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News That Illustrates: April 23, 2012
Sermon Illustrations
News That Illustrates: April 23, 2012
The Secret Service and Entertaining Prostitutes
As of today, 11 Secret Service agents have been placed on leave amid allegations that they entertained prostitutes during President Obama's trip to Colombia. Apparently, some of the agents paid $60 apiece to owners of the Pleyclub, a strip club in an industrial section of the city of Cartagena, to bring the women back to the hotel where Obama's advance team was staying. Of course the incident has left many observers both outraged and befuddled—as in "What were you thinking?" How could Secret Service agents commit such an obvious breach of their role? On one level, this shows the seductive, overpowering presence of sin in our fallen hearts. But Secret Service Director Mark Sullivan also said something that applies to all followers of Christ: "[It is] imperative … to always act both personally and professionally in a manner that recognizes the seriousness and consequences of our mission."
PREACHING ANGLES: Focus; Mission; Sin; Temptation
The Hunger Games: The Power of Hope
In case you've been cut off from popular culture for the past two months, the hottest movie going these days is the first installment of the novel turned into film The Hunger Games. Here's a quick summary: "[Suzanne Collins] creates a dystopian future where the remnants of the United States are ruled by a despot who enforces his rule with an annual 'game' that's a cross between Roman gladiator contests and a modern reality TV show. A couple of people from each province are chosen by lottery to enter into a group battle to the death, all televised. Last person standing is the winner." The film has a powerful scene where President Snow, the bad guy who runs the regime, asks the lead Gamemaker why he thinks there's a winner. Snow answers his own question: "[Hope] is the only thing stronger than fear. A little hope is effective; a lot of hope is dangerous. A spark is fine, as long as it is contained. So contain [hope]."
PREACHING ANGLES: Future; Hope; Vision
Is Facebook Making Us Lonely?
Here's a fantastic article chock-full of preachable quotes and stories about the connection between social media and loneliness. The author argues, "Over the past three decades, technology has delivered to us a world in which we need not be out of contact for a fraction of a moment. In 2010, at a cost of $300 million, 800 miles of fiber-optic cable was laid between the Chicago Mercantile Exchange and the New York Stock Exchange to shave three milliseconds off trading times. Yet within this world of instant and absolute communication, unbounded by limits of time or space, we suffer from unprecedented alienation. We have never been more detached from one another, or lonelier. In a world consumed by ever more novel modes of socializing, we have less and less actual society. We live in an accelerating contradiction: the more connected we become, the lonelier we are. We were promised a global village; instead we inhabit the drab cul-de-sacs and endless freeways of a vast suburb of information." The entire article is worth the read.
PREACHING ANGLES: Community; Loneliness; Technology
Big Data Is Watching You
As Obama and Romney gear up for this year's election, an army of marketers are helping them to focus their campaigns. They'll use what's called "microtargeting" to zero in on the detailed choices and preferences of our lives. And they know a lot about us because we all leave behind what's called "data exhaust," which includes the trail left by our emails, Amazon orders, Google searches, resume uploads, and our tweets—to name just a few things that leave a trail of exhaust. Whether you want it or not, every campaign tracks what you do and what you like. All of this raises some interesting, challenging questions: What does your "data exhaust" say about you? Does your public world match your private world?
PREACHING ANGLES: Confession; Integrity; Secrets
Planned Parenthood Sets Up "40 Days of Prayer"
If you're looking for a story about rationalizing evil, you won't find anything better than this. Taking a page from Rick Warren and a pro-life group's "40 Days for Life" campaign, a California abortion business developed their own "40 Days of Prayer." "We believe life is holy," the pamphlet says. "That's why we believe in your right to choose to be a parent or not." On Day 1 you can pray "for women for whom pregnancy is not good news, that they know they have choices." Day 36 invites people to "pray for the families we've chosen. May they know the blessing of choice." Day 38 says, "Today we pray for a cloud of gentleness to surround every abortion facility. May everyone feel calm and loving."
PREACHING ANGLES: Abortion; Rationalization; Sanctity of Life
What Does Your State Do Best?
This chart claims that "every state is number one in something." For instance, did you know that Delaware has more doctoral-level scientists, as a percentage of the population, than any other state? South central Indiana is the nation's leading producer of building limestone. Iowa produces more corn per year than any other state. Washington has the highest percentage of non-religious people. Minnesota has the nation's largest mall. Mississippi is the most generous state (based on giving versus annual income). It's a fun way to set up a sermon on church vision (our church's greatest strengths) or spiritual gifts.
