusa, except Muwatalli II who moved him to Tarhuntassa to better defend himself against the Egyptians, but the transfer did not last long, as his son Urhi-Tesub moved the capital back to Hattusa.
One of the constants of Hittite history is the threat of the Kaskas, who, appearing for the first time in the time of Hantili II, came to capture the capital in the time of Arnuwanda I, the Hittites having to wait until Tudhaliya III to reconquer the city.
After the fall of the Hittite Empire (1200 BC, approx.) The track of Hattusa is lost, although it is suspected that the Kaskas or some Phrygian tribe destroyed it.
However, some doubt that.
The end of the Hittite empire came abruptly.
After the destruction of Hattusa, the site remained isolated until it was rediscovered in modern-times.
Curiously, scholars indicate how around the same time when Hattusa destroyed, other great cities of the Near East also faced annihilation. Experts conclude that a set of massive fires brought the city of Hattusa and other sites in the area to their knees.
Great centers were burnt down mysteriously. From cities of Palestine to the fortresses of Syria, and even ancient Egyptian cities of the delta succumbed and were quickly turned to ash.
It remains an enigma as to what exactly occurred during that time, and what kind of army had in their possession such advanced weaponry as to bring down powerful cities.
Some scholars argue that these cities were not burned down by invading armies but were destroyed by a force, not from Earth.
The city of Hattusa was home to formidable walls which were considered among the strongest defensive walls of any bronze age city in the Near East or elsewhere in the ancient world.
This has led some exerts to question whether it is possible that the city of Hattusa was destroyed by perhaps a comet, or asteroid impact in the distant past.
At its peak, the city of Hattusa was home to around 50,000 inhabitants.
Experts in stone masonry
The builders of the ancient city of Hattusa were advanced stonemasons. Evidence of their advanced stone-working skills can be found all over the ruins today.
The Great Temple of Hattusa is notable for a distinct megalithic construction. Its base is made out of massive andesite stone. Other elements include large stones ranging between 6 to 8 meters in length, and weighing well over 50 tons.
Some authors have mentioned how some elements of the Great Temple of Hattusa are eerily similar to design elements found half-way across the world in Peru, at the Qorikancha temple.
But perhaps the most significant mystery– concerning stone masonry–are the enigmatic drill holes found all over the site.
Numerous drill holes–perfectly drilled–have been found across the site. It remains a profound mystery as to how the builders of the city created these nearly perfect holes in andesite stone.
Furthermore, there is no conclusive explanation as to what the purpose of the drill holes was.
Some boulders found at the site include dozens of drill holes; their purpose remains a mystery.
Another great mystery, and perhaps a feature by which Hattusa is best-known is a massive gree-stone boulder, found within the area where the Great Temple once stood.
The enigmatic stone has been the subject f debate among experts who cannot agree on the origins of the stone itself. Some argue that the mysterious boulder was a gift from Ramses II after the peace treaty of Kadesh, however, due to the lack of ancient texts describing it, this theory cannot be proven yet.
The Green Stone is perfectly polished to the point it almost acts as a mirror.
It reflects light, and many people who have touched it say it gives off strange energies.
Many argue that because the green stone is found within the premises of the ancient temple, it may have had a religious function. |
Prep football: Marietta Tigers to play in homecoming game Friday night
September 22, 2011
But one of these East Central Ohio League schools will be halting a three-game slide after a hookup on the gridiron at Don Drumm Stadium at 7:30 p.m. Friday.
The other, of course, will fall to 1-4 at the halfway point of the 2011 campaign.
MHS (1-3 overall, 0-0 in the ECOL) is 1-1 at Don Drumm with a season-opening 29-14 win against Morgan and a 44-24 setback to Warren. The Tigers then went on the road and dropped two straight to Parkersburg High (34-7) and Gallia Academy (31-8), respectively.
Marietta's game against visiting River View will be its ECOL opener. It's also the Tigers' homecoming.
"It is our homecoming game, and we will perform," said first-year MHS head football coach Bob Springer.
At Gallia Academy's Memorial Field last Friday night, MHS was down 18-0 before Tiger tailback Dedder Baker broke one for 57 yards and a score late in the second quarter.
Overall, though, it was a tough night offensively as Marietta managed just 105 total yards. Baker led the way, rushing for 82 yards on 12 carries.
"Mitchel Gearhart blocked his tail off for Baker," Springer said.
Springer also singled out Eddie Kimbrough for his line play on both sides of the ball.
In the air, MHS quarterbacks' Justin Futrell and Anthony Kimbrough combined to have three of their passes picked off.
"It was our worst game offensively," Springer said. "We were constantly either digging ourselves out of a deep hole or trying to correct an offensive mistake."
Austin Gaskins had five punts for a 36-yard average.
Defensively, the Tigers struggled as well as the Blue Devils (3-1) amassed almost 300 yards of total offense. The second half was better, though, as the orange and black limited the home team to one TD.
"The second half was a different story for the defense as the Tigers really stepped up their game," Springer said.
Gearhart and Baker led the defense with a combined 20 tackles and 22 assists. Spencer Frum finished with five tackles and two assists, and Tanner Leach and Nick Spurr were also big hitters.
Marietta, outpointed a combined 65-15 on the road, is hoping its return to Don Drumm, where it's averaging 26.5 points a game this season, is more offensively productive.
The Tigers are hoping to get more stops on defense as well.
Meanwhile, at Warsaw's Don Rushing Stadium - the home gridiron of River View - last Friday night, the Black Bears (1-3, 0-1) suffered a fate similar to Marietta, dropping a 35-7 decision to undefeated Claymont (4-0) of Uhrichsville. Granted, the Mustangs were ranked second in Ohio Division III, Region 11 going into the game. So, the Black Bears definitely had their work cut out for themselves.
River View is coming into Don Drumm, believing it can win (so is Marietta). But the Black Bears will need to be more efficient offensively to accomplish their goal and spoiling the Tigers' homecoming in the process.
Since beating West Muskingum 47-24 in its season opener, River View has been outpointed by the combined total of 131-14 in its last three games to West Holmes (41-7), Cambridge (55-0) and Claymont, respectively.
Against Claymont, junior Clay Holsclaw had River View's lone touchdown, a 74-yard dash to paydirt in the third quarter. The Black Bears actually outgained the Mustangs 140-16 in that period.
Jason Hammond, a senior, is expected to take center snaps for River View. He also does the Black Bears' place-kicking.
"River View is a big, physical team," Springer said. "They run a 3-5 stunting defense and ofensively they run multiple sets." |
Vascular and other tissue calcification in peritoneal dialysis patients.
Cardiovascular disease is the leading cause of mortality in patients with end-stage renal disease (ESRD) and is attributed to a combination of traditional and non-traditional cardiovascular risk factors. In recent years, there has also been an increasing recognition of a very high prevalence of cardiovascular calcification in the ESRD population, including in patients receiving long-term peritoneal dialysis (PD). Numerous observational cohort studies have demonstrated the prognostic importance of cardiovascular calcifications in these patients. The mechanisms are not completely understood, but are likely multifactorial. The present article reviews the prevalence, clinical course, prognostic significance, and some contributing factors for vascular and valvular calcification in ESRD patients, including patients receiving PD therapy. |
;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;
;;
;; MODULE : init-plantuml.scm
;; DESCRIPTION : Initialize PlantUML plugin
;; COPYRIGHT : (C) 2020 Darcy Shen
;;
;; This software falls under the GNU general public license version 3 or later.
;; It comes WITHOUT ANY WARRANTY WHATSOEVER. For details, see the file LICENSE
;; in the root directory or <http://www.gnu.org/licenses/gpl-3.0.html>.
;;
;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;
(use-modules (dynamic session-edit) (dynamic program-edit))
(define (plantuml-serialize lan t)
(with u (pre-serialize lan t)
(with s (texmacs->code (stree->tree u) "SourceCode")
(string-append s "\n<EOF>\n"))))
(define (python-command)
(if (url-exists-in-path? "python3") "python3" "python2"))
(define (python-exists?)
(or (url-exists-in-path? "python3")
(url-exists-in-path? "python2")))
(define (plantuml-launcher)
(if (url-exists? "$TEXMACS_HOME_PATH/plugins/tmpy")
(string-append (python-command)
" \""
(getenv "TEXMACS_HOME_PATH")
"/plugins/tmpy/session/tm_plantuml.py\"")
(string-append (python-command)
" \""
(getenv "TEXMACS_PATH")
"/plugins/tmpy/session/tm_plantuml.py\"")))
(plugin-configure plantuml
(:require (url-exists-in-path? "plantuml"))
(:require (python-exists?))
(:launch ,(plantuml-launcher))
(:serializer ,plantuml-serialize)
(:session "PlantUML"))
|
Gosling Emacs was an Emacs implementation written in 1981 by James Gosling in C; it was the first Emacs implemention to run under Unix. It used "mocklisp" as its extension language, whose syntax appeared similar to Lisp, but which had no lists or other structured datatypes. Gosling initially allowed Gosling Emacs to be freely redistributed, but later sold it to UniPress[?]. Since Gosling had permitted its free redistribution, Richard Stallman used some Gosling Emacs code in the initial version of GNU Emacs[?]. However, since UniPress was now selling Gosling Emacs (which it renamed Unipress Emacs) as a commercial product, it forced Stallman to stop distributing Gosling Emacs source code. Thus all Gosling Emacs code was removed from GNU Emacs in version 16.56.
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A top former White House official on Friday accused President Trump Donald John TrumpSteele Dossier sub-source was subject of FBI counterintelligence probe Pelosi slams Trump executive order on pre-existing conditions: It 'isn't worth the paper it's signed on' Trump 'no longer angry' at Romney because of Supreme Court stance MORE of wrongfully taking credit for the announcement of a strong second quarter economic report.
Richard Stengel, who served as undersecretary of State during the Obama administration, said on Twitter that Friday's economic report should be attributed to former President Barack Obama Barack Hussein ObamaObama warns of a 'decade of unfair, partisan gerrymandering' in call to look at down-ballot races Quinnipiac polls show Trump leading Biden in Texas, deadlocked race in Ohio Poll: Trump opens up 6-point lead over Biden in Iowa MORE.
“Yup, our economy is the envy of the world because Barack Obama steered us out of the Great Recession and set up structures and policies that reduced unemployment and raised GDP,” Stengel wrote.
“You’re just a lagging indicator,” Stengel added, referring to Trump.
Yup, our economy is the envy of the world because Barack Obama steered us out of the Great Recession and set up structures and policies that reduced unemployment and raised GDP. You’re just a lagging indicator. https://t.co/rzOtZuxRUQ — Richard Stengel (@stengel) July 27, 2018
Stengel's remarks came hours after Trump took a victory lap at the White House, touting his policies as drivers of the best economic growth in nearly four years.
“Once again, we are the economic envy of the entire world,” Trump declared from the White House's South Lawn. “As the trade deals come in, one by one, we’re going to go a lot higher than these numbers.”
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According to the Commerce Department, the U.S. economy expanded at a 4.1 percent rate, the highest level since growth hit 5.2 percent in the third quarter of 2014.
Stengel has taken aim at the president before, criticizing Trump for his tweets as proof of his "unfitness for the job."
"He does not see himself as representing the citizens of the United States (that's the job desc) but himself as a kind of petulant emperor who needs to be fawned over to do his job. Unpresidential in the extreme,” Stengel tweeted in response to Trump's tweets riticizing LaVar Ball, the father of a UCLA basketball player arrested in China on shoplifting charges. |
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tx-waco-nwp-wde_1876-12-30_01
VOLUME IY. WACO, TEXAS, SATURDAY, DECEMBER 30, 1876. NUMBER 221.
TERMS OF SUBSCRIPTION:
(StriiUlu in Advance.)
(.’ALLY, per Annum............................... $ 8 00
“ “ 0 months.............................. 4 60
“ “ B mouths............................. 2 50
WEEKLY, per Annum......................... 2 00
Postage- Daily, per annum, B0 cents ad-
.H'lonal; Weekly, per annum, 15 cents addi-l*’
iai.
A cop)’ free to (tvary club of ten.
A copy of tlie Weekly will be sent to the
Master of every Subordinate Grange, he to
'rausrn.it name*} of subscribers and funds
lie rail by Postofflcc Order, registered letter
r bank check. A idress
.1. W. DOWN8,
Waco, Texas.
Yi.'VttKTisisJG Kates—Daily or Weekly.
READ AND REMEMBER!
1 i 1 i | i
in-chk* 'Time!Week M'tL
.i I i
3
Mo’?
6
Mo's
1
Year
1 $1 50 $3 0oj$0 09jl5 00 $35 00i$40 00
i
3
2 00
8 00
5 OOjlO 00 25 00 85 00! 60 00
8 00 14 09 30 00 45 00 80 00
4 4 00 10 00 IS 0J 35 00 55 00 90 00
5 oo
G00
12 00 13 00 40 00 65 00 LOO 00
b 14 00 m oo 45 00 75 eo 110 00
7 7 00 16 00 38 00 50 CO 85 00 120 00
•S 8 00 18 00 30 00 55 00 90 00 130 00
Vi y oo 30 00 33 00 60 00 95 00 140 00
10 10 00 35 00 35 00 65 09 100 00 150 00
15 15 00 35 00 50 00 80 00 125 00 200 00
1 Col. 20 00 40 00 60 00 $100 150 00 250 00
Standing Advertisement! in Local column
36 per cent, additional.
Transient Advertisements 15 cents a line
.'or first Insertion, 7% cents for every subse-quent
insertion.
The ab jve rates are for either the Daily or
Weekly editions; on advertisements in both
* discount of 25 per cent, is allowed.
No advertisements Inserted for less than
1.50.
Obituary notices under 10 linos, free; all
>ver teu lines will be charged at 15 cents a
One.
For 8 hools and Benevolent Institutions,
lalf ratrs.
Trann'entor Legal Advertisements paya-ble
strictly In advance.
Bunding Advertisements are payable
monthly or quarterly in advance, or in Dank-
•hie draft.
■A.klress the Proprietor,
J. W. DOWNS, Waco, Texas.
Professional Cards.
PHYSICIAN AND SUHGE0N
DR. P. W. HIVKH*.
Of South Carolina,
(y^n be always found at the Waco
Bous?. dee7dtf
I J. M. WILLIS . JO8 3. WILLia.
^TILUS A WILLIS.
Flijsiciuiis and Surgeons,
WACO, TEXAS.
Ofi'IOB—Rtvelre’s orug si ore.. Residences
Nos. 40 and 41, South Fourth St. d22Sm
W. F. BUCK. o. I. HAluBEKT.
Dk*KS. BUCK* HALBERT, Office at Graves’ Drug Store.
I>r. Buck can be found at Graves’Drug
su re, day and night.
Dr Halbert can be found at night at Mr.
Journey*8 residence, in East Waco,
noviald&wlm_____________ _
l 5 W. BLACK, M. D.,
PHYSICIAN, NIIBUKON AND OB-
3TKTRIC1AN
I. it or# hi. professional seryices to the
al.-zcus of McLennan county.
Residence and office near Flatroek
crossing, on North Bosque, 10 miles north-west
ol Waco. nvolflw'y
c 8. NELLIS, M. D.,
(Late Surgeon on U. P. R. K.)
Homceopatkist
?HySICI.'lN,SUBGKON AOB8TETRIOAS
Office 27>£ Ati-tlu Avenue, adjoining Dr.
Jl residence, 4J South Third street.
; tj/" special atu.-n.iou given to diseases ol
» uua. OCtld&w8m
l Ft ANS, J. T. PA VT3.
UTVr NS A DAVIS,
lOineysACounselors at Law,
Waco, Texas,
are, in connection, again re.uuied
.ho practice of the law m all its de-j.
q f■ tm a '< t fs. ap!8(i&wtf
H. It. W" SE8, M. U. B. B. UAMLETT, M. B.
YY ILK KS A HAMI.KTT,
Vaysieiaus and Surgeons,
Waco, Texas.