PREACHING ANGLES: Focus; Self-esteem; Spiritual gifts; Vision
Married Couple Celebrates 83 Years of Love
Here's a fun article about marriage, commitment, communication, or conflict. "At ages 17 and 19, Eunice and Lloyd Ford were married in secret late one night by a Baptist preacher in Paris, Texas …. That was the night of April 9, 1929. Lloyd, 102, and Eunice, 100, recently celebrated their 83rd wedding anniversary." They claim that over that 83-year span they've never had a fight. Although Eunice did qualify that: "We've gotten mad at each other, but we never have fought. Usually if he got on me about anything, I walked off and left him." Then she offered this bit of advice for married couples: "Most of the time, if you get mad, walk off until you cool off."
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This Word for Word scripture song written to the classic Christmas passage from Luke 2:8-14 illustrates the majesty of the message delivered by the angels of “good news of great joy that will be for all people...a Savior has been born to you...He is Christ the Lord.” All of the Seeds Of Christmas videos capture the wonder of the birth of Jesus and direct young hearts to worship Him during the Christmas season. The hand motion versions are excellent for children’s church worship. Both split screen and picture-in-picture versions included. [ Read More ]
This Word for Word scripture song written to the classic Christmas passage from Luke 2:8-14 illustrates the majesty of the message delivered by the angels of “good news of great joy that will be for all people...a Savior has been born to you...He is Christ the Lord.” All of the Seeds Of Christmas videos capture the wonder of the birth of Jesus and direct young hearts to worship Him during the Christmas season. The download includes the full and instrumental tracks. This song also has an additional video available for children’s worship with hand motions. [ Read More ]
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Tomorrow is the Oscars! A swanky night for all the Hollywood celebs means I get to cozy up at home and serve up some fun snacks to nibble while we watch those shiny golden statues get handed out. In celebration of golden Oscar, this year I whipped up these Golden Caramel Coconut Popcorn Bites. Each bite of crunchy fresh popcorn is coated in a buttery, coconut-y, rich and sweet caramel coating. Caramel-coated nuts speckled in between the fluffy popcorn.
And with only four base ingredients, this vegan recipe is a simple sweet treat to try! Especially if you are a popcorn or caramel corn lover.
This was my first recipe experimenting with organic coconut palm sugar. I also used virgin coconut oil. Double coconut flavor made these bites simple, buttery and blissful. Yes they are sweet and rich, so all you really need is a tiny bite to experience the flavor. Join me in a caramel corn toast to Oscar night! (Or any movie-watching night!)..
On Caramel Making.. So normally when people make caramel corn they get all fancy and use a candy thermometer. Now I do not own one of those lovely items :) And I usually just wing my caramel. I know, I know, true candy and dessert-savvy chefs would roll their eyes at me, but I find that my methods usually work out quite well so I keep winging it! You just want to make sure that you bring the sugar mixture to a slow boil for a minute or so, without over-heating (you do not want to burn it or wait too long until it starts hardening and turns to candy texture too fast.) Give my method a try and if you like to use a thermometer - go for it!
Lighten it Up: And if you want to tone down the sweetness, you can simply add more popcorn to this recipe and the coating will be a bit thinner and lighter overall.
Sugar Substitutes. Yes you can absolutely substitute with another dry sugar. But you might want to reduce the amount by 1/4 cup since coconut sugar is kinda mildly sweet.
1. Air pop your popcorn to make about 6-7 cups. Set aside, be sure to pick or strain out any loose, un-popped seeds.
2. In a small sauce pan add the water, sugar and coconut oil. Over medium heat, stir continuously until a liquid forms. Keep stirring as the mixture slowly turns to a simmer and slow boil. Stir and boil for about one minute and then reduce heat to low and stir for another minute.
3. Remove the pot from heat and pour the sugar mixture into a large mixing bowl - stainless steel or glass bowls work best. Roll the liquid in the bowl for a minute until it cools a tiny bit and looks like it is about to thicken.
4. Add the nuts to the wet mixture and stir until they are well coated.
5. Next fold in the popcorn until well coated. (Again, you can add in more popcorn if you'd like a lighter caramel corn .. more popcorn will mean you may need a larger dish or two dishes to fill.)
6. Lightly grease your dish and pack in the popcorn. Flatten until smooth. Place in the freezer for about 15-20 minutes or until the popcorn cools and chills to a firm state so that you can slice the popcorn into bites and serve. Store leftover bites in the fridge or freezer. Best consumed same day.
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Browse
http://www.worldpoliticsreview.com/articles/12698/african-union-s-complicated-record-belies-continent-spanning-narrativesThe African Union was formed against an inauspicious backdrop of conflict, state collapse, failed peacekeeping missions and even genocide. Just over a decade later, the AU can claim some modest successes, as democratic government, however imperfect, has been accepted as the norm and military rule as an aberration. But how the AU addresses democratization in the future will shape the organization’s prospects.
A little more than a decade ago, in July 2002, the African Union (AU) was formed against an inauspicious backdrop. For Africa, the previous decade had been defined by conflict, state collapse, failed peacekeeping missions and even genocide. So dire had Africa’s condition become that in May 2000 the Economist captured its malaise under the infamous rubric, “the hopeless continent.” The AU’s mission over the past decade was in part to challenge and rewrite such bleak narratives. Looking back, its record is mixed, particularly in its attempts to position itself as the principal vehicle for the advancement of democratization on the continent.
The AU’s formation marked a break with the depressing history of its flawed predecessor, the Organization of African Unity (OAU), which proved largely irrelevant as many African states descended into civil war or despotism and the continent became a theater of Cold War competition. The AU’s novel features included an explicit commitment to democratization and good governance and a recognition of the legitimacy of intervention in the event of crimes against humanity or genocide. The latter was an early articulation of the “responsibility to protect” doctrine that placed the AU ahead of the United Nations itself and represented a firm repudiation of the OAU’s noninterference doctrine. In addition, the AU rejected unconstitutional changes of government, with suspension from AU membership for those states where such changes occurred. The AU has also been active in designing a new continental security architecture, and has already conducted peace operations with varying degrees of effectiveness in Burundi, Sudan and Somalia. ...
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Why is an elephant bigger than a mouse? Why, luckily, are our arms precisely the same size? While developmental genetics over the past 20 years has provided us with fascinating insights into how segments form, limbs bud, and axons find their targets, we have made little progress towards answering these obvious questions in biology. Rather than attempting to provide the answers, we will try to frame the questions in a developmental context and highlight some approaches towards answering them. Somewhat artificially, we will consider separately the mechanisms of cell, organ, and body size control.
What Controls the Size of Eukaryotic Cells? {#s2}
===========================================
The size of a cell depends on intrinsic and extrinsic factors. For example, cell size can vary dramatically with cell type---some neurons or glia cells are up to 1,000 times larger than epithelial cells. Cell size is also influenced by the number of genome sets (ploidy). A haploid Drosophila epithelial cell is only about half the size of a diploid cell. A polyploid salivary gland cell, on the other hand, is more than 1,000 times larger than a diploid cell. Amongst the extrinsic factors, the availability of nutrients and temperature are well known for their effect on cell size. Starvation not only prolongs the cell doubling time in yeast and in Drosophila cells, it also reduces the size at which they divide.
Work from Zetterberg ([@pbio.0000086-Killander1]) in mammalian fibroblasts and subsequently from Nurse and Hartwell in yeast provided evidence for a cell size checkpoint ([@pbio.0000086-Nurse1]; [@pbio.0000086-Johnston1]). In budding yeast, the protein Cln3p acts as a sizer. Cells only initiate the critical cell cycle step from G1 phase to S phase, when Cln3p has reached a certain threshold. The accumulation of Cln3p is, in turn, dependent on efficient translation of the *Cln3* mRNA, which is inefficiently translated until sufficient numbers of ribosomes have been generated ([@pbio.0000086-Polymenis1]). In this way, the presence of an efficient translation machinery is a prerequisite for passing the cell size checkpoint. Indeed, in a whole-genome survey of mutants affecting cell size in budding yeast, many size mutants exhibited defects in ribosome biogenesis ([@pbio.0000086-Jorgensen1]).
Ribosome biogenesis also appears to be an important regulator of cell size in multicellular organisms. Phosphorylation of the ribosomal protein S6 by S6 kinase (S6K) results in the preferential translation of ribosomal proteins and thus in the replenishment of the protein synthesis machinery. Drosophila cells lacking functional S6K grow more slowly and are smaller than normal cells, possibly because of the earlier accumulation of a cell sizer analogous to Cln3p in yeast ([@pbio.0000086-Thomas1]).