U£t e in Womaok & Kellett’s Drug
Store. I)r. Wilkes’ residanoe. next
ioor to the Cumberland Presbyterian
Chut eh, on Washington street, tiwVreen
Third and Fourth.
Di. llamlett’s residence, opposite Fe-
■> ale College, on Clay street, between
Second and Third. Iulv24d&w3m
yy C. DODSON,
CONSTRUCTIVE AND SUPERVISING
ARCHITECT,
Office Corner South Third St. and Square,
Waco, Texas. fuovlOdtg
DANIEL B. HATCH,
Attorney & Counselor at Law,
Office, 129 West Stiand,
(Osterman Building.] GALVESTON.
sp8dtf.
A. W. EUBANK, W. R. VfVRETT,
gUBANK & VIVRETT,
Attorneys at Law,
Office in the Fort and Trice building, Com-merclal
Row, Waco, Texas
Special attention given to collecting.
sept20dlj
P'OONTAIJN JONES, M. D..
Surgeon and Homeopathic
Physician,
Waco, Texas,
fenders his professional services to
the citizens of Waco and vicinity.
Special attention paid to Obstetrics
and Chronio Disease*.
Office, up stairs, next door to Peter-son
& Blafler, Austin Avenue.
Residence Austin Avenue, between 8th
sal 10th streets.
LARGE SALES, SMALL PROFITS
VOX" Our Motto!
Determined Not to be Undersold!
SANGER BROS.J
New Stock!
Everything Fresh from First Hands!
B
tiaoth
At his Mammoth New Store in the McClelland Row
on Austin Avenue, is offering a Stock of Goods
Unequal ted in this City in
QUALITY. STILE 4ND PRICE !
XjABIESS !
NEWS BY TELEGRAPH.
Associated Press Dispatches.
FROM WASHINGTON.
elected by majorities ranging- from
1100 downwards.
, A Magnificent Selection of Dress Goods, Consisting of Black nod Colored Silks
Beg to inform their numerous P* rona in the City, McLennan and ad joi niiig and Alpacas, Pisplins, Plaids, Suitings, Brocade*, Cashmeres, Merino,, Empress
Counties, that by instn eti >n from their Buyer in the Eastern Mar- | Cloths,
ket their iniment* S ock of Goods now iu Store and A Tempting Display Of FaRCy GOOdS, Drily Arriving
MUST AND SHALL BE REDUCED!
And Sold at Prices
Defying any and ALL COMPETITION I
OUR TOOK
In our New and commodious Building, 80 feet front by 115 feet running back,
is now filler! to its u’most capacity, comprising oae of the
Largest and Best Assorted Stocks
-IN-------
Staple and Fancy
Dry Goods!
BOOTS AND SHOES!
Of Every Description, suttal le for the youngest Infant to the stalwart Farmer,
in either pegged, machine or hand made.
For Boy8, Youths and Men, in Suits from $3 to $50.
Furnishing Goods of Every Style
AND NOVELTY
For the Ladies, Misses, Children, Men or Boys,
From 40c up to $5 a piece.
Trunks, Satchels and Valises in Every Size,
Style and Quality,
From 75 Cents up to Twenty Dollars.
BLANKETS, QUILTS and GUVERLIUS.
EVERY DESCRIPTION OF Carpets, Mattings, Rugs, &c., &c.
w Our Store, the finest iu Central Texas, acknowledged so by men who
have visited most all portions of the State, ib now managed with such precise
and business-like system, and by polite and attentive clerks, that we are ena-bled
to wait on everybody—Large or Small. A child can come to onr Store
and receive the same attention as an adult. Our aim is to please everybody if
possible.
No Trouble to Show Our Goods. Give us a Call
and Satisfy Yourself.
We Employ No Street Drummers.
E. D. Co.voer, P,es. H. E. CoNOKit, V-Pres. A. Wsbexyr, Seo. & Treat
)f ST A
Iron Works
M
Company,
Suoh a* Collars a id Caffs, Rushiags, Ribbo i •. Trimmings, Handkerchiefs,
Scarfs, Shawls, Etc., Etc.
All Kinds of House Furnishing Goods,
Such as Napkins, Quarter Sheetings and Table Linens.
Gentlemen and Boys CLOTHING of Every Description and Quality.
A Splendid assortment of GENTS’ FURNISHING GOODS. Hats and Caps
for Men and Boys, including the Latest Styles.
Also a Splendid Assortment of Ladies', Misses and Childrens’ Hats.
Ladies’, Gentlemens’ and Childrens’ Boots aud Shoes for the Ball Room,
Pavement or Farm.
m~ a fine line of BRUSSELS and other CARPETING.
Trunks and Valises of all kinds.
The Salesmen are all courteous gentlemen.
The friends of Mr. John R. Cox, cue of the oldest and best salesmen iu the
city, will find him ar this Establishment.
No Trouble to Show Goods—Remember the Place.
McClelland how, austin street, waco, texas.
Dealer in
Ury Goods, Shoes, Hats & Notions,
Cooper Building, Austin Avenue,
WACO. TEXAS.
No drumming allowed iu our Establishment,
janf.dv
CORNER OF SEVENI’H AND AUSTIN SI'S., WACO.KTBXAS,
Manufacturers of and Agents for
IMPROVED BALANCE VALVE STEAM ENGINES, BOILERS,
SMOKE STACKS, COTTON GINS
-AND-Iron
and Brass Castiugs, Coru Mills,.Shafting, Pul-lies,
Mill Geariug, Horse Powers, Segments,
and Pinions for Horse Gins and In-dined
Wheels, House Fronts,
Iron Roofing, Tailing for Cemetery Fences,
AND GENERAL IRON WORK.|
IMPROVED EUREKA CAIN MILLS AND EVAPORATORS.
19* Repairing Gins anil other work a specially. Work as low and ,de as (good
l work ae e»n be dehe anywhere, with full g* iffitec. a«7dw2m.
GRAND CONSOLIDATION!
LYONS. LINBENTHAL & CU.,
SUCCESSORS TO
Lyons & Cohn and Llndenthal & Solomon.
Two of the largest DRY GOODS aud CLOTHING Houses in Waco tmvtng
consolidated, the new house is now the largest in the oity or in Cextral Texas.
A large amount of capital invested in their business. Goods by the oar load
are arriving daily. Everything In the line of
Dry Goods, Ladies’ Wear, Trimmings, Ribbons,
Millinery Goods, Etc., Etc.
CLOTHING ol every qu*bly aud price for men aud boys. BDOTS and SHOES
of every style and price lor ladies. Children’s SHOES, Misses’ BOOTS and
SHOES for the Ball Room, Pavement or Farm;. HATS, CAPS and EUR GOODS.
GENTS’ FURNISHING GOODS, including elegant SHIRTS, GLOVES and
NECKTIES. Five large Store Rooms filled with Goads I
There Is nothing In the lino ol Dry Goods, Clothing, Bools and Shoes, Hats aud
Caps, Ladies’Wear, Gents’Furnishing Wear, etc., that they are unprepared to
sell, both at wholesale and retail.
Prices greatly reduced on account of saving in cost of transporting large bills
of goods. Special inducements offered to the wholesale trade. They will fill
any order for goods at satisfactory prices. Every one entering this store will
be treated with the utmost courtesy, by both the proprietors aud theemployees
of the establishment.
LYONS, LINDENTHAL & CO.,
spld4m ;lt and 54 Austin Street, WACO, TFXA
M. L>. HERRING. J. M. ANDERSON.
T>. A. KELLEY.
JERKING, ANDERSON A VKLLEY,
*ucc-sssors to Coke, Herring <& Anderson'
Attorneys at Law,
Waco, Texas.
Office in Odd Fellows’ Buildlug
se5 D2in Wlv
F. H. SLEEPER. W. W. KENDALL.
B. A. JONES.
^DEEPER. JONES * KENDALL.
Attorueys-at-Law,
A ACO, - - - TEX
ug23dl2m.
\D. MANNING,M.D., M. JOSBPHTUAL, M. J j,
\i ANNING & JOSEPHTHAU
Oculists ami Aurists,
Waco, Texas,
At Dr. Clifton’s Office,
a’fiee hours from 9:30 a. m. to 13 m.,
*utt from H :30 to 5 p. m. feb6
A.M, CURTIS, M. D.
Offers his professional services to the eiti
sens of Waco, and McLennan eounty.
Office at J. M. Rtveiro’s Drug Store, No.
7, South.Thlvd street. uovlSdSui
YY PEARRE UNTHICUM,
ATTORNEY AT LAW,
(Offiee In Downs’ Building.)
Waco, Texas.
Special attention given to < \ llee-ions,
etc. ~s.pl: ilj
76! Old Hundred l 76.
—THE—
EXAMINED & PAT HON,
TV ACO, TEXAS,
AND LOUISVILLE
Weekly Courier-Journal
One year for $3.00; two papers for little
more than the price of one. Bend us $3.09
aud receive the best Texas Weekly paper
with the Courier-Journal, the best, wittiest,
orightest and ablest City Weekly In the
ouutry. novlvd&wtf
I JOSEPH WOIJI,
FASHIONABLE
Boot and Shoe Maker.
No. 50 Austin Avenue, Waco.
Finished workmen, and best quality of
material. Satisfaction guaranteed.
ool21 d3m
The Electoral Vote for Bayes, and
the Gubernatorial for Hampton.
Residence for sale—one „f the
most desirable and beautifully located
residences in Waco. Six large, coinforta-ble
rooms, with hall below and up stairs;
perfectly new; tine, large shade trees,
about two acres of ground, all under a
splendid new fence. Stable, out houses, all
new and complete, situated about one huu-dred
aud fifty yards from the business part
of East Waco. Will take pleausure In show-lng
the premises to any one desirous of
purchasing. J3YBON MoKEEN,
datdlOL Bast Wan.
New York, Dec. 29.—The Herald’s
Columbia, S. 0., special says that
the House Committee has, in conclu-ding
its labors here, ascertained that
the Hayes electors have an average
majority of about six hundred votes
over the Tilden electors in this State.
This result was reached early Thurs-day
morning by the accountants of
the committee, and is based upon the
returns of the precinct managers,
and the actual votes cast, as near as
the committee could get at them. It
was with some difficulty that the
sub-committee remaining here could
be persuaded to give this aunounce-ment
to the press, and it was then
qualified by the remark that there
were certain illegal boxes, irregular-itics
and discrepancies that would
have to be considered by the entire
committee when it again assembles
at Washington. The two sub-corn-mittees
at Charleston will meet the
one now here at Florida in a few
days, when the entire committee
will proceed to Washington to com-plcte
its labors. It is safe to say that
the committee will be unanimous in
declaring that the solid electoral
vote of South Carolina was cast for
Hayes and Wheeler on the 7th of No-vember
last.
The committee, while it did not go
into a formal investigation as to the
election ot State officers, was re-quested
to do so incidentally in as-certaining
the facts as to the elec-toral
vote, and it is generally safe to
say that the gentlemen composing it
are almost unanimous in th* opin-ion
that Hampton and the remainder
of Ike Deoaecratio State ticket are
A Memorial to Congress from Got.
Wade Hampton.
Huwli wai Kec-eivedln (be Senate.
Minor Political Topics.
Washington, Dec. 29.—In the Sen-j
ate Mr. G-ordon, of Georgia, pre-
Rented a memorial of Wade Hamp-ton,
Wm. B. Simpson, W. D. Wai-lace,
aud 58 senators and representa-tives
in the General Assembly of
South Carolina, addressed to Con-
| gress and reciting at length the
points which have recently trans-pired
in the State, interference of
the military, etc., and asking Con-gress
to take such action as will
cause a cessation of military inter-ference
in the affairs of the State,
and enable the Governor and legis-lature
to exercise the duties of the
offices to which they were elected.
The memorial having been read Mr.
Gordon moved that it be referred to
the Senate Judiciary committee.
Mr. Freliughuysen moved to amend
so as to refer it to the committee on
Privileges and Elections, instead of
the Judiciary committee.
Pending discussion Mr. Gordon,
by unanimous consent, submitted a
resolution recognizing the Hampton
government as the legal government
of South Carolina, but objection was
made to it by Mr. Morton and
others, aud it was laid over.
The question being on Mr. Fre-linghuysen’s
amendment, twelve
senators voted in the affirmative and
thirteen in the negative.
The chairman presented a tele-gram
from Gen. John A. Logan, of
Illinois, now in Chicago, stating that
he would not be able to return to
Washington in time, as a member
of the special committee, to devise
means for the count of the electoral
vote, and asking to be excused from
further attendance as a member of
said committee. No objection being
made, Mr. Logan was excused, 'and
Mr. Conkling, of New York, was
appointed to fill the vacancy.
There being no quorum present
tlie Senate at 1:80 adjourned toTues-day,
Jan. 2d, as had been previously
determined upon.
House—A memorial was present-ed
asking for an appropriation to
improve the navigation of Red River,
from its mouth to Jefferson, Texas.
It was ordered published in the Con-gressional
Record, and to-morrow a
hill will be introduced appropriate
ing one hundred thousand dollars
for the purpose indicated in the me-morial.
The Republican electoral vote of
Louisiana has been received by mail,
but none from either party yet by
messengers.
Not more than fifty members of
the House were present, and a few
pension bills were the only measures
that passed. No committees met.
SOUTH CAROLINA.
The Result of the Honse Committee’s
Investigation.
FROM LOUISIANA
Slow Progress of the Investigations
at New Orleans.
New Orleans, Dec. 29.—The Sen-ate
sub-committee Was engaged this
morning in hearing rebutting testi-mony
in regard to Ouachita parish.
Saulsbury asked for information in
regard to a seeming inaccuracy in
reference to the statement of the Ro-publican
electors.
The chaii man said that all neces-sary
documents would be furnished.
After hearing one witness the
committee adjourned to Eliza Pinks-ton’s
residence to take her testi-monv.
The House sub-committee is ex-amining
Col. Patton, chairman of
the Democratic Central Committee,
but up to noon were not able to do
much, having no stenographer at.
hand. It is said that the House
committee will re-examine all the
witnesses who have been before the
Senate committee.
Kellogg, in replying to a protest
against barricading the State House,
says that as Governor he assumes
the right to control the approaches
to the House of Representatives.
Tn. Oregon Imbroglio.
Washington, Dec. 29.—The com-mittee
of Privileges and Elections
commenced on the Oregon case to-day.
Chadwick, Secretary of State
of Oregon, testified that the first in-timation
he had of Watts being a
postmaster, was after the election.
The Governor and himself agreed to
be governed in making the lists by
the acts of Congress and the statutes
of Oregon. Heard the arghments
before acting Odell, the republican
elector, testified during the proceed-ings.
Odell was elected President
and Cartwright Secretary. Watts
tendered his resignation, which was
accepted. Cronin then said, “You
refuse to recognize me?” Witness
said, “No sir, but we want the certi-ficates.
You must not think we will
not act with you, and you must
never go .from here and say wo
would not act with you.” Cronin
then left and the college proceeded
to cast the vote, Watts being elected
to fill the vacancy caused in the col-lege
by his own resignation.
Uor4on’a Resolution.
Washington, Dec. 29.—The follow-ing
is Senator Gordon’s South Caro-lina
resolution, which can be called
up by him at any time, and will be
regularly before the Senate:
“Resolved by the Senate, That the
State government now existing in
South Carolina and represented by
Wade Hampton as Governor, is the
lawful government of said State,
that it is republican in form, and that
every assistance necessary to sustain
its proper and lawful authority in
said State should he given by the
United States when properly called
upon for that purpose, to the end
that the laws may be faithfully and
promptly executed, life and property
protected and defended, and all vio-lators
of the laws, State or Na-tional,
be brought to speedy punish-ment
for their crimes.”