But is there a need for a cell size checkpoint in multicellular organisms? One would assume so, because otherwise cells would either become progressively smaller or larger. However, it has been suggested that this may be a problem for exponentially growing cells like yeast, but that mammalian cell growth is linear and, under these conditions, the need for a cell size checkpoint may be less stringent. Indeed, [@pbio.0000086-Conlon2] did not observe a cell size checkpoint in rat Schwann cells grown under different growth factor conditions (see also [@pbio.0000086-Grewal1]). Furthermore, the existence of cell size checkpoints may be cell-type dependent and stage specific. During Drosophila imaginal disc development, for example, cells are larger at the beginning of imaginal disc growth and become progressively smaller during later stages ([@pbio.0000086-Madhavan1]).
Until recently, more emphasis has been placed on understanding the genetic control of cell cycle progression than on the mechanisms regulating cell growth. This has often led to the use of cell proliferation and cell growth as synonymous terms. Analysis in Drosophila imaginal discs using cell clones either deficient in cell cycle progression or expressing cell cycle regulators that accelerate or slow down the cell cycle, however, have shown clearly that cell cycle progression alone is not sufficient to promote growth ([@pbio.0000086-Weigmann1]; [@pbio.0000086-Neufeld]). In summary, cell size is altered by changing ploidy, by uncoupling cell cycle progression from cell growth, and by pathways regulating cell growth such as the insulin (see below) and S6K pathways. Of these three, only the modulation of cell growth has an effect on overall growth at the next level, the organ.
How Is the Size of Organs Controlled? {#s3}
=====================================
Changes in organ size are only partly due to changes in cell size. In Drosophila, the reduction in wing size in S6K mutant flies or in flies raised at higher temperature is caused by a reduction in cell size ([@pbio.0000086-Partridge1]; [@pbio.0000086-Montagne1]); in contrast, starvation or mutations in genes coding for insulin signaling components that mediate the starvation response affect body size and organ size by reducing cell size and cell number ([@pbio.0000086-Garofalo1]). The effect of insulin pathway activity on growth is largely autonomous to cells and multicellular regions, called compartments. Specific reduction of dAkt function, an essential component of the insulin signaling pathway, in either the anterior or the posterior compartment of the wing imaginal disc results in a severe reduction of the respective compartment. Astonishingly, the small compartment is properly patterned and the size and patterning of the adjacent compartment remain untouched ([Figure 1](#pbio.0000086-g001){ref-type="fig"}), demonstrating that the insulin pathway has a profound effect on the final size of an organ without interfering with the patterning mechanism.
![The Insulin Signaling Activity Controls Organ Size in a Compartment-Specific Manner\
Mosaic Drosophila wings with compartment-specific manipulations of dAkt function display striking size defects but normal patterning.\
(A) Selective reduction of dAkt function in the posterior compartment by means of FLP-mediated mitotic recombination in posterior cells (using *engrailed--Gal4* to drive the expression of *UAS--Flp*) results in a small P compartment largely consisting of *dAkt^3^* mutant cells. The smaller compartment size is due to fewer and smaller cells.\
(B) Wild-type wing for comparison.\
(C) Expression of dAkt in posterior cells (*engrailed--Gal4 UAS--dAkt*) of wings with reduced dAkt function (*dAkt^3^*) restores the size of the P compartment, whereas the A compartment remains small. The red lines mark the anterior--posterior compartment boundary. Note that similar results in the wing disc have been obtained by [@pbio.0000086-Teleman1].](pbio.0000086.g001){#pbio.0000086-g001}
Recently, a novel signaling complex that restricts organ size by controlling both proliferation arrest and apoptosis has been discovered ([@pbio.0000086-Ryoo]). Mutations in either hippo, salvador, or warts result in a failure of cell cycle exit and in a protection from cell death, thus leading to massively overgrown organs. How an organ *knows* when it has reached its final size, however, is still mysterious and thus challenging.