The South Carolina memorial will
come “before the Senate again on
Tuesday next.
Condensed Telegrams.
Bremaher, Moore & Co’s large pa-per
mills, at Laurel, Indiana, burn-ed;
loss, li>150,000.
Latest European dispatches indi-cate
no material new developments
in the East.
The ship Harvey Mills caught fire
and w>"* burned at Port Royal, S. C.,
yesterday.
The weather probabilities in the
Gulf States to-day are fair and cleat-weather,
northerly and westerly
winds, with lower temperature.
Haw l» lour iLlver?
Are you troubled with headache?
dullness? incapacity to keep the mind
on any subject? dizzy, sleepy or ner-vous
feelingB? gloomy forebodings? ir-ratability
of temper? oi haveyoua bad
taste in the mouth upon gettiu g up in
he morning? palpitation? unsteady
ppelite? ohoakmg sensation in the
iroat? pains in the side or about the
t luiders or back? coldness of extrem-n
b? If you have any of these eymp- '
ton 8, be sure your liver is out of order,
an go to your druggist, J. M. Riveire,
anu get Dr. Sherman’s Prickly Ash
Bitters—they arc the best and most
pleasant Liver Medicine ever pul up
Sample bottles for trial. iulld w 1 y
Waco National XSattlc.
Waco, Tjbxas, Dec. 1, 1870.
The annual meeting of the stockholders
of thisBauk will take plane at their Banking
House, on Tuesday, the day of January
next, at 10 o’clock, a in.., when an di ction
will be held for directors for the ensuiug
year. Wm. A. Fokt,
dec2tjaul0 President.
------------------- ■■ ■
special Notlie.
To our friends and the public generally
we wish to 6aT we have now In su>re a larger
and more complete stock of furniture than
ever before, and wish to call especial at ten
tlon to our line ol dreeing case suits,
which are unsurpassed in. this market lor
beauty of design and iinish. The prices are
low and the styles are sure to please the
eye. We have &!»o a nice liae of carpet s of
beautiful patterns
UQTl#d4> W3m VV. P. MLahtah <X iiKo |
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That’s basically the whole city. But Max Rose is not running in that district.
Republican attacks take aim at non-white congressional candidates Read more
The 31-year-old military veteran of the war in Afghanistan, running for office for the first time, has a tougher mission. He aims to flip Staten Island, the least well known of New York’s five boroughs, and the only congressional district represented by a Republican in this deep blue city.
Staten Island voted for Donald Trump, the only borough in the president’s hometown to do so, and it wasn’t close: he beat Hillary Clinton there by 17 points.
But Rose, whose well-funded campaign is taking on congressman Dan Donovan, is not fazed. The district, which also includes a slice of Brooklyn, has “consistently voted for the person, not the party”, he said.
“A Democrat cannot win just because that Democrat has a pulse. We don’t find a situation here where a Democrat can win just because of national dynamics,” Rose told the Guardian at his Staten Island campaign office. “Well, guess what? I don’t want to run in a district like that. I don’t want to live in a place like that. People deserve a choice, so we’re giving them one.”
Staten Island, sometimes dubbed the “forgotten borough”, is enough of an outlier within New York that it once voted to secede from the city in a non-binding referendum.
Though registered Democrats outnumber Republicans in the district, it has had a Republican representative for all but two years in the last three and a half decades.
I can’t vote for these Democrats. They’re disgusting. I’m a Donald Trump fan Paul Binder, voter
“It’s just not like the rest of the city. It looks like much of the rest of the country. It’s more suburban than urban,” said Richard Flanagan, a political science professor at the College of Staten Island and the author of Staten Island: Conservative Bastion in a Liberal City.
And so, like in many swing districts around the country, the race features two candidates running as moderates and focusing relentlessly on local issues. “He’s an underdog, but a strong Democrat’s always in striking range,” Flanagan said of Rose. “It’s never been an entirely safe seat for a Republican.”
Outside a ShopRite last week on the island’s south shore, its most conservative bastion, Donovan shook shoppers’ hands and reminded them to vote.
“The national Democratic party doesn’t understand the Democrats here,” he said. “They’ve always voted for me and they’re going to do it again. I’ve done everything I promised them. I’ve done it with integrity. I’ve taken stances that hurt me politically.”
Facebook Twitter Pinterest Dan Donovan talks to Rotary Club members in Staten Island. Donovan has been endorsed by Donald Trump. Photograph: Seth Wenig/AP
He’s counting on registered Democrats like Paul Binder, 61, who enthusiastically greeted his congressman after exiting the supermarket with a cart piled high with groceries. Binder calls himself a “former liberal”, who now dislikes both parties, but especially the Democrats. He likes Donovan because, as the former Staten Island district attorney, “I heard he’s tough on crime, and that’s good enough for me.”
“I can’t vote for these Democrats. They’re disgusting,” Binder said. “I’m a Donald Trump fan.”
Donovan doesn’t bring up Trump too often these days. He says the president has done a “remarkable job”, especially on foreign policy, but stresses that he voted against two crucial pieces of legislation, the GOP healthcare bill and the tax overhaul plan.
Things looked different a few months ago, when Donovan faced a primary challenge from ex-con and ex-congressman Michael Grimm. Grimm held the seat until he pleaded guilty to tax fraud and went to prison in 2015.
Donovan got Trump’s coveted endorsement, and put the president’s name on campaign signs in letters as big as his own, not to mention a two-story billboard promoting the endorsement. He introduced a bill to require every post office in the country to display a picture of Trump.
'There is no more Republican party': will California’s Orange county swing Democratic? Read more
Donovan says nothing has changed: he supports Trump, but puts his constituents first.
Rose sees the shift less charitably. “If Dan Donovan read a poll tomorrow that said he could win this race by wearing an Abolish Ice T-shirt, you’d see Dan Donovan parading around in an Abolish Ice T-shirt,” he said, referring to the movement on the left to abolish the federal Immigration and Customs Enforcement agency.
The challenger has received high-profile endorsements from former president Barack Obama and former vice-president Joe Biden, and a financial boost from his inclusion in the Democratic congressional campaign committee’s Red to Blue program, which targets districts the party thinks it can wrench away from Republican control as it seeks to take over the House of Representatives.
But Rose says he won’t support Nancy Pelosi as the party’s House leader, and is quick to point out he opposes single-payer healthcare insurance, and doesn’t want to abolish Ice. He frequently criticizes the city’s Democratic mayor, Bill de Blasio, who is deeply unpopular on Staten Island.
At his headquarters in a former guitar shop, there are signs from liberal groups promoting abortion rights and opposition to the Citizens United supreme court decision to allow unlimited political spending by interest groups. They share space with handwritten posters listing platform points on infrastructure, gun reform, taxes, healthcare, education and the opioid crisis – a particular worry in a borough where 101 people died of overdoses last year.
New York’s lieutenant governor, Kathy Hochul, joined Rose at his office last week to go after Donovan for his handling of the epidemic, criticizing him for disbanding a narcotics unit in the district attorney’s office and receiving campaign contributions from executives tied to Purdue Pharma, the company that makes Oxycontin. She called his actions “lessons in what not to be doing”.
Rose, who spent almost five years on active duty in the army, led an infantry platoon in Afghanistan. He became a healthcare executive after leaving active duty but remains a member of the national guard, taking a break from the campaign trail in August to complete training.
He is part of a wave of veterans running as Democrats across the country, but in New York City, he is the first combat veteran who signed up after 9/11 who is now running for office.
Democrats wary of 'luxury of hope' in Wisconsin's divided bellwether Read more
Rose was injured when his vehicle hit an improvised explosive device, and says the incident taught him that Congress isn’t completely hopeless. They had appropriated money to make military Strykers more blast resistant. “If I had hit that IED in 2004 instead of 2013, I would have died,” he said. “In this odd way, I’m alive today because Congress got something done. So we know it’s possible.”
There have been no public polls in the race, leaving it a question mark just how close the only competitive race in the city is.
“I think it’s Donovan’s to lose,” said city councilman Joe Borelli, who is one of three Republicans on the 51-member council and known for his outspoken Trump support. “It’s tough to paint him in a way that Staten Islanders don’t like or wouldn’t like. Even a lot of Democrats happen to think Dan is a nice guy and a good congressional representative.” |
Medicare program; Geographical Classification Review Board; procedures and criteria--HCFA. Interim final rule with comment period.
This interim final rule with comment period implements provisions of the Omnibus Budget Reconciliation Act of 1989 establishing the Medicare Geographical Classification Review Board (MGCRB) and sets forth criteria for the MGCRB to use in issuing its decisions concerning the geographic reclassification of hospitals for purposes of payment under the prospective payment system. |
The truth shall set you free, but not this truth
The truth shall set you free, but not this truth
The truth shall set you free, but not this truth
As the drama surrounding Julian Assange escalates, it is worth momentarily distinguishing WikiLeaks from its mercurial founder, and instead asking what WikiLeaks itself means today. Thus far, the story has been cast as a struggle between WikiLeaks and the United States empire. The central issue, then, is whether the publishing of confidential state documents is an act in support of the freedom of information, of the people’s right to know, or an act of terrorism that poses a threat to stable international relations.
But what if this isn’t the real issue? What if the crucial ideological and political battle is going on within WikiLeaks itself – that is, between the radical act of publishing secret state documents and the way this act has been reinscribed into the hegemonic ideologico-political field by, among others, WikiLeaks itself?
This reinscription does not primarily concern “corporate collusion” – i.e., the deal WikiLeaks made with five big newspapers, giving them the exclusive right selectively to publish the documents. Much more important is the conspiratorial mode of WikiLeaks: a “good” secret group attacking a “bad” one in the form of the United States State Department.
From this perspective, the real enemy are those American diplomats who conceal the truth, manipulate the public and humiliate their allies in the ruthless pursuit of their own interests. “Power” is held by the bad guys at the top, and is not regarded as something that permeates the entire social body, determining how we work, think and consume.
WikiLeaks got a taste of this dispersion of power when Mastercard, Visa, PayPal and the Bank of America joined forces with the state to sabotage it. The price one pays for engaging in the conspiratorial mode is to be treated according to its logic. (No wonder theories abound about who is really behind WikiLeaks – the CIA?)
But this conspiratorial mode is supplemented by its apparent opposite, the liberal appropriation of WikiLeaks as another chapter in the glorious history of the struggle for the “free flow of information” and the “citizens’ right to know.” This view reduces WikiLeaks to a radical case of “investigative journalism.” |
FSB organized the second MBA Entrance Examination
In 5-6 November, FPT School of Business (FSB) – FPT University held the MBA entrance examimation for candidates registered in Hanoi. The exam attracted 98 contestants.
Most of contestants highly evaluated the examnination quality such as the consistent exam questions, serious and professional organization, friendly and helpful attitudes of FSB staff that helped decreasing candidate tension. Candidates were enthusiasticly supported from the document preparation to the exam notification.
Besides, those contestants who joined the examination also appreciated the contents of the exams. Mr Nguyễn Văn Linh, a former student of Bank Academy of Vietna, assessed: “I was impressed by the interesting design concept of exams. Questions are very consistent with candidates and open enough to allow contestants to apply their practical experience instead of academic knowledge to answer.”
With three subjects including GMAT, Management and English, FSB’s exams comprise of multiple-choice test to examine general knowledge and essay questions with case studies to classify candidates and evaluate practical understanding. Ms Nguyễn Thu Trang, who is working for Honda, said: “Questions of exams are suitable for candidate abilities and not too difficult to provide many examples connecting knowledge and actual exprerience. There are many exciting questions about cases of hot issues all over the world”.
Many of MBA candidates are leaders or managers of companies. Mr Trần Quốc Oai, a contestant, stated: “My awareness was from many friends of mine and they had good reviews about FSB. That was the reason why I chose this course. I hope to experience and acquire from FSB professionals and lectures”. |
Primatologist Frans de Waal believes that the way humans experience emotion is not unique: "That's a spectrum of behavior that we have, and the same thing is true for many other species." |
Some people say to face your fears. I disagree. I say to look PAST your fears. If you face your fears, that means you focus on them. If you focus on them, they become larger. They become more real. Don’t focus on your fears, focus PAST them. In martial arts board breaking, we don’t focus […]
Have you ever reached for a goal and failed? If so, read on: Just before takeoff, the space shuttle would thrust toward the sky with nearly 16 million horsepower of force. That’s the approximate power of 16 million horses all pulling at the same time! Yet it goes nowhere. It can’t go anywhere. Something is […]
https://terrylfossum.com/wp-content/uploads/2016/09/TerryLogo_02.2_350x280-300x240.png00Terryhttps://terrylfossum.com/wp-content/uploads/2016/09/TerryLogo_02.2_350x280-300x240.pngTerry2018-11-13 19:01:482018-11-13 19:02:25Have you ever reached for a goal... and failed?
As a 45-year Scouter, former Scoutmaster, Vice President for Program for the Inland Northwest Council who represented Boy Scouts of America on a Prime-time network television reality show (and won!), I’m asked all the time about my thoughts about girls joining the Boy Scouts of America, and recently did a quick news story on my way […]
The oldest person on the competition (the token old guy), Terry surprised everyone by WINNING Season 1 of Fox’s new survival reality show, Kicking & Screaming, with his novice partner, Natalie Casanova! Terry represented the entire Boy Scouts of America by wearing his Scoutmaster uniform the entire time on the show. He’s now traveling across […]
https://terrylfossum.com/wp-content/uploads/2016/09/TerryLogo_02.2_350x280-300x240.png00Terryhttps://terrylfossum.com/wp-content/uploads/2016/09/TerryLogo_02.2_350x280-300x240.pngTerry2017-01-28 05:48:482017-02-10 18:26:23Terry to appear in Jungle Survival Reality Show 'Kicking and Screaming' on FOX!
Do not hate people; hate hatred. Do not look down on others; lift them up. Don’t search for attributes that make people different; find the commonality. If we reach out with a fist, we force others to do the same. If we reach out with understanding, we inspire others to do the same. Anger creates […]
A dad came up to me the other day and asked if I would work with his son. It seems his son got caught sneaking a backpack full of booze to school, and was being expelled. The boy is 15. It didn’t end there, though. The complaints were that he was cussing like a […]
https://terrylfossum.com/wp-content/uploads/2016/09/TerryLogo_02.2_350x280-300x240.png00Terryhttps://terrylfossum.com/wp-content/uploads/2016/09/TerryLogo_02.2_350x280-300x240.pngTerry2017-01-07 01:40:102017-01-13 20:02:26BE the man you want your son to be, because he will.
Always make time for those who are most important in your life. Terry L. Fossum Who will be with you at your deathbed? Who will mourn you most when you’re gone? Whose life will have that hole left in it that only you can fill? Your boss? Your coworkers? The boys (or girls) at the […]
https://terrylfossum.com/wp-content/uploads/2016/09/TerryLogo_02.2_350x280-300x240.png00adminhttps://terrylfossum.com/wp-content/uploads/2016/09/TerryLogo_02.2_350x280-300x240.pngadmin2016-11-05 01:05:192016-11-07 20:12:58THIS is most important of all
Excerpts from Terry Fossum’s keynote at the dedication ceremony for the Terry Fossum center in Rwanda, to help train the widows and orphans of the Genocide in marketable skills: “There are those who would tear down; and those who would build. There are those who would spread hate; and those who would spread love. There […] |
ZenithOptimedia has downgraded its global ad spend forecast from 4.6% growth this year to 4.2%, in the light of the “devastating earthquake” in Japan and the political turmoil in the Middle East playing out on the world stage.
The Publicis Groupe-owned global media agency indicated that “these events had immediate consequences for advertising in the affected markets” and pared its 2011 ad spend forecast to $471 billion.
In Egypt – by far the largest ad market to be caught up in the Middle Eastern uprisings – ZenithOptimedia said “there was almost no advertising on TV during the revolution,” and in the aftermath, advertisers have been very careful about the content and placement of their messages.
The network also recorded that Japanese broadcasters replaced almost all commercial ad slots with public service announcements for weeks after the earthquake, and blackouts and distribution problems will hinder media consumption for months to come.
The agency said it did not expect these shocks to derail the global recovery in the long term. However, it expects some of the missing advertising to reappear later in the year, followed by strong growth in these markets in 2012 thanks to the easy comparison with the first quarter of this year.
Japan is forecasted to shrink 4.1% this year, then grow 4.6% next year, while Egypt follows this year's 20% drop with a 12.1% recovery in 2012.
The agency has increased its 2012 forecast from the 5.2% it indicated in December to 5.8%.
This, it said, is partly the result of the expected rebound in Japan and the Middle East, and partly thanks to further strengthening in Western and Central and Eastern Europe, where advertisers are becoming “more confident of the long-term economic prospects.”
The agency said the large disparity in growth rates between developed and developing markets will continue.
It forecasted that North America will grow by an average of 3.1% per year between 2010 and 2013, and Western Europe will grow by 3.5%.
Japan will grow just 0.7% a year, though this obscures the big drop in 2011 followed by the recovery of lost ground over the next two years, according to ZenithOptimedia.
It also forecasted just 0.1% annual growth in the Middle East, as advertisers tread carefully amid political instability. However, Latin America is set to grow by 8.2% a year, Central and Eastern Europe by 12.4%, Asia Pacific by 6.6%, and Asia Pacific, excluding Japan, to grow by 10.2%.
Developing markets – which it defined as everywhere outside North America, Western Europe and Japan – will increase their share of the global ad market from 30.9% in 2010 to 35.1% in 2013.
ZenithOptimedia said there are two “developing” markets in the world's top 10 ad markets, but there will be three in 2013. China, which it forecast will grow at an average 13.6% a year to 2013, will overtake Germany, which will grow at an average 2.4%, to become the world's third-largest ad market in 2011 and stay at that position throughout the forecast period.
China is just over half (54%) the size of Japan, the second-largest ad market, and will be just over three-quarters (77%) of its size in 2013.
Brazil, with 15.4% annual growth, will overtake France, with 2.9%, to take sixth place in 2011. Russia (23.3% growth) will rise from 12th place in 2010 to 10th in 2011, eighth in 2012 and then seventh in 2013.
The agency said that the sheer size of the US – 3.5 times the next-largest market – means it will contribute the most new ad dollars to the global market over the next three years ($14.2 billion), despite its slow growth.
However, the next five-largest contributors are all developing markets: China, which contributes almost as much as the US ($10.8 billion), Russia ($6.9 billion), Brazil ($3.3 billion), India ($2.5 billion) and Indonesia ($2.4 billion).
Overall, developing markets will contribute 62% of new ad dollars over the next three years.
ZenithOptimedia also expects the Internet will overtake newspapers to become the world's second-largest advertising medium in 2013. The agency indicated that this is the first time this has fallen within its forecast period.
Newspaper ad expenditure was still 51% larger than Internet ad expenditure in 2010, but newspaper expenditure is shrinking by 1.4% a year as circulations continue to fall in developed markets, and readers migrate to the Internet.
Internet advertising continues to grow at “breakneck pace,” at a forecast average rate of 14.4% a year between 2010 and 2013.
The agency forecasted that newspaper ad expenditure will fall from $95.2 billion in 2010 to $91.2 billion in 2013, while Internet ad expenditures rise from $63 billion to $94.5 billion in the same period.
This year, display advertising took over from search as the main driver of Internet ad growth, according to the agency.
Display, broadly defined to include online video and social media, has been invigorated by fast-growing sectors, said ZenithOptimedia.
The agency said that affordable, do-it-yourself tools to create streaming video ads have opened online video to small and local advertisers.
Social media sites are also attracting huge audiences though click-through rates, and therefore costs are often very low. ZenithOptimedia said it expects global display ad expenditure to grow at an average of 16.4% a year to 2013, while paid search grows by 12.8% and classified by 10.2%.
TV is by far the largest medium, and continues to increase its market share. TV attracted 40.4% of global ad expenditure in 2010, up from 37.3% five years earlier, and is expected to account for 41.7% in 2013.
Bigger and higher-quality displays and more channels delivered by digital networks mean more people are watching TV than ever, according to the agency network.
It forecasted that global TV ad expenditure will rise from $180.3 billion in 2010 to $216 billion in 2013.
MediaWeek is the sister publication of Direct Marketing News. Both are owned and operated by Haymarket Media. |
Kathmandu: Eight Indian nationals have
been arrested from Nepal`s only international airport in the
capital for possessing fake identity cards and posing as the
staff of the national flag carrier.
They were arrested from the hanger of the Tribhuvan
International Airport (TIA) as their behaviour was suspicious,
according to Superintendent of Police Kedar Rijal, who heads
the Kathmandu Metropolitan Police Circle.
They were posing as the staff of the Nepal Airlines
Corporation (NAC), raising fears over the security at the
airport.
They entered the airport premises claiming they were
working under technical section of NAC, according to Rijal.
We are further investigating the matter, he said.
During preliminary investigation, they told the police
that they paid ransom to the airlines staff to get fake
identity cards.
According to aviation expert, it raises serious
question over the security of the airport. The Kathmandu
airport is frequently used by criminals involved in smuggling
of counterfeit currency notes to India and drug trafficking.
In December 1999, Indian Airlines Flight 814 with 176
passengers was hijacked from TIA by Pakistan-based
Harkat-ul-Mujahideen terrorists and taken to Kandahar in
Afghanistan.
Nepal and India have an open border, allowing their
citizens to travel across the border without any special
document. |
The final leg—Colombo to New York, around the Cape of Good Hope—took 33 days, longer than expected owing to a Force 10 gale in the South Atlantic. I remember the feeling of barely controlled panic as I took my turns at the helm, the unwelcome knowledge that 31 lives depended on my ability to steer a shuddering, heaving 520-foot ship straight into mountainous seas. When the next man relieved me, my hands were too cramped and shaky to light a cigarette. Even some of the older guys, who’d seen everything, seemed impressed by this storm: “Maybe ve sink, eh?” one winked at me, without detectable mirth.
They were Norwegian, mostly, and some Germans and Danskers (sorry, Danes). The mess crews were Chinese. I was awoken on the first cold (November, as it happened) morning by a banging on my cabin door and the shout “Eggah!” It took me a few days to decipher. Eggs. Breakfast.
This was long before onboard TVs and DVD players. Modern freighters, some of which carry up to 12 passengers, come with those, plus three squares a day, plus amenities: saunas, pools, video libraries. If I embarked today as a passenger aboard a freighter, I’d endeavor not to spend the long days at sea—and they are long—rewatching The Sopranos. I prefer to think that I’d bring along a steamer trunk full of Shakespeare and Dickens and Twain. Short of taking monastic vows or trekking into the Kalahari, a freighter passage might just offer what our relentlessly connected age has made difficult, if not impossible: splendid isolation.
You can’t tell what’s aboard a container ship. We carried every kind of cargo, all of it on view: a police car, penicillin, Johnnie Walker Red, toilets, handguns, lumber, Ping-Pong balls, and IBM data cards. A giant crate of those slipped out of the cargo net and split open on the deck as we were making ready to leave San Francisco. A jillion IBM data cards, enough to figure out E = mc2. It fell to me to sweep them into the Pacific. I reflected that at least they made for an apt sort of ticker tape as we left the mighty, modern U.S. in our wake and made for the exotic, older-world Far East.
The crossing took three weeks. I didn’t set foot onshore in Manila until four days after we landed. As the youngest man on board, I had drawn a series of cargo-hold watches. My job, ostensibly, was to prevent the stevedores from stealing, a function I performed somewhat fecklessly. On the last day in Manila, after I’d stood a 72-hour watch, another huge crate slipped its straps and crashed to the deck. Out poured about 5,000 copies of The Short Stories of Guy de Maupassant intended for Manila’s public schools. The stevedores seemed confused as to whether these were worth stealing. By now I was beyond caring. I yawned and told the foreman, “Good book. Go for it.”
At sea in those latitudes, temperatures on the ship’s steel decks could reach 115 degrees. During lunch breaks, I’d climb down the long ladder to the reefer (refrigerated) deck at the bottom of Number Two Hold. There were mounds, hillocks, tons—oh, I mean tons—of Red Delicious apples from Oregon. I would sit on top in the lovely dark chill, munching away, a chipmunk in paradise. One day I counted eating eight. I emerged belching and blinking into the heat, picked up my hydraulic jackhammer, and went back to chipping away at several decades of rust and paint. |
Current status of multidrug resistant tuberculosis in a tertiary care hospital of East Delhi.
Multidrug resistant tuberculosis (MDR-TB) is caused by infection due to Mycobacterium tuberculosis which is resistant to both isoniazid (INH) and rifampicin (RIF). It is caused by selection of resistant mutant strains due to inadequate treatment and poor compliance. MDR-TB is a major public health problem as the treatment is complicated, cure rates are well below those for drug susceptible tuberculosis and patient remains infectious for months despite receiving the best available therapy. The drug susceptibility pattern of M. tuberculosis is essential for proper control of MDR-TB in every health care setting, hence the study was initiated with the aim of studying the prevalence of MDR-TB in patients attending a tertiary care hospital in east Delhi. Five hundred and forty-three pulmonary and extrapulmonary samples from suspected cases of tuberculosis received in the mycobacteriology laboratory from November 2009 through October 2010 were investigated for M. tuberculosis. All the samples were subjected to direct microscopic examination for demonstration of acid fast bacilli followed by culture on Lowenstein-Jensen (LJ) medium to isolate M. tuberculosis. Identification was done by conventional biochemical methods. Drug susceptibility of isolated M. tuberculosis strains was done by conventional 1% proportion method followed by sequencing of RIF resistant isolates to detect mutations to confirm resistance. M. tuberculosis was isolated from 75 out of 543 suspected cases of pulmonary/extrapulmonary TB. Three of the total 75 M. tuberculosis isolates (4%) showed resistance to any one of the first line drugs. Prevalence of MDR-TB was 1.3%. The sequencing of single MDR strain showed mutations at codons 516, 517, and 518. Amplification of rpoB and sequential analysis of the amplicon is a better way of detection of mutation and the evidence of new mutation in this study indicate that mutations continue to arise, probably due to the ability of M. tuberculosis to adapt to drug exposure. |
LONDON - London could not remain Europe’s financial centre if Britain left the European Union at an upcoming referendum, top European politicians said on Monday, warning that reaching a free trade agreement with Britain would not be the bloc’s priority.
A European Union flag and the United Kingdom's Union flag fly outside Europe House, the office of the European Commission in London, Britain January 20, 2016. REUTERS/Stefan Wermuth
Painting a bleak picture for Britain outside the EU during a simulated negotiation of what would happen in the event of an “out” vote, politicians from several European countries said Britain would not be able to “cherry pick” a new deal post-exit.
“There is no such thing as a free lunch. Brexit is something which does not only affect you but affects our country,” said former German deputy finance minister Steffen Kampeter.
“The cherry-picking proposal, after torturing us over months, is not acceptable.”
Kampeter said Germans would not back their government agreeing to a post-Brexit deal that gave London an advantage over Frankfurt as a financial centre, while former Irish Prime Minister John Bruton said Dublin would seek to take London’s crown.
Former Italian prime minister Enrico Letta said Italy would support moving Europe’s financial centre away from London if Britain left the bloc, while France’s Noelle Lenoir, a former minister of European Affairs, said the opportunity to move the EU’s financial hub to a euro zone country “could be a blessing”.
“How can you expect that after you leaving the European economy ... that economy would accept that its financial centre is outside its borders,” said Karel de Gucht, former European Commissioner for Trade, representing the EU institutions in the debate hosted by think tank Open Europe.
Representing Britain, former finance minister Norman Lamont said Britain would seek to cooperate with its former partners in areas such as trade and security, but the other eight countries represented quickly lined up to make clear it would not get an easy ride.
“You were our best friend, and we had a marriage. Now we are divorced,” said former Swedish Minister for Trade Ewa Bjorling.
Bruton said Ireland expected the European Commission “to drive a very tough deal” with Britain in any trade talks, while others said the EU’s priority would be completing existing negotiations such as the TTIP deal with United States.
Others were wary of making exit attractive to increasingly popular anti-EU groups in countries such as France and Spain.
“The common interest of the remaining members is to deter other exits,” said Leszek Balcerowicz, former Deputy Prime Minister of Poland. “This should have an impact on the terms Britain gets - they should not be too generous.” |
This version of the VR short film "Conscious Existence" is meant for personal use only. For LBE (location-based entertainment), events, festivals and other commercial use cases please refer to the mail adress provided in the 'Support Contact Info' section.
[WARNING] The experience contains a scene with flashy/stroboscope-like effects - if you are sensitive to those kind of sensations please use with caution.
And if you, or anyone in your family has an epileptic condition or has had seizures of any kind, consult your physician before playing. |
Superheroes
How To Make An Epic DIY Lamp From Cheap Action Figures from Boredpanda: http://www.boredpanda.com/diy-toy-lamp-avengers-disney/ How To Make An Epic DIY Lamp From Cheap Action Figures After you got that Green Lantern last Christmas, you thought your superhero lamp collection was complete. But you were wrong. Like a real Human Torch, Imgurian downtwobane has set […] |
City
Name
Filtered by Best of Year: Best of Delaware 2010, County: Sussex County, City: Rehoboth Beach, Name: W
Subcategory: 2013: Best Radio Station for News
2013: Best Radio Station for Sports
2012: Best Radio Station for News
2011: Best Radio Station for News Talk
2010: Best Radio Station for News
2009: Best Radio Station for News |
A box is plotted for each month of the year that has data. The extents of the black box mark the
lower quartile (25% of data values are less than this value) and upper quartile (75% of data values
are less than this value), a red line indicates the median, and a dark green line indicates the
mean. The black lines above and below the box, the "whiskers", show the extent of the remaining data
but have a maximum length of 1.5L, where L is the length in meters from the lower quartile to the
upper quartile. Data values that extend beyond the whiskers are "outliers" and are indicated with
red crosses. |
%description:
Test that stray "namespace" words inside cplusplus {{ }} sections do not mess
up parsing.
%file: test_ns.h
namespace std_before { int foo(); };
namespace std_after { int foo(); };
%file: test.msg
cplusplus {{
#include "test_ns.h"
using namespace std_before;
}}
namespace foo;
cplusplus {{
using namespace std_after;
}}
message Dummy {
}
%includes:
#include "test_m.h"
%activity:
// nothing
%contains-regex: test_m.h
.*
using namespace std_before;
.*
namespace foo \{
.*
using namespace std_after;
.*
class Dummy.*
|
/*=========================================================================
*
* Copyright Insight Software Consortium
*
* Licensed under the Apache License, Version 2.0 (the "License");
* you may not use this file except in compliance with the License.
* You may obtain a copy of the License at
*
* http://www.apache.org/licenses/LICENSE-2.0.txt
*
* Unless required by applicable law or agreed to in writing, software
* distributed under the License is distributed on an "AS IS" BASIS,
* WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied.
* See the License for the specific language governing permissions and
* limitations under the License.