It is clear that autonomous and nonautonomous factors control organ size, but their relative contribution varies depending on organ type and species. Multiple transplanted fetal thymus glands each grow to their normal size while multiple transplanted fetal spleens grow collectively to the size of one spleen (reviewed in [@pbio.0000086-Conlon1]). In Drosophila, immature imaginal discs (larval structures that undergo metamorphosis and develop into structures such as legs, wings, and eyes in the adult) transplanted into a third instar larva do not undergo metamorphosis until they reach the final size ([@pbio.0000086-Bryant1]). But the size of insect appendages is not only controlled autonomously. Ablation of the hind wing discs in butterflies increases the size of the fore wings ([@pbio.0000086-Nijhout2]).
The Role of Cell Competition {#s4}
============================
Based on experiments in mammalian systems, it has been suggested that the competition for limiting growth or survival factors may be a general mechanism for organ size control ([@pbio.0000086-Conlon1]). In Drosophila, cell competition is observed in imaginal discs. Slowly growing cells are eliminated when they are next to cells that grow at a normal rate ([@pbio.0000086-Simpson1]). The slowly growing cells in these studies were heterozygous at one of several *Minute* (*M*) loci, some of which encode ribosomal proteins.
Recently, a link has been established between cell competition and signaling by the secreted factor Decapentaplegic (Dpp) ([@pbio.0000086-Moreno1]). The elimination of slowly growing *M*/+ cells is preceded by the upregulation of the gene *brinker* (*brk*), which triggers cell death. Expression of *brk* is downregulated by high Dpp levels. As in *M*/+ cells, *brk* upregulation and cell elimination by apoptosis are also triggered in cells close to the Dpp source that are unresponsive to Dpp because they lack the Dpp receptor Thickveins (Tkv). Slowly growing cells may be outcompeted because they may be less efficient in internalizing Dpp via endocytosis and thus receive fewer survival signals. The problem with this simple model is that cells away from the anterior--posterior boundary---the site of Dpp production---possess high levels of Brk but do not die and grow at the same rate as cells close to the Dpp source. Indeed, *tkv* mutant clones also survive in these regions ([@pbio.0000086-Burke1]). Therefore, *brk* levels do not correlate with the growth and survival potential of cells in all circumstances.
An alternative explanation for the observed parallels between the elimination of *tkv* mutant cells and *M*/+ cells is that the juxtaposition of cells with different cell surface properties is the trigger for elimination. The upregulation of *brk* in *M*/+ cells may trigger different surface properties (positional identities) in the same way as in *tkv* mutant cells. Thus, cell competition may be a cell-policing mechanism that eliminates cells that for various reasons do not fit into the community. Whether this mechanism of cell competition plays a major role in organ size control is still unclear.
How Are Pattern Formation and Growth Connected? {#s5}
===============================================
Organ size is coupled to pattern formation. Interfering with patterning mechanisms, for example, by implanting a bead soaked in the secreted factor Sonic hedgehog (Shh) into the anterior of the chick wing bud or by the ectopic expression of Hedgehog (Hh) or Dpp in the Drosophila wing, causes pattern duplications and concomitant growth. Conversely, partial loss-of-function mutations in *dpp* reduce wing size ([@pbio.0000086-Potter]) ([Figure 2](#pbio.0000086-g002){ref-type="fig"}). In contrast to the effects caused by modulating insulin pathway activity, the stimulation of growth by Dpp appears to be tightly linked with pattern formation. How is patterning coupled to growth? This is one of the major unsolved questions in the field. It does not appear that the patterning morphogens like Dpp act by directly promoting growth since the cell division rates are the same in regions of high and low Dpp concentrations ([@pbio.0000086-Milan1]).
![Changing the Patterning Mechansims during Wing Development Affects Growth\
Compared with a wild-type wing (A), loss of Dpp function results in reduced growth and loss of pattern elements (B). Ectopic expression of Dpp in a clone of cells results in pattern duplications associated with massive extra growth (C). The region of Dpp expression in (A) and (C) is indicated by the green color. ([@pbio.0000086-Zecca1]; pictures courtesy of B. Müller and K. Basler.)](pbio.0000086.g002){#pbio.0000086-g002}
An attractive hypothesis put forward based on a previous model of regeneration postulates that the individual cells of an organ primordium measure the concentration gradients of specific signaling molecules, such as Dpp in the Drosophila wing disc and Shh in the vertebrate limb bud ([@pbio.0000086-Day1]). In immature small primordia, the gradients are steep and cells continue to grow and divide. Since the source of the gradient stays approximately constant, its concentration gradient flattens as the tissue grows. When the difference in the morphogen concentration sensed by the two ends of the cells along the axis of the gradient falls below a certain threshold, the cells stop growing. Although this model could explain why cell growth and division are not concentrated around sources of morphogens, experimental evidence does not support it. Clones of cells expressing a constitutively active version of the Dpp receptor Tkv show increased growth when surrounded by cells of low Tkv activity. Furthermore, constant overexpression of activated Tkv in the entire disc also promotes growth, arguing against growth being induced by a differential of Tkv activity across the cell ([@pbio.0000086-Lecuit1]; [@pbio.0000086-Nellen1]).