*
*=========================================================================*/
#ifndef itkComputeImageExtremaFilter_hxx
#define itkComputeImageExtremaFilter_hxx
#include "itkComputeImageExtremaFilter.h"
#include <itkImageRegionConstIterator.h>
namespace itk
{
/**
* ********************* Constructor ****************************
*/
template< typename TInputImage >
ComputeImageExtremaFilter< TInputImage >
::ComputeImageExtremaFilter()
{
this->m_UseMask = false;
this->m_SameGeometry = false;
}
template< typename TInputImage >
void
ComputeImageExtremaFilter< TInputImage >
::BeforeStreamedGenerateData()
{
if( !this->m_UseMask )
{
Superclass::BeforeStreamedGenerateData();
}
else
{
// Resize the thread temporaries
m_Count = NumericTraits< SizeValueType >::ZeroValue();
m_SumOfSquares = NumericTraits< RealType >::ZeroValue();
m_ThreadSum = NumericTraits< RealType >::ZeroValue();
m_ThreadMin = NumericTraits< PixelType >::max();
m_ThreadMax = NumericTraits< PixelType >::NonpositiveMin();
if( this->GetImageSpatialMask() )
{
this->SameGeometry();
}
else
{
this->m_SameGeometry = false;
}
}
}
template< typename TInputImage >
void
ComputeImageExtremaFilter< TInputImage >
::SameGeometry()
{
if( this->GetInput()->GetLargestPossibleRegion().GetSize() == this->m_ImageSpatialMask->GetImage()->GetLargestPossibleRegion().GetSize()
&& this->GetInput()->GetOrigin() == this->m_ImageSpatialMask->GetImage()->GetOrigin() )
{
this->m_SameGeometry = true;
}
}
template< typename TInputImage >
void
ComputeImageExtremaFilter< TInputImage >
::AfterStreamedGenerateData()
{
if (!this->m_UseMask)
{
Superclass::AfterStreamedGenerateData();
}
else
{
const SizeValueType count = m_Count;
const RealType sumOfSquares(m_SumOfSquares);
const PixelType minimum = m_ThreadMin;
const PixelType maximum = m_ThreadMax;
const RealType sum(m_ThreadSum);
const RealType mean = sum / static_cast<RealType>(count);
const RealType variance = (sumOfSquares - (sum * sum / static_cast<RealType>(count)))
/ (static_cast<RealType>(count) - 1);
const RealType sigma = std::sqrt(variance);
// Set the outputs
this->SetMinimum(minimum);
this->SetMaximum(maximum);
this->SetMean(mean);
this->SetSigma(sigma);
this->SetVariance(variance);
this->SetSum(sum);
this->SetSumOfSquares(sumOfSquares);
}
}
template< typename TInputImage >
void
ComputeImageExtremaFilter< TInputImage >
::ThreadedStreamedGenerateData(const RegionType & regionForThread)
{
if( !this->m_UseMask )
{
Superclass::ThreadedStreamedGenerateData( regionForThread );
}
else
{
if( this->GetImageSpatialMask() )
{
this->ThreadedGenerateDataImageSpatialMask( regionForThread );
}
if( this->GetImageMask() )
{
this->ThreadedGenerateDataImageMask( regionForThread );
}
}
} // end ThreadedGenerateData()
template< typename TInputImage >
void
ComputeImageExtremaFilter< TInputImage >
::ThreadedGenerateDataImageSpatialMask( const RegionType & regionForThread )
{
const SizeValueType size0 = regionForThread.GetSize( 0 );
if( size0 == 0 )
{
return;
}
RealType realValue;
PixelType value;
RealType sum = NumericTraits< RealType >::ZeroValue();
RealType sumOfSquares = NumericTraits< RealType >::ZeroValue();
SizeValueType count = NumericTraits< SizeValueType >::ZeroValue();
PixelType min = NumericTraits< PixelType >::max();
PixelType max = NumericTraits< PixelType >::NonpositiveMin();
if( this->m_SameGeometry )
{
ImageRegionConstIterator< TInputImage > it (this->GetInput(), regionForThread );
for( it.GoToBegin(); !it.IsAtEnd(); ++it )
{
if( this->m_ImageSpatialMask->GetImage()->GetPixel( it.GetIndex()) != NumericTraits< PixelType >::ZeroValue() )
{
value = it.Get();
realValue = static_cast<RealType>( value );
min = std::min( min, value );
max = std::max( max, value );
sum += realValue;
sumOfSquares += ( realValue * realValue );
++count;
}
} // end for
}
else
{
ImageRegionConstIterator< TInputImage > it( this->GetInput(), regionForThread );
for( it.GoToBegin(); !it.IsAtEnd(); ++it )
{
PointType point;
this->GetInput()->TransformIndexToPhysicalPoint( it.GetIndex(), point );
if( this->m_ImageSpatialMask->IsInsideInWorldSpace( point ) )
{
value = it.Get();
realValue = static_cast<RealType>( value );
min = std::min( min, value );
max = std::max( max, value );
sum += realValue;
sumOfSquares += ( realValue * realValue );
++count;
}
} // end for
} // end if
std::lock_guard<std::mutex> mutexHolder(m_Mutex);
m_ThreadSum += sum;
m_SumOfSquares += sumOfSquares;
m_Count += count;
m_ThreadMin = std::min(min, m_ThreadMin);
m_ThreadMax = std::max(max, m_ThreadMax);
} // end ThreadedGenerateDataImageSpatialMask()
template< typename TInputImage >
void
ComputeImageExtremaFilter< TInputImage >
::ThreadedGenerateDataImageMask( const RegionType & regionForThread )
{
const SizeValueType size0 = regionForThread.GetSize( 0 );
if( size0 == 0 )
{
return;
}
RealType realValue;
PixelType value;
RealType sum = NumericTraits< RealType >::ZeroValue();
RealType sumOfSquares = NumericTraits< RealType >::ZeroValue();
SizeValueType count = NumericTraits< SizeValueType >::ZeroValue();
PixelType min = NumericTraits< PixelType >::max();
PixelType max = NumericTraits< PixelType >::NonpositiveMin();
ImageRegionConstIterator< TInputImage > it ( this->GetInput(), regionForThread );
it.GoToBegin();
// do the work
while( !it.IsAtEnd() )
{
PointType point;
this->GetInput()->TransformIndexToPhysicalPoint( it.GetIndex(), point );
if( this->m_ImageMask->IsInsideInWorldSpace( point ) )
{
value = it.Get();
realValue = static_cast<RealType>( value );
min = std::min( min, value );
max = std::max( max, value );
sum += realValue;
sumOfSquares += ( realValue * realValue );
++count;
}
++it;
}// end while
std::lock_guard<std::mutex> mutexHolder(m_Mutex);
m_ThreadSum += sum;
m_SumOfSquares += sumOfSquares;
m_Count += count;
m_ThreadMin = std::min(min, m_ThreadMin);
m_ThreadMax = std::max(max, m_ThreadMax);
} // end ThreadedGenerateDataImageMask()
} // end namespace itk
#endif
|
Naloxone-induced changes in tachykinin NK3 receptor modulation of experimental anxiety in mice.
This study investigates the influence of naloxone, an opioid antagonist, upon the effects of drugs acting on tachykinin NK3 receptor in the elevated plus-maze test. Mice were intracerebroventricularly (i.c.v.) injected either with vehicle, 10 pmol of senktide, an NK3 agonist, or 100 pmol of [Trp7beta-Ala8]NKA(4-10) or SR142801, NK3 antagonists. Senktide alone significantly increased the frequency of entries and the time spent in open arms, an anxiolytic-like effect, whereas the NK3 antagonists alone showed no effect at the dose used. Naloxone alone did not alter the behavior of the animals on the plus-maze apparatus. Nevertheless, animals pretreated with naloxone (2 mg/kg, i.p.) showed an increase in senktide's anxiolytic-like effect and a similar profile of action for [Trp7beta-Ala8]NKA(4-10), but not for SR142801, which presented an anxiogenic-like effect. Altogether, these findings indicate a putative neurokinin-opioid relationship in the modulation of experimental anxiety in mice. |
Introduction
============
Melanoma -- a type of skin cancer -- constitutes a small proportion (\<5%) among different skin cancers, yet accounts for the vast majority of skin-cancer-related deaths [@R1]. An estimated 87 110 new cases of melanoma of the skin were diagnosed in the USA in 2017, with 9730 associated deaths [@R2]. While 5-year survival rates for localized melanoma are over 90%, metastatic melanoma generally has a poor prognosis, with a 5-year survival of 15--20% [@R1].
For a long time, therapeutic options for patients with metastatic melanoma were limited to cytotoxic chemotherapy despite lack of evidence for overall survival benefit [@R3]. Recent advances in molecular diagnostics have enabled identification of several oncogenes as important prognostic markers in metastatic melanoma. Mutation in the *BRAF* (V600) gene is the most commonly identified oncogene, present in ∼50% of cutaneous melanoma cases (*BRAF*+ melanoma) [@R4], with the remaining patients having unmutated BRAF melanoma. The *BRAF* mutation leads to the activation of RAF/MEK/ERK cell-signaling pathways -- the protein product of this oncogene can selectively target metastasized cells and clinically undetected cells that harbor the *BRAF* mutation. *BRAF* gene mutation is an important tool for diagnosis, treatment, and predicting patient outcomes, and may have an impact on prognosis [@R5],[@R6]. The NCCN clinical practice guidelines recommend *BRAF* mutation testing in patients with unresectable or metastatic melanoma to guide treatment decisions as patients harboring a *BRAF* mutation may have different treatment options [@R7]--[@R9].
Molecularly targeted agents have been developed to specifically target *BRAF*-mutated melanoma. Tyrosine kinase inhibitors, vemurafenib, and subsequently, dabrafenib and trametinib monotherapy demonstrated remarkable clinical benefits for patients with advanced or metastatic *BRAF*-mutated melanoma [@R3],[@R10],[@R11], although response durability was variable due to drug resistance [@R12],[@R13]. However, using a combination of *BRAF* and *MEK* inhibitors has led to prolonged response and decreased incidence of secondary skin malignancies compared with *BRAF* monotherapies [@R11],[@R14]. In particular, combination therapy with dabrafenib and trametinib has shown durable long-term overall and progression-free survival in patients with *BRAF*-mutated metastatic melanoma [@R15].
In parallel, advances in immune-oncology, notably the discovery of immune-checkpoints- molecules responsible for dampening immune response, including programmed cell-death protein 1 (PD-1), and cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors, have offered more treatment options for patients with *BRAF*-mutated metastatic melanoma and other melanoma subtypes [@R16],[@R17]. CTLA-4 inhibitors, ipilimumab and tremelimumab, and PD-1 inhibitors, nivolumab and pembrolizumab, have shown survival benefit for advanced or metastatic melanoma regardless of *BRAF* mutation status [@R18],[@R19]. Despite slower initial response and higher risk for severe autoimmune toxicity compared with targeted therapies, some immunotherapies can result in durable long-term survival in patients with metastatic melanoma [@R20],[@R21]. Combination therapy with ipilimumab and nivolumab has shown more rapid response rates and longer overall survival compared with monotherapy [@R22].
With the current repertoire of mono and combination targeted therapies and immune checkpoint inhibitors options for metastatic *BRAF*-mutated melanoma, choosing the appropriate therapy is a complex decision. Current considerations that may influence treatment decisions include various clinical and patient considerations including disease-related symptom burden, performance status, presence of brain metastases, possible adverse events of different agents, or patient preference for oral vs. intravenous medications [@R23],[@R24]. However, in the absence of head-to-head comparisons between immune checkpoint inhibitors and targeted therapies many questions remain unanswered with respect to the optimal treatment sequence in metastatic melanoma [@R23]. A better understanding of treatment patterns and *BRAF* testing in real-world practice is needed to identify unmet needs in this patient population. However, data regarding real-world treatment practices and patterns of *BRAF* testing remain scarce. Using two large commercial claims databases in the USA, this study aimed to describe patterns of *BRAF* testing and treatment with immune checkpoint inhibitors and targeted therapy in patients with metastatic melanoma presumed to have *BRAF* mutations (*BRAF*+) in the years following the approval of the newer generation of immune checkpoint inhibitors and targeted therapies (2014--2016).
Methods
=======
Data sources
------------
The study used data from two large commercial pharmacy and medical claims databases in the USA: the Truven Health Analytics MarketScan (Truven, Ann Arbor, Michigan, USA) and IQVIA (Danbury, Connecticut, USA) Real-World Data Adjudicated Claims -- USA database (IQVIA RWD Adjudicated Claims -- USA). As the two databases cannot be combined, analyses were performed separately on the two samples.
Truven database contains health services claims for more than 230 million individuals from ∼100 employers and several health plans. IQVIA RWD Adjudicated Claims -- US contains health services claims for more than 87 million members from over 100 health plans across the US. Both databases include demographic characteristics, enrollment history, and claims for medical (provider and institutional) and pharmacy services. Truven data are representative of all census regions, predominantly the South and North Central (Midwest) regions. IQVIA RWD Adjudicated Claims -- USA database is representative of the national commercially insured population. Both databases contain data from large employers that tend to have generous coverage, especially for new agents. The databases are fully compliant with the Health Insurance Portability and Accountability Act, and thus, no ethics board review was required [@R25].
Study design
------------
A retrospective cohort design was employed. In both samples, patients were assigned an index date corresponding to the date of initiation of the first immune checkpoint inhibitor(s) or targeted therapy for metastatic melanoma after a diagnosis of melanoma. The baseline period was the 6 months prior to the index date and was extended until the earliest of the end of eligibility (due to disenrollment or death), or the end of data availability (30 June 2016 for Truven and 30 September 2016 for IQVIA RWD Adjudicated Claims -- USA).
Study sample
------------
Both samples (Truven and IQVIA RWD Adjudicated Claims -- USA) included patients with metastatic melanoma as identified by claims for melanoma after 1 January 2014, and a systemic therapy with immune checkpoint inhibitors or targeted therapy for metastatic melanoma. Patients were included in the study if they (a) were at least 18 years old on the index date; (b) had at least one diagnosis of melanoma (International Classification of Disease, 9th ed., clinical modification code 172.xx), from 1 January 2008 to end of data availability specific to each database; (c) had initiated at least one immune checkpoint inhibitor (ipilimumab, pembrolizumab, nivolumab) or targeted therapy (vemurafenib, dabrafenib, trametinib), on or after 1 January 2014 either as monotherapy or as combination regimens; (d) had a first diagnosis of melanoma before or on the index date; (e) had continuous healthcare plan eligibility (including drug coverage) during the baseline period and at least 1 month after the index date; (f) were not enrolled in a clinical trial at any time after the melanoma diagnosis date; and (g) received two or more lines of therapy after the index date, of which at least one line included targeted therapy (i.e. patients were presumed to be *BRAF*+). At least two lines of treatment were required for all patients as those treated with immune checkpoint inhibitors in 1L had to have two or more lines of therapy to be identified as presumed *BRAF*+. A small number of patients who received combined immune checkpoint inhibitors and targeted therapy in first line (\<1%) were excluded (Supplementary Fig. 1A and 1B, Supplemental digital content 1, [*http://links.lww.com/MR/A65*](http://links.lww.com/MR/A65)).
Study measures and statistical analyses
---------------------------------------
All analyses were descriptive. Frequencies and proportions were reported for categorical variables, and means (SD), medians, and ranges were reported for continuous variables. For each of the two samples, reported treatment patterns post-index date included sequence of lines of therapies as well as all treatment regimens used in first (1L), second (2L), and third (3L) lines post-index date. Identification of lines of pharmacological therapy was adapted from previously published algorithms [@R26]--[@R28]. All agents -- single or combination of multiple agents -- received during the first 28 days of the line of therapy start constituted the treatment regimen. For regimens with immune check-point inhibitors (intravenous) the length of a cycle was assumed to be 21 days, while for targeted agents (oral) duration of treatment was based on the days' supply. In both cases, gaps of more than 45 days were allowed between consecutive treatments with the same regimen. Thus, a line of therapy was considered to be discontinued if there was a gap of more than 45 consecutive days without treatment or if a new agent (i.e. new line of therapy) was initiated. In the case of immune check-point inhibitors, gaps up to 180 days were allowed if the patient received steroids. Lines of therapy were censored if the patient was still on treatment at the end of the study follow-up.