How then does normal graded Tkv activity produce homogenous growth? One possible solution to this problem comes from the observation that Dpp in the Drosophila wing is secreted basal--laterally as well as apically ([Figure 3](#pbio.0000086-g003){ref-type="fig"}). While Dpp secreted on the basal--lateral side in the epithelium has been detected in a concentration gradient ([@pbio.0000086-Teleman1]), Dpp secreted on the apical side accumulates in the disc lumen formed by the disc epithelium proper and the peripodial membrane, whose cells also secrete Dpp ([@pbio.0000086-Gibson1]). It is tempting to speculate that Dpp in the lumen functions as a general growth-promoting factor, while Dpp secreted in a graded fashion from the basal--lateral side induces pattern formation. A growth-promoting function has been suggested for the luminally produced Dpp ([@pbio.0000086-Gibson1]). This model implies that Dpp received on the apical side of the cell triggers a different cellular response (growth, survival, or both) than Dpp received on the basal--lateral side (patterning) and would probably require an unequal distribution of Dpp receptors or signaling components along the apical--basal axis of the cell.
{#pbio.0000086-g003}
At present, the most attractive hypothesis for how intrinsic control of organ size is achieved postulates that a secreted growth-promoting factor accumulates in the organ primordium and that its function is counteracted by an inhibitor accumulating with a delay ([@pbio.0000086-Nijhout1]). Once the inhibitor reaches a certain threshold and/or the growth factor is consumed, organ growth stops ([Figure 3](#pbio.0000086-g003){ref-type="fig"}). Although hypothetical, activator and inhibitor models have been postulated for many patterning processes. Dpp and related transforming growth factor β (TGFβ) molecules provide a particularly well-established case. TGFβ agonists and antagonists are involved in patterning the dorsal--ventral axis in the Drosophila embryo and the left--right asymmetry in the vertebrate embryos ([@pbio.0000086-Capdevila1]). Further genetic and biochemical experiments are needed to identify the components involved in intrinsic organ growth control.
Which Growth Promoting Pathways Are Regulated by Secreted Factors with Patterning Functions? {#s6}
============================================================================================
Although little is known about the connection between patterning factors and growth pathways, a few potential links have been described. For example, in the Drosophila eye imaginal disc, Hh regulates growth directly by controlling the expression of cyclin E, a promoter of the G1/S transition, and by cyclin D, a promoter of cell growth ([@pbio.0000086-Duman-Scheel1]). Whether this is a general mechanism by which Hh controls cell growth and cell division is unclear, however, since in the wing disc at least, the effect of Hh appears to be mediated by Dpp. Comprehensive surveys of target genes regulated by these patterning factors in the specific developing tissues using microarray technology may provide further insight into how they control cell growth directly or indirectly.
How Is Body Size Controlled? {#s7}
============================
Can the question of body size regulation be reduced to simply summing up the mechanisms that regulate the size of individual organs? In contrast to organ size control that involves local cell interactions, locally produced growth factors as well as systemic growth factors, overall body size is controlled primarily by systemic factors. Vertebrate body size is controlled by growth hormone and the subordinate insulin-like growth factors (IGFs) ([@pbio.0000086-Butler]). In invertebrates, growth and body size are also regulated by the insulin/IGF system in response to nutrients. In addition, final body size in insects is determined by the number of molting cycles, and these are under the control of the steroid hormone ecdysone and the sesquiterpenoid juvenile hormone ([@pbio.0000086-Nijhout1]). Nevertheless, changing ecdysone or insulin-like peptide levels in invertebrates or overproducing growth hormone in vertebrates can increase body size only within a certain range. It is obviously not possible to turn a mouse into the size of an elephant, although the recent identification of fossils of Phoberomys pattersoni indicates that rodents were once a great deal larger than they are today ([@pbio.0000086-Sanchez-Villagra]). In addition to the hormonal control of body size, there are intrinsic genetic constraints to organ and body size. Understanding the mechanism underlying these constraints will be another challenge for the future.
Conclusions {#s8}
===========
In contrast to the control of cell fate, segment number, or patterning, which is largely determined by genetic regulatory mechanisms, the control of size is influenced by genetic, hormonal, and environmental inputs. Understanding this phenomenon requires a combination of developmental genetic, physiological, and evolutionary approaches. Given the significant interest that has been generated in growth control, it should not be long before some of these old mysteries in biology are explained. This will not only reward us with a better understanding of this important aspect of developmental biology, but it will also provide better insight into human diseases, such as cancer, that are associated with a misregulation of cellular growth.
Ernst Hafen and Hugo Stocker are both at the Zoologisches Institut at the Universität Zürich, in Zürich, Switzerland.
\*To whom correspondence should be addressed. E-mail: <hafen@zool.unizh.ch>
*brk*
: *brinker*
Dpp
: Decapentaplegic
Hh
: Hedgehog
IGF
: insulin-like growth factor
*M*
: *Minute*
S6K
: S6 kinase
Shh
: Sonic hedgehog
TGFβ
: transforming growth factor β
Tkv
: Thickveins
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1. Introduction {#sec1-molecules-23-02902}
===============
Natural products (NPs) play vital roles in drug discovery. More than half of the drugs that have been approved over the past 30 years are natural compounds or compounds based on these \[[@B1-molecules-23-02902]\]. Approximately 68% of anti-infectives are classified as nature-derived or inspired, and 80% of all anticancer compounds fall into this category \[[@B2-molecules-23-02902]\]. Examples of well-known drugs derived from natural products are paclitaxel or doxorubicin (anticancer), artemisinin (antimalarial), daptomycin (antibacterial), and morphine (analgesic). The most striking feature of many natural products is their structural diversity, which is still largely untapped. About 40% of the chemical scaffolds found in NPs are still absent in today's medicinal chemistry \[[@B3-molecules-23-02902]\]. The importance of NPs in drug development has been described in a number of reviews and reports \[[@B2-molecules-23-02902],[@B4-molecules-23-02902],[@B5-molecules-23-02902],[@B6-molecules-23-02902],[@B7-molecules-23-02902],[@B8-molecules-23-02902],[@B9-molecules-23-02902],[@B10-molecules-23-02902]\].
Jacaranone (**1**) and its derivatives, phytoquinoids isolated from several *Jacaranda* and *Senecio* species, exhibited promising pharmacophore qualities in previous investigations. The remarkable cytotoxic and antiprotozoal properties of jacaranone have been especially well-studied both in vitro and in vivo \[[@B11-molecules-23-02902],[@B12-molecules-23-02902],[@B13-molecules-23-02902],[@B14-molecules-23-02902]\]. Related nitrogenous NPs (e.g., verongiaquinol (**2**) or melodamide A (**3**)) are also valuable drug candidates that possess antiproliferative, antibiotic, antiviral, antiprotozoal, and anti-inflammatory activities \[[@B15-molecules-23-02902],[@B16-molecules-23-02902],[@B17-molecules-23-02902],[@B18-molecules-23-02902],[@B19-molecules-23-02902],[@B20-molecules-23-02902]\].
Herein, we report the design and synthesis of jacaranone-inspired *N*-containing cyclohexadienones and our findings on the antiproliferative, antiplasmodial, and antitrypanosomal activities of these NP-derived quinols ([Figure 1](#molecules-23-02902-f001){ref-type="fig"}).
2. Results and Discussion {#sec2-molecules-23-02902}
=========================
2.1. Chemistry {#sec2dot1-molecules-23-02902}
--------------
Imide derivatives are a valuable group of bioactive compounds. In spite of their wide applicability, available procedures for their synthesis are limited \[[@B21-molecules-23-02902]\]. During the course of our work on jacaranone imides, we searched for an efficient method that we could use to construct the *N*-dienone scaffold.
During our initial attempts, we followed a Mitsunobu route \[[@B22-molecules-23-02902]\] as summarized in [Scheme 1](#molecules-23-02902-sch001){ref-type="scheme"} (method A). Starting from the commercially available compound, methyl 4-hydroxyphenyl acetate (**4**), the temporarily protected alcohol **5** was obtained in two steps in almost quantitative yields. The introduced thexyldimethylsilyl (TDS) group is superior in comparison with other commonly used silyl protecting strategies because of its greater stability and ease of handling \[[@B23-molecules-23-02902]\].