The proportion of patients presumed *BRAF*+ for whom *BRAF* testing was performed from the date of first melanoma diagnosis to 2L start, and the timing of *BRAF* testing by sequence of therapy were described. Identification of *BRAF* testing was based on procedure codes for *BRAF*-specific and sequencing tests \[i.e. *BRAF* gene analysis and other multigene sequencing tests did not include immunohistochemistry (IHC)\]. Procedure codes for *BRAF*-specific testing also captured other methods of *BRAF* testing including the Droplet Digital PCR test (Bio-Rad, Hercules, California, USA) and Idylla *BRAF* Mutation Test (Biocartis, Mechelen, Belgium). Patient characteristics during the baseline period, including demographic characteristics, underlying tumor burden, comorbidities, and healthcare utilization and costs were outlined by the type of therapy received in 1L in patients with and without a BRAF test claim before 1L initiation.
Results
=======
A total of 2231 and 2632 patients with at least one diagnosis of melanoma and at least one immune checkpoint inhibitor administration or dispensing of targeted therapy on or after the index date were identified from the Truven database and IQVIA RWD Adjudicated Claims -- USA database, respectively. From these, 162 patients from the Truven database, and 247 patients from the IQVIA RWD Adjudicated Claims -- USA database with metastatic melanoma and presumed *BRAF*+ met the inclusion criteria and were included in the study (Supplementary Fig. 1A and 1B, Supplemental digital content 1, [*http://links.lww.com/MR/A65*](http://links.lww.com/MR/A65)). In the Truven sample, mean age was 56 years and ∼60% of the patients were men. In the IQVIA RWD Adjudicated Claims -- USA sample, mean age was 53 years and ∼62% were men.
Treatment patterns
------------------
In the Truven sample, 107 (66%) of presumed *BRAF*+ patients were initiated in 1L on targeted therapies and 55 (34%) were initiated on immune checkpoint inhibitors (Fig. [1](#F1){ref-type="fig"}a). In 2L, 86 (55%) and 61 (38%) received targeted therapy and immune checkpoint inhibitors, respectively; seven (4%) were treated with combination targeted therapies and immune checkpoint inhibitors in 2L. Fifty percent of patients treated with targeted therapy in 1L switched to immune checkpoint inhibitors in 2L and 78% of patients receiving immune checkpoint inhibitors in 1L switched to targeted therapy in 2L (Fig. [1](#F1){ref-type="fig"}a). In the IQVIA RWD Adjudicated Claims -- USA sample, 152 (62%) of presumed *BRAF+* patients were initiated on targeted therapy and 95 (38%) were initiated on immune checkpoint inhibitors (Fig. [1](#F1){ref-type="fig"}b). In 2L, 124 (50%) and 77 (31%) received targeted therapy and immune checkpoint inhibitors, respectively; 29 (12%) were treated with combination targeted therapies and immune checkpoint inhibitors in 2L. Forty-two percent of patients treated with targeted therapy in 1L switched to immune checkpoint inhibitors in 2L and 73% of patients receiving immune checkpoint inhibitors in 1L switched to targeted therapy in 2L (Fig. [1](#F1){ref-type="fig"}b).
{#F1}
Figure [2](#F2){ref-type="fig"} depicts the distribution of specific treatment regimens by line of therapy. In both Truven and IQVIA RWD Adjudicated Claims -- USA samples, during the 2014--2016 study period, the most common immune checkpoint inhibitor regimen used in 1L and 2L was ipilimumab monotherapy, while pembrolizumab monotherapy was the most common immune checkpoint inhibitor regimen in 3L. Dabrafenib and trametinib combination therapy was the most commonly prescribed targeted therapy in 1L, 2L, and 3L (Fig. [2](#F2){ref-type="fig"}a and b).
![Distribution of immune checkpoint inhibitors (I-O), targeted therapy (TT), and other regimens by line of therapy: (a) Truven sample, (b) IQVIA Real-World Data Adjudicated Claims -- USA sample. Other combinations include: nonstandard combinations of I-O or TT drugs, combinations of I-O or TT drugs with other antineoplastic agents, I-O in combination with TT (not in 1L by design), or other antineoplastic agents (not in 1L by design) [@R1]. 1L, first line of therapy post-index; 2L, second line of therapy post-index; 3L, third line of therapy post-index.](cmr-29-301-g002){#F2}
BRAF testing
------------
In the Truven sample, 100 of 162 (62%) of presumed *BRAF*+ patients had a *BRAF* test claim between melanoma diagnosis and 2L, including 57% of patients who initiated targeted therapy and 56% who initiated immune checkpoint inhibitors. The majority of those with a *BRAF* test claim (92%) had the test between the first melanoma diagnosis and 1L initiation (Table [1](#T1){ref-type="table"}). In the IQVIA RWD Adjudicated Claims -- USA sample, 168 of 247 (68%) of presumed *BRAF*+ patients had a *BRAF* test claim between melanoma diagnosis and 2L, inclusive of 65% of patients who initiated targeted therapy and 61% who initiated immune checkpoint inhibitors; 94% were tested between first melanoma diagnosis and 1L initiation (Table [1](#T1){ref-type="table"}).
######
Timing of *BRAF* testing by treatment sequence
Table [2](#T2){ref-type="table"} describes the characteristics of patients presumed to be *BRAF+* with and without a *BRAF* test claim before 1L initiation stratified by type of therapy received in 1L, in the Truven and IQVIA RWD Adjudicated Claims -- USA samples, respectively. In the Truven sample, among those with claim(s) for *BRAF* test, the proportion of patients with emergency department visits and renal disease during the baseline period was significantly higher in patients who initiated targeted therapy compared with those who initiated immune checkpoint inhibitors (*P*\<0.05). Likewise, in the IQVIA RWD Adjudicated Claims -- USA sample, among those with claim(s) for *BRAF* test, the proportion of patients with inpatient admissions was significantly higher among patients who initiated targeted therapy compared with those who initiated immune checkpoint inhibitors (*P*\<0.05). No statistically significant differences were observed between patients treated in 1L with immune checkpoint inhibitors versus targeted therapies among those without a *BRAF* test claim prior to 1L.
######
Patient characteristics stratified by *BRAF* testing and treatment used in 1L
Even though not statistically significant, a tendency towards more patients with brain metastases, anemia, immune diseases, and liver disease was observed among patients treated with targeted therapies in 1L as compared with patients treated with immune checkpoint inhibitors in 1L, especially in the Truven sample. At the same time, there were numerically more patients with cardiovascular diseases among those treated with immune checkpoint inhibitors than those treated with targeted therapies. In both samples, more than half of the patients who did not have a claim for *BRAF* test before 1L initiation had claim(s) for IHC test in the same period.
Overall, in the Truven sample, patients with a *BRAF* test claim prior to 1L initiation had more brain metastases, a higher number of metastatic sites, and higher Charlson comorbidity score than patients who did not have a claim for *BRAF* test prior to 1L initiation (Supplementary Table 1A, Supplemental digital content 1, [*http://links.lww.com/MR/A65*](http://links.lww.com/MR/A65)). They also had higher all-cause cost during the baseline period, and more IHC tests before 1L initiation. In the IQVIA RWD Adjudicated Claims -- USA sample, patients with a *BRAF* test claim prior to 1L initiation had more surgeries, a higher number of metastatic sites, and more IHC tests before 1L than patients who did not have a claim for *BRAF* test prior to 1L initiation (Supplementary Table 1B, Supplemental digital content 1, [*http://links.lww.com/MR/A65*](http://links.lww.com/MR/A65)). They also had a tendency towards having more brain metastases, although this was not statistically significant.
Discussion
==========
This study documents patterns of treatment and *BRAF* testing among patients diagnosed with melanoma and presumed *BRAF*+ in a real-world clinical setting. A higher proportion of patients presumed to be *BRAF+* were treated with targeted therapy than immune checkpoint inhibitors in 1L and subsequent lines. Approximately two-thirds of presumed *BRAF+* patients received targeted therapy in 1L and half received targeted therapy in 2L. Although recently approved targeted therapies and immune checkpoint inhibitors were commonly used; surprisingly, older agents particularly ipilimumab monotherapy, continued to be used for some patients during the study period. Only two-thirds of patients presumed to be *BRAF*+ had a *BRAF*-specific or sequencing test between melanoma diagnosis and 2L, although many of those without a *BRAF*-specific or sequencing test had an IHC test. Among patients who had a claim for a *BRAF* test, over two-thirds received targeted therapy in 1L.
Studies of treatment patterns specifically among patients with *BRAF*-mutant metastatic melanoma in real-world settings remain scare. To our knowledge, no study to date has examined patterns of *BRAF* testing among patients with metastatic melanoma in real-world settings, with the exception of one study that investigated treatment patterns and outcomes in *BRAF*-mutant melanoma patients with brain metastases receiving vemurafenib, a subgroup of patients that is likely not representative to all patients with metastatic melanoma [@R29]. Furthermore, there are no head-to-head comparisons between targeted therapies and immune checkpoint inhibitors in metastatic melanoma [@R23], even though there is evidence showing efficacy of both targeted therapy and immune checkpoint inhibitors relative to older therapies in 1L [@R19],[@R30],[@R31]. Therefore, past studies are of limited relevance to the present study that describes treatment patterns in a broader population of melanoma patients presumed *BRAF*+-treated with a wide range of targeted or immune checkpoint inhibitors regimens in real clinical practice.
In the absence of hard evidence of optimal treatment sequence, it remains unclear how physicians select 1L and subsequent treatments in real-world settings and which treatments are favored by the physicians at present [@R23]. The results of the current study suggest approximately two-thirds of patients presumed to be *BRAF*+ receive targeted therapy in 1L and subsequent lines of therapy, while approximately one-third receive immune checkpoint inhibitors. Furthermore, some patients appear to continue to be treated with older therapies (i.e. ipilimumab, targeted agents in monotherapy) even after the approval of the new generation of immune checkpoint inhibitors and targeted therapies. A proportion of patients treated with targeted therapy in 1L continued on targeted therapy in 2L. The reasons for discontinuing or restarting a treatment regimen are not known in claims data and our study algorithm counts as a different line of therapy if the patient restarts one or more agents from the initial regimen after a gap of more than 45 days without treatment (in Truven this pattern was observed for 53.5% of patients who received targeted therapy in both 1L and 2L; in IQVIA RWD Adjudicated Claims -- USA sample the pattern was observed for 30.9%). For the remaining patients in both samples, 2L included at least one new agent (i.e. either an add-on to the regimen used in 1L or a switch to a completely new regimen; for 18.6 and 30.9%, respectively, the change was from vemurafenib monotherapy in 1L to regimens with newer agents in 2L).
The choice of treatment in this patient population is likely influenced by numerous patient-specific and treatment-specific factors such as patient's tumor and comorbidity profile, treatment adverse effects profile, as well as physician preference. The present study suggests that targeted therapy may be channeled towards more frail patients with higher comorbidity burden including those with brain metastases. Patients receiving targeted therapy had a higher comorbidity burden compared with those receiving immunotherapy in the IQVIA RWD Adjudicated Claims -- USA sample; in the Truven sample, the proportion of patients with brain metastases was numerically higher among patients receiving targeted therapy compared with those receiving immune checkpoint inhibitors (all patients regardless of *BRAF* testing: 39 vs. 22%, *P*=0.02). Healthcare utilization \[emergency department visits (Truven sample) and inpatient admissions (IQVIA RWD Adjudicated Claims -- USA sample)\] during the baseline period, which may be indicative of higher comorbidity burden, was also higher among patients who were treated with targeted therapy compared with those who received immune checkpoint inhibitors. Previous studies also suggested that the underlying comorbidity and tumor burden are important clinical factors influencing treatment choice. For example, in cases of extensive or rapidly progressing visceral metastases or high disease-related symptom burden, targeted therapy may be favored to achieve rapid response and disease stabilization [@R32]. Similarly, in the setting of brain metastases, targeted therapy may be favored over immune checkpoint inhibitors based on the numerous studies supporting its use in this patient population [@R33]--[@R35]. However, immune checkpoint inhibitors were also shown to have activity in this setting [@R36], which may partly explain why some patients with brain metastases in this study received immune checkpoint inhibitors.
In the absence of head-to-head randomized clinical trials comparing targeted therapies and immune checkpoint inhibitors, physician preference likely plays a role. It is possible that physician's choice of immune checkpoint inhibitors instead of targeted therapy in treating *BRAF*+ metastatic melanoma is based on evidence of long-term disease control achieved with immune checkpoint inhibitors in some patients. Physicians may deem the benefit of achieving durable response with immune checkpoint inhibitors to outweigh risk of severe immune-related adverse events. However, recent long-term clinical trial outcome data suggest that patients treated with first-line targeted therapy may also achieve durable disease control [@R37]. Moreover, resistance and toxicity observed with single agent targeted therapy have been overcome by combination of *BRAF* and *MEK* inhibition that has greatly improved the efficacy and safety profile of targeted therapies [@R11],[@R30]. A recent meta-analysis that estimated relative efficacy and safety of systemic therapies for advanced treatment-naive *BRAF*-mutated melanoma found no significant difference in overall survival between PD-1 and *BRAF*/*MEK* inhibitors [@R8]. A significant advantage of *BRAF*/*MEK* inhibition compared with all other treatment strategies (i.e. targeted monotherapies, CTLA-4/GM-CSF, CTLA-4/chemo, MEK/chemo, chemo) was found for progression-free survival. Moreover, first-line use of combination *BRAF*/*MEK* targeted therapy was the most effective treatment regimen for patients with bulky or highly symptomatic disease [@R8]. It is unclear why older therapies continue to be used after the introduction of new treatments with improved efficacy and safety profiles. One possibility is the delayed uptake of newer treatments, particularly outside academic settings. This hypothesis is supported by the trends in use of immune checkpoint inhibitor and targeted therapy regimens in the period from 2014 to 2016 in our data. For immune checkpoint inhibitors, there was a gradual shift away from ipilimumab monotherapy (100% in 2014 to \<10% in 2016) to treatment with newer immune checkpoint inhibitor regimens, in particular ipilimumab+nivolumab combination. Likewise, for targeted therapy regimens, there was a shift away from monotherapy with dabrafenib (\~10% in 2014 to 0% in 2016) and vemurafenib (\~25% in 2014 to \<15% in 2016), to combination therapy with dabrafenib+trametinib (Supplementary Fig. 2A and 2B, Supplemental digital content 1, [*http://links.lww.com/MR/A65*](http://links.lww.com/MR/A65)). Two-thirds of patients had a *BRAF* test claim between melanoma diagnosis and 2L, inclusive, with the majority tested prior to 1L. The remaining patients may have been tested later or may have had a *BRAF* test that was not reimbursed by a commercial insurer, and therefore not captured in the data. In addition, procedure codes used to identify *BRAF*+ status in this study were restricted to *BRAF*-specific or sequencing tests. However, approximately half of patients presumed to be *BRAF*+, who did not have claims for *BRAF*-specific or sequencing tests, had claims for IHC tests prior to 1L. Given the high specificity of IHC [@R38], it is possible that in a subset of patients the choice of treatment was guided by IHC results. Although the NCCN guidelines state that positive VE1 (an anti-*BRAF* V600E monoclonal antibody) IHC results are sufficient for initiating targeted therapy, it is recommend that all VE1 IHC results should be confirmed by sequencing [@R7].
This study was subject to common limitations of studies based on healthcare claims data, such as occasional coding errors. However, potential inaccuracies are expected to affect all groups to a similar extent. The findings are only generalizable to the population and time period studied. Although the treatment landscape in metastatic melanoma is rapidly shifting, a lag of 6--9 months exists in the database and data were available only up to 30 June 2016 (Truven) and 30 September 2016 (IQVIA RWD Adjudicated Claims -- USA). In addition, identification of *BRAF* testing based on procedure codes has limitations and *BRAF* testing that was not reimbursed by the patient's commercial insurer was not captured. Moreover, barriers to pharmacogenetic testing may exist and reimbursement practices vary across providers that require different criteria for reimbursement of pharmacogenetic tests [@R39]--[@R41]. In some cases the insurer or the hospital may cover the cost of testing, and in some cases patients may pay out of their pocket [@R42]. Accessibility to pharmacogenetic tests, particularly multigene tests, is made challenging by the complex and time-consuming process of ordering these tests [@R40],[@R42]. As it was not possible to distinguish between *BRAF*+ and *BRAF*− in the data, *BRAF*+ was defined based on the use of targeted therapy in at least one line of treatment. Given that only patients who received two or more lines of therapy were included, those who stopped treatment after 1L due to either death or adequate response to treatment were not observed, and therefore findings apply only to patients who receive two or more lines of therapy. As *BRAF*+ patients who experience progression or relapse during or after treatment with immune checkpoint inhibitors in 1L are likely to receive targeted therapy in 2L [@R7], this is a reasonable method of identifying *BRAF*+ patients.
Given the rapidly evolving therapeutic landscape of metastatic melanoma, it is important to understand treatment patterns and factors that influence treatment decisions in real-world practice, before the introduction of newer agents. This study provides real-world insight into treatment patterns in patients with metastatic melanoma that reflect the diversity of therapeutic agents used in real-world clinical practice. The multitude of effective targeted therapy and immune checkpoint inhibitors options available to patients with *BRAF*+ metastatic melanoma, and the complexity of the disease, may lead to variable treatment patterns and lack of consensus regarding the optimal treatment of patients with *BRAF*+ metastatic melanoma in real-world practice. Further studies are needed to clarify the prognostic importance of *BRAF* mutation status in the metastatic melanoma setting.
Supplementary Material
======================
###### SUPPLEMENTARY MATERIAL
Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal\'s website, [www.melanomaresearch.com](www.melanomaresearch.com).
Medical writing assistance was provided by Sara Kaffashian, an employee of Analysis Group Inc. Analysis Group received consulting fees from Novartis for the conduct of this study.
This study was funded by Novartis Pharmaceuticals Corporation.
Conflicts of interest
=====================
S.G., B.N., and A.N. are employees of Novartis. S.G. is a stock shareholder for Provectus Biopharmaceuticals Inc. and Mannkind Corporation. R.I-I, R.B., and F.L. are employees of Groupe d'analyse, Ltée and received consultancy fees from Novartis. M.S.D. is an employee of Analysis Group Inc., and received consultancy fees from Novartis.
|
Plastic Bank to Tackle Pollution and Poverty in Indonesia with Crypto
SC Johnson, a U.S.-based manufacturer of household cleaning supplies, has partnered with Plastic Bank to help increase recycling rates and tackle poverty in Indonesia.
The non-profit uses a cryptocurrency token system to pay people for handing over recyclable plastic in order to address the global crisis of ocean plastic.
Plastic Bank Fights Pollution and Poverty with Tokens in Exchange for Plastic Scheme
Plastic Bank was founded in 2013 to fight plastic waste leaking into the ocean.
A report by McKinsey and Ocean Conservancy, found that China, Indonesia, the Philippines, Vietnam, and Thailand accounted for more than 55 percent in 2014. The non-profit aims to raise collection rates to about 80 percent across those five countries to reduce leakage by approximately 23 percent.
The mission in Indonesia will include opening eight recycling centers together with SC Johnson, where local waste collectors can bring plastic and exchange it for digital tokens, which can be used to buy goods and services. Fisk Johnson, chair and CEO of SC Johnson applauded the use of distributed ledger technology in defense of the environment.
“We want to help recover plastic equal to the amount we put into the world, through innovative recycling and recovery programs. In this way we can neutralize our environmental impact and, at the same time, do some good in communities that have excessive plastic pollution.”
Indonesia has the world’s highest levels of marine biodiversity. The government pledged up to $1 billion per year to reduce pollution in its waters, aiming at a 70 percent reduction in marine waste by 2025. The Plastic Bank program could also improve the financial lives of the people of the country, where nearly 28 million live below the poverty line.
Plastic collectors are rewarded with premiums called Plastic Bank Rewards, which are distributed and authenticated through the blockchain-powered Plastic Bank app. The plastic collected is then sorted, recycled, and sold to “forward-thinking brands to use in their manufacturing instead of new plastics”, the company said, adding that its goal is to provide large-scale sustainable premiums in every recycling community around the world.
The distributed ledger system was developed together with IBM and IBM customer Cognition Foundry. Plastic Bank uses a cryptocurrency token reward system in order to avoid the danger and mistrust involved in using a cash-based system. The transparency blockchain provides is also a plus for investors.
The non-profit plans to add analytics capabilities to the blockchain-powered app as a tool to help recycling centers better manage their business. IBM cognitive technology might also be used to help identify different types of plastic and provide more reward for highly valued types. |
Overweight in Children
Updated:Jul 5,2016
Today, about one in three American kids and teens is overweight or obese. The prevalence of obesity in children more than tripled from 1971 to 2011.. With good reason, childhood obesity is now the No. 1 health concern among parents in the United States, topping drug abuse and smoking.
Among children today, obesity is causing a broad range of health problems that previously weren’t seen until adulthood. These include high blood pressure, type 2 diabetes and elevated blood cholesterol levels. There are also psychological effects: Obese children are more prone to low self-esteem, negative body image and depression.
And excess weight is associated with earlier risk of obesity-related disease and death in adulthood.. Perhaps one of the most sobering statements regarding the severity of the childhood obesity epidemic came from former Surgeon General Richard Carmona, who characterized the threat as follows:
“Because of the increasing rates of obesity, unhealthy eating habits and physical inactivity, we may see the first generation that will be less healthy and have a shorter life expectancy than their parents."
What is "overweight" in children?
When defining overweight in children and adolescents, it's important to consider both weight and body composition. Among American children ages 2–19, the following percentages of children are obese, using the 95th percentile or higher of body mass index (BMI) values on the CDC growth chart:
For non-Hispanic whites, 17.5 percent of males and 14.7 percent of females.
For non-Hispanic blacks, 22.6 percent of males and 24.8 percent of females.
For Mexican Americans, 28.9 percent of males and 18.6 percent of females.
The prevalence of obesity (BMI-for-age values at or above the 95th percentile of the 2000 CDC growth charts in children ages 2-5 increased from 4.8 percent in 1971-74 to 12.1 percent in 2009-2010. For 6–11 year old children, the prevalence of obesity increased from 4.0 percent in 1971–74 to 18.0 percent in 2009–10. The prevalence of overweight in adolescents ages 12–19 increased from 6.1 percent to 18.4 percent.
How do you prevent and treat overweight in children?
Reaching and maintaining an appropriate body weight is important. The healthiest way to change weight is gradually. That's why recommendations that focus on small but permanent changes in eating and physical activity may work better than a series of short-term changes that can't be sustained. The importance of continuing these lifestyle changes well past the initial treatment period should be emphasized to the entire family. Learn our tips for preventing childhood obesity for parents and caretakers of children.
How is body fat measured?
Body mass index (BMI) assesses weight relative to height. It provides a useful screening tool to indirectly measure the amount of body fat for both children and adults, although different measuring tools must be used. The AHA's BMI Calculator for adults should not be used to measure a child's BMI. The CDC has an online BMI calculator for children (link opens in new window) which factors in children’s age, gender, height, and weight. |
If you like creativity and vibrant colors, then you will love this Las Vegas wedding. From the bridesmaid’s vibrant colored jumpsuits to the heartfelt words on the cake, this wedding shows that the beauty really lies within the details! Enjoy! |
Q:
UITableViewCell bottom margin constraint
I have the following UITableViewCell , where based on a condition, the redView.heightConstraint.constant = 0 , this works fine.
But the the bottom space turns out to be a+b = 20, where
a = 10 between green an red view
b = 10 between red and bottom of the superview
The expected bottom space , when height of the redView is set to 0 should be 10. How should I set the constraint to achieve the expected bottom margin of 10, when redView height is set to 0 ?
A:
Changing the height of that red view does not change its position with regards to to bottom of the superview, so that the green view has first a 10 pix margin to the top of that view, and an additional 10 pix to the bottom of the superview.
Option 1: Change 2 constraints
redView.heightConstraint.constant = 0
redView.bottomConstraint.constant = 0
Do these two changes together, and the red view will effectively become a zero height view at the bottom of its superview ; the green view will just follow suit.
Option 2: Embed the red view inside an invisible placeholder
placeholder.heightConstraint.constant = 0
The placeholder (gray rectangle) is anchored to the bottom of the superview ; it contains the red view and its vertical spacer. The blue view is no longer spaced with regards to the top of the red view but to the top of its placeholder. This solution involves less lines of code, traded for a slightly more complicated resource.
Either way, you may store the Storyboard resource constant when the view is first loaded to avoid hardcoding:
// At the class level
let originalHeight = someView.heightConstraint.constant
// At the method level, toggle
someView.heightConstraint.constant = (fullHeight) ? originalHeight : 0
|
BJP MP acquitted in assault case
A New Delhi court has acquitted BJP MP Ramesh Bidhuri. He was acquitted by the court for assaulting a man during a function in New Delhi in 2004. Ramesh Bidhuri represents South-Delhi Lok Sabha constituency.
The court observed that there were contradictions in the testimonies of the witnesses. The court also noted the absence of a medico-legal certificate by the hospital which was needed to prove that the complainant was assaulted.
Bidhuri and his four aides are charged with IPC sections 323 (voluntarily causing hurt) and 34 (acts done by several persons in furtherance of common intention).
The case was lodged by a social activist Ram Shankar. He accused that Bidhuri and his aides abused and assaulted him and also threatened him with a revolver at a function on June 26, 2004. |
NORFOLK, Va. - Old Dominion University athletics announced today that football season tickets are sold out for the sixth straight year, however fans still have the ability to purchase Flex Tickets, which provide a ticket to every home game in varied seat locations throughout the stadium.
Football was reinstated on the Old Dominion campus in the fall of 2009, and Monarch fans have sold out all 35 home contests at Foreman Field at S.B. Ballard Stadium, which has a seating capacity of 20,118. This marks the second straight year the Monarchs have sold a record number 14,508 fixed-seat season tickets, however the introduction of the Flex Ticket Package last year took the 2013 numbers to an all-time high of 14,940. Fans are guaranteed a ticket to all six home games with the Flex plan provided through anticipated ticket returns from opponents and other allotments. Flex holders enjoy many of the same benefits as season ticket holders, including earning priority points through the Old Dominion Athletic Foundation toward future season ticket purchases. A limited number of flex tickets are available and can be purchased at www.YNottix.com.
“Nothing shows better on TV than a sold out stadium with an electric atmosphere and that is what our fans have created for our home games,” says ODU Athletic Director Dr. Wood Selig. “We are becoming a destination for national and regional television coverage thanks to our passionate fans, which also helps us better brand the University and our athletic programs. It’s important we maintain this energy as we move into FBS and C-USA play."
ODU kicks off the 2014 schedule on Aug. 30 at 3:30 p.m., when regional rival Hampton University comes to S.B. Ballard Stadium. The Monarchs will also entertain Eastern Michigan on Sept. 13, along with C-USA opponents Middle Tennessee in a nationally televised game on Fox Sports on Sept. 26, Marshall on Oct. 4, FIU on Nov. 8 and Louisiana Tech on Nov. 22.
"Our team is incredibly grateful for the continued support from the most loyal fan base in the country,” says ODU Head Football Coach Bobby Wilder. "We are the only program in the history of college football to sellout every game we have ever played as a program and our players talk often about how special it is to play in front of sold out crowds at S.B. Ballard Stadium. We are 28-7 in our 35 home games, winning 80% of our games in front of our 12th Monarchs."
Tickets for most individual games are anticipated from opposing teams and unclaimed single game tickets. Individual game tickets will be placed on sale on Monday, the week of each home game, at www.YNottix.com. For more information, please contact the ODU Athletic Ticket office at 757-683–4444. |
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<h2 title="Class BindTargets" class="title">Class BindTargets</h2>
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<pre>public class <span class="typeNameLabel">BindTargets</span>
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<div class="block">Simple task which bind some targets to some defined extension point</div>
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<td class="colOne"><code><span class="memberNameLink"><a href="../../../../../org/apache/tools/ant/taskdefs/BindTargets.html#BindTargets--">BindTargets</a></span>()</code> </td>
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<td class="colFirst"><code>void</code></td>
<td class="colLast"><code><span class="memberNameLink"><a href="../../../../../org/apache/tools/ant/taskdefs/BindTargets.html#execute--">execute</a></span>()</code>
<div class="block">Called by the project to let the task do its work.</div>
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<td class="colFirst"><code>void</code></td>
<td class="colLast"><code><span class="memberNameLink"><a href="../../../../../org/apache/tools/ant/taskdefs/BindTargets.html#setExtensionPoint-java.lang.String-">setExtensionPoint</a></span>(java.lang.String extensionPoint)</code> </td>
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<td class="colFirst"><code>void</code></td>
<td class="colLast"><code><span class="memberNameLink"><a href="../../../../../org/apache/tools/ant/taskdefs/BindTargets.html#setOnMissingExtensionPoint-org.apache.tools.ant.ProjectHelper.OnMissingExtensionPoint-">setOnMissingExtensionPoint</a></span>(<a href="../../../../../org/apache/tools/ant/ProjectHelper.OnMissingExtensionPoint.html" title="class in org.apache.tools.ant">ProjectHelper.OnMissingExtensionPoint</a> onMissingExtensionPoint)</code> </td>
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<td class="colFirst"><code>void</code></td>
<td class="colLast"><code><span class="memberNameLink"><a href="../../../../../org/apache/tools/ant/taskdefs/BindTargets.html#setOnMissingExtensionPoint-java.lang.String-">setOnMissingExtensionPoint</a></span>(java.lang.String onMissingExtensionPoint)</code> </td>
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<td class="colFirst"><code>void</code></td>
<td class="colLast"><code><span class="memberNameLink"><a href="../../../../../org/apache/tools/ant/taskdefs/BindTargets.html#setTargets-java.lang.String-">setTargets</a></span>(java.lang.String target)</code> </td>
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<code><a href="../../../../../org/apache/tools/ant/Task.html#bindToOwner-org.apache.tools.ant.Task-">bindToOwner</a>, <a href="../../../../../org/apache/tools/ant/Task.html#getOwningTarget--">getOwningTarget</a>, <a href="../../../../../org/apache/tools/ant/Task.html#getRuntimeConfigurableWrapper--">getRuntimeConfigurableWrapper</a>, <a href="../../../../../org/apache/tools/ant/Task.html#getTaskName--">getTaskName</a>, <a href="../../../../../org/apache/tools/ant/Task.html#getTaskType--">getTaskType</a>, <a href="../../../../../org/apache/tools/ant/Task.html#getWrapper--">getWrapper</a>, <a href="../../../../../org/apache/tools/ant/Task.html#handleErrorFlush-java.lang.String-">handleErrorFlush</a>, <a href="../../../../../org/apache/tools/ant/Task.html#handleErrorOutput-java.lang.String-">handleErrorOutput</a>, <a href="../../../../../org/apache/tools/ant/Task.html#handleFlush-java.lang.String-">handleFlush</a>, <a href="../../../../../org/apache/tools/ant/Task.html#handleInput-byte:A-int-int-">handleInput</a>, <a href="../../../../../org/apache/tools/ant/Task.html#handleOutput-java.lang.String-">handleOutput</a>, <a href="../../../../../org/apache/tools/ant/Task.html#init--">init</a>, <a href="../../../../../org/apache/tools/ant/Task.html#isInvalid--">isInvalid</a>, <a href="../../../../../org/apache/tools/ant/Task.html#log-java.lang.String-">log</a>, <a href="../../../../../org/apache/tools/ant/Task.html#log-java.lang.String-int-">log</a>, <a href="../../../../../org/apache/tools/ant/Task.html#log-java.lang.String-java.lang.Throwable-int-">log</a>, <a href="../../../../../org/apache/tools/ant/Task.html#log-java.lang.Throwable-int-">log</a>, <a href="../../../../../org/apache/tools/ant/Task.html#maybeConfigure--">maybeConfigure</a>, <a href="../../../../../org/apache/tools/ant/Task.html#perform--">perform</a>, <a href="../../../../../org/apache/tools/ant/Task.html#reconfigure--">reconfigure</a>, <a href="../../../../../org/apache/tools/ant/Task.html#setOwningTarget-org.apache.tools.ant.Target-">setOwningTarget</a>, <a href="../../../../../org/apache/tools/ant/Task.html#setRuntimeConfigurableWrapper-org.apache.tools.ant.RuntimeConfigurable-">setRuntimeConfigurableWrapper</a>, <a href="../../../../../org/apache/tools/ant/Task.html#setTaskName-java.lang.String-">setTaskName</a>, <a href="../../../../../org/apache/tools/ant/Task.html#setTaskType-java.lang.String-">setTaskType</a></code></li>
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<code><a href="../../../../../org/apache/tools/ant/ProjectComponent.html#clone--">clone</a>, <a href="../../../../../org/apache/tools/ant/ProjectComponent.html#getDescription--">getDescription</a>, <a href="../../../../../org/apache/tools/ant/ProjectComponent.html#getLocation--">getLocation</a>, <a href="../../../../../org/apache/tools/ant/ProjectComponent.html#getProject--">getProject</a>, <a href="../../../../../org/apache/tools/ant/ProjectComponent.html#setDescription-java.lang.String-">setDescription</a>, <a href="../../../../../org/apache/tools/ant/ProjectComponent.html#setLocation-org.apache.tools.ant.Location-">setLocation</a>, <a href="../../../../../org/apache/tools/ant/ProjectComponent.html#setProject-org.apache.tools.ant.Project-">setProject</a></code></li>
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<pre>public void setExtensionPoint(java.lang.String extensionPoint)</pre>
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<pre>public void setOnMissingExtensionPoint(java.lang.String onMissingExtensionPoint)</pre>
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<pre>public void setOnMissingExtensionPoint(<a href="../../../../../org/apache/tools/ant/ProjectHelper.OnMissingExtensionPoint.html" title="class in org.apache.tools.ant">ProjectHelper.OnMissingExtensionPoint</a> onMissingExtensionPoint)</pre>
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<pre>public void execute()
throws <a href="../../../../../org/apache/tools/ant/BuildException.html" title="class in org.apache.tools.ant">BuildException</a></pre>
<div class="block"><span class="descfrmTypeLabel">Description copied from class: <code><a href="../../../../../org/apache/tools/ant/Task.html#execute--">Task</a></code></span></div>
<div class="block">Called by the project to let the task do its work. This method may be
called more than once, if the task is invoked more than once.
For example,
if target1 and target2 both depend on target3, then running
"ant target1 target2" will run all tasks in target3 twice.</div>
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|
All Four Disney Parks in One Day – Courtney, Gina and Joe
We put together a plan first. This is a must. Know what you are going to do before you even leave home/hotel. We decided the order of the parks, the transportation and the activities that would be done. We also knew to stay hydrated and take it slow because if you burn yourself out too quickly, you won’t enjoy the journey.
We started at Animal Kingdom. This was actually the only FP+ we used all day. We wanted to get on the Safari right away. We went to the bakery and had a haystack and white chocolate chip cookie. Breakfast of champions! We walked around a little after the great safari (the animals were really awake and close to the trucks) and stopped by Starbucks for some caffeine. What a wonderful job they did in there!
We then jumped on the bus (furthest stop ever #17) to Hollywood Studios. It was actually a little more crowded than I would have anticipated at the entrance. My Magic Band has been having issues and needs to be replaced but luckily my crew didn’t dump me and leave me behind.
We checked out wait times and decided to go to Muppet Vision 3D. Yippee, one of my favorites! We again walked around a bit and checked out the fun times on Pixar Street. We stopped for a churro because they rock! We did share it at least (I’m pretty sure Joe got the biggest piece). Again, I was a little surprised by how crowded this park was getting.
We then hopped on the boat to Epcot. We entered through the International Gateway and ate again. We wanted real food so we stopped by the United Kingdom. We had the quick service version of fish & chips made even better because Courtney paid. Always get the free ice water. Nice little cool down. We had to check out the Doctor Who merchandise and walked out to see a musical quartet. How cool is that?
I can’t believe how crowded the food stands for the Food and Wine Festival were. We had been two days earlier for the preview, so luckily I had most of the dishes I wanted. I figure we’ll try that on an early Epcot day again.
We went to the Land and rode Living with the Land. It had been closed briefly earlier in the month for some maintenance and it feels fresher. Always a great ride. We had done the Behind the Seeds tour which gives you a whole new appreciation for the work that is accomplished in Epcot.
We did stop in the old Wonders of Life Pavilion to check out the festivities. We watched an interesting movie on the work that goes into the Food & Wine Festival and also ate some chocolate samples.
We then boarded the Monorail to the TTC and then onto the Magic Kingdom. We had moved slower in Epcot but decided to really relax and enjoy now. We had hit four parks and needed ice cream! We stopped at Plaza Ice Cream Parlor and enjoyed our scoops sitting at the Tomorrowland Terrace. We could see the Festival of Fantasy Parade from that spot. My only complaint is that the music from the parade can’t be heard very well over the pumped in futuristic music.
We went to The Carousel of Progress next. I could go to this show every day and love it more and more each time! Such a happy tune that gets stuck in your head! We needed to visit the charging outlets in the Space Mountain gift shop afterwards. They have been somewhat relocated to the right hand back side of the store. There are changes going on in the store where you will be able to customize phone covers – similar to the Co-op in Disney Springs.
We wondered a bit, soaking up the surroundings when Gary (brother- CM) called for dinner. So we jumped on the Monorail, met him at the Grand Floridian Café and let him buy us a meal. This is such a gem. We are always able to get last minute reservations here. We ended up at home around 10:30pm tired but happy.
Wrap up:
Animal Kingdom: haystacks, cookie, found a hidden Mickey, safari, coffee, bus
Hollywood Studios: Kermit, churro, discussions on changes and excitement for the future, boat
Epcot: fish & chips, wondering why they don’t have a full sized Tardis, the Land, free chocolate, saw our cousin Kelsey and family, Monorail
Magic Kingdom: ice cream, fire breathing dragon, there’s a great big beautiful tomorrow, gift shop rehab
Grand Floridian: my favorite restaurant in all of WDW!
PD |
Q:
Best way to use ajax front-end?
The question is about which way is the best / easiest way to make a theme with ajax, using admin-ajax.php or normally.
I ask because I see that complicates using admin-ajax.php for everything and use jquery plugin to enable your browser history for example.
that think?
Sorry for my English!!!
A:
Never ever use your theme/plugin files directly for ajax calls, always use admin-ajax.php. This is the only recommended way of doing ajax to ensure maximum compatibility with wordpress (including future versions) & 3rd party plugins/themes
The best/easiest way depends on the situation & is debatable but i would ask you to use admin-ajax.php even if it is hard or inefficient
|
[Topographic anatomy of the tibial nerve in the medial malleolus: application to the effect of nerve block anesthesia].
To better understand the anatomical variations and pathogeny of tarsal tunnel syndrome, the tibial nerve were dissected in 20 ankles of fresh black African cadavers. The tibial nerve located to 1.75 cm on average from the posterior side of the malleolus and to 2 cm from medial side of the calcaneus tendon. The nerve always ended according to dichotomic method. 90% cases of bifurcation were noted under the flexor retinaculum at 1 cm from the malléolo_calcaneus line; in 10% of dissections, we found proximal bifurcation at 5 cm from this line. The medal calcaneus branch which is a collateral branch of tibial nerve was constant, unique in 80% of cases and double in 20% of cases. The anatomical constatations allow a more precise anesthesia of tibial nerve block. We use constant anatomical marks formed by calcaneus tendon and internal malleolus tip. Olso we more understand the possibility of lesion of tibial nerve at the ankle during the synovites, or ossifications of flexor rétinaculum. |
/*
* Copyright 2017 Red Hat, Inc. and/or its affiliates.
*
* Licensed under the Apache License, Version 2.0 (the "License");
* you may not use this file except in compliance with the License.
* You may obtain a copy of the License at
*
* http://www.apache.org/licenses/LICENSE-2.0
*
* Unless required by applicable law or agreed to in writing, software
* distributed under the License is distributed on an "AS IS" BASIS,
* WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied.
* See the License for the specific language governing permissions and
* limitations under the License.
*/
package org.jbpm.integrationtests;
import java.util.ArrayList;
import java.util.List;
import org.jbpm.test.util.AbstractBaseTest;
import org.junit.jupiter.api.Test;
import org.kie.api.KieBase;
import org.kie.api.io.ResourceType;
import org.kie.api.runtime.KieSession;
import org.kie.api.runtime.process.ProcessInstance;
import org.kie.internal.builder.KnowledgeBuilder;
import org.kie.internal.builder.KnowledgeBuilderFactory;
import org.kie.internal.io.ResourceFactory;
import static org.junit.jupiter.api.Assertions.assertEquals;
public class ExecutionFlowControlTest extends AbstractBaseTest {
@Test
public void testRuleFlowUpgrade() throws Exception {
final KnowledgeBuilder kbuilder = KnowledgeBuilderFactory.newKnowledgeBuilder();
// Set the system property so that automatic conversion can happen
System.setProperty( "drools.ruleflow.port", "true" );
kbuilder.add( ResourceFactory.newClassPathResource("ruleflow.drl", ExecutionFlowControlTest.class), ResourceType.DRL);
kbuilder.add( ResourceFactory.newClassPathResource("ruleflow40.rfm", ExecutionFlowControlTest.class), ResourceType.DRF);
KieBase kbase = kbuilder.newKieBase();
final KieSession ksession = kbase.newKieSession();
final List list = new ArrayList();
ksession.setGlobal("list", list);
ksession.fireAllRules();
assertEquals(0, list.size());
final ProcessInstance processInstance = ksession.startProcess("0");
assertEquals( ProcessInstance.STATE_COMPLETED,
processInstance.getState() );
assertEquals( 4,
list.size() );
assertEquals( "Rule1",
list.get( 0 ) );
list.subList(1,2).contains( "Rule2" );
list.subList(1,2).contains( "Rule3" );
assertEquals( "Rule4",
list.get( 3 ) );
assertEquals( ProcessInstance.STATE_COMPLETED,
processInstance.getState() );
// Reset the system property so that automatic conversion should not happen
System.setProperty("drools.ruleflow.port", "false");
}
}
|
What is the Range of a CB Radio System?
Nowadays, It is one of the burning question that people new to CB radio operations frequently ask, What is the range of a CB radio? OR another What can I expect for CB radio distance? Those are very good questions, but hard to answer. It is something like asking how long it takes to get from one side of Atlanta or any other large city to the another side. It depends on the time and situation.
It is difficult to say what the range of a CB Radio is just because there are many factor that effects CB radios’ range. One of the most important factor is your antenna. Some people say that you should be able to get one-two miles per foot of length on your CB radio Antenna if all other factors are configured perfectly.
The main variables that affects range are as follows:
CB Radio Power Output
Location and Environment
Radio variables
Portable/Handheld Radio vs. Mobile
CB Antenna Type, Length, Height and placement
Installation Quality
Base Station vs. Mobile
Increasing Range
CB Radio Power Output
The FCC allows a maximum of 4 watts of output power for CB radios to bypass signal interference with different devices, such as TV and emergency communication radios. That varies because a manufacturer can be punished for putting out a radio with excess power, so they provide output values between 3 and 4 Watts, and in rare cases, only 2 Watts. Tuning your radio will support it put out the highest power.
Location and Environment
The range is determined mostly by where you are. If you’re at the highest Mt. Mitchell overlook on the Blue Ridge Parkway in western North Carolina for example, you’ll achieve significantly longer transmit ranges and experience ranges than usual. On the other hand, if you’re winding through a heavily wooded valley lined with rock walls, your range may be just as far as you can see the vehicle ahead of you on the twisty road.
Those are true in the city also. If tall buildings surround you, you’re essentially in an urban canyon that reflects signals rather than passes them on. If, on the other hand, you’re in a desert area near Las Vegas or prairie in Kansas where there are flat, wide-open spaces, you’ll get the best range.
Radio Variables
The design of the CB radio, including the sensitivity of the receiver and the operation of the squelch, has an effect on radio range. Try to get a radio with a manual squelch, if possible. With a squelch, you can modify the sensitivity of your CB radio to adjust for varying signal strengths. You can get signals from farther away using a lower squelch level. The downside is that you’ll get extra background noise. On the other hand, higher squelch levels allow you to reduce the background noise, but you won’t receive lower transmissions. If you have a manual squelch, you’ll be able to tweak it to your liking.
Portable CB Radio Range
If you’re managing a portable CB radio while walking around in the shopping mall, your range may be as little as 100 yards only. If you use portable units for communication between two vehicles, you can expect about a one-mile range. There is a glimmer of hope for increased range if you change the antenna. You may be stuck with the standard short, inefficient antenna that came with the unit. However, sometimes you can substitute a longer antenna that might provide a little more range, especially if you can get height working in your favor. Sometimes if you move a few inches, you can get a clearer signal.
CB Antenna Type, Length, Height, and Placement
The taller your antenna is, and the higher up it is mounted, the greater its range will be. This is because a taller antenna has a lower angle of radiation, meaning the CB signal travels close to the ground for a longer distance.
There is general agreement that the most important thing that you can do to improve your effective range for both transmitting and receiving signals is to choose the best antenna, to properly tune it, to install it in the best position on your vehicle, and to provide the best possible ground plane and ground.
Long Range CB Antenna Types
Here are some range approximations for different types and lengths of antennas- please note that this is assuming that you have properly installed your system, tuned your antenna, have your SWR within an acceptable range and that you are on flat ground:
Dual Center-Load Antennas:
IC56 102″ Stainless Steel Whip:
Magnetic Antennas (mounted in the center of your roof):
Base Station Antennas (range can vary hugely on surroundings/environment):
Approximately 15 – 50 miles
No Ground Plane Antennas (generally 70% of the range you can get from a standard CB antenna):
2′ Length: 1 – 2 miles3′ Length: 2 – 3 miles4′ Length: 3 – 5 miles
Installation Quality
Even if you have all of the best CB components for your system, the quality of the installation can play a huge role in the overall performance of your system. Here are some crucial items to consider:
Properly ground your antenna mount- your antenna mount should be grounded to your vehicle chassis. An improper ground can lead to not being able to properly tune your antenna and/or extremely high SWR readings.
Ideally, at least 2/3 of your antenna will stick up above the best part of your vehicle. At a minimum, you should try to have the top of your antenna at least one foot higher than the top of your vehicle.
Base Station Antennas
Base stations have an inherent benefit because various types of antennas can be used with the system, and they can be mounted higher and in stable locations. That, however, makes it difficult to estimate the range of a base station, which can vary from 10 to about 50 miles.
How can I increase CB range legally?
Although the FCC limits CB radios to a standard 4 Watts of power, there is an exception. If you want the best range, you may want a radio with single sideband (SSB) capability. SSB radios, such as the Cobra 148 GTL transmit at approximately 12 Watts, or three times the normal power. The potential drawback is that the receiver must also have an SSB radio.
My Radio Lab is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to amazon.com. Content on this site may contain affiliate links. These links take you to third-party sites, such as Amazon.com. If you make a purchase, My radio lab may receive a small commission at no additional cost to you. We thank you for your support! |
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