Subsequently, the intermediates **6a**--**c** were prepared from TDS ether **5** under Mitsunobu conditions and then treated with an excess amount of tetrabutylammonium fluoride (TBAF) \[[@B24-molecules-23-02902]\] to afford the unprotected imides **7a**--**c** in moderate overall yields (58--71%).
Walker \[[@B25-molecules-23-02902]\] reported that yields of the crucial Mitsunobu reaction could be increased by simply altering the order in which the reagents were combined. Although we observed these instructions, following the Mitsunobu route still did not allow us to produce a wide range of imide derivatives.
Therefore, we focused on tyramine (**8**) as a commercially available and more suitable starting material for our imide design. A previously described method \[[@B26-molecules-23-02902]\] used **8** for the chemoselective condensation with phthalic anhydride in refluxing acetic acid. Following this published protocol as shown in [Scheme 1](#molecules-23-02902-sch001){ref-type="scheme"}, a series of cyclic imides (**7a**--**j**) were synthesized in generally good to excellent yields (method B). Furthermore, tyramine has an advantage in that it is significantly more reactive than the formerly used alcohol **5**, and the tedious process of protecting the phenolic group is not necessary. Interestingly, the preparation of **7f** and **7g** failed using this procedure, perhaps due to its basicity (**7f**) or hydrolytic degradation (**7g**).
Recently, we have become interested in the development of synthetic methods using polyethylene glycol (PEG) as a novel, environmentally and industrially friendly medium and promoter \[[@B27-molecules-23-02902]\]. It is known that PEG can act as an excellent reaction medium for the synthesis of *N*-alkyl and *N*-arylphthalimides \[[@B28-molecules-23-02902]\]. For this reason, we investigated whether the substitution of the established solvent acetic acid (method B) by the nontoxic, inexpensive, nonionic liquid PEG 400 (method C) was a viable alternative procedure for the condensation of various anhydrides with **8**.
Initially, the modified procedure provided only poor yields because PEG acted as a solubilizer. This led to difficulties during the workup of the highly water-soluble imides. By referring to a PEG-assisted solvent and catalyst-free synthesis of 3,4-dihydropyrimidinones \[[@B29-molecules-23-02902]\], we significantly decreased the amount of PEG used in our synthesis. In fact, the results obtained by modifying the method demonstrated that we could considerably increase the product yield in most cases, including the cases of the elusive imides, **7f** and **7g**.
Overall, upon comparing the yields achieved with methods A and B/C, respectively, we could clearly demonstrate the great advantage of using tyramine (**8**) as a starting material to prepare the cyclic imides, **7a**--**j**, as well as the potential of using PEG as an excellent reagent to promote organic reactions.
Next, we turned our attention to the preparation of the jacaranone-derived amines. *N*-alkyl amines can be obtained by the catalytic amination of alcohols \[[@B30-molecules-23-02902]\] or by the reaction of the respective amine with alkyl halides and an auxiliary base \[[@B31-molecules-23-02902]\]. Heterocyclic *N*-imides have also been smoothly converted into the corresponding amines with LiAlH~4~ in excellent yields \[[@B32-molecules-23-02902],[@B33-molecules-23-02902]\]. This route was initially adopted for the synthesis of amines **11a**--**d** from the previous synthesized imides ([Scheme 2](#molecules-23-02902-sch002){ref-type="scheme"}, method D).
Watson et al. \[[@B32-molecules-23-02902]\] showed that the reduction of the phthalimide functionality might be problematic due to the comparatively facile oxidation of the emerging isoindoline to the respective isoindole. Surprisingly, the conversion of phthalimide **7a** with LiAlH~4~ gave essentially the isoindoline, **11a,** in good yields, whereas the reduction to the amines, **11b**--**d**, failed. In contrast, the partially reduced derivative, **12**, was exclusively obtained when **7h** was treated with LiAlH~4~.
As an alternative route to the desired jacaranone-derived amines, we examined the frequently used iridium-catalyzed alkylation of alcohols \[[@B34-molecules-23-02902]\] (method E). However, treatment of the primary alcohol, **5**, with pyrrolidine in the presence of \[Cp\*IrCl~2~\]~2~ \[[@B35-molecules-23-02902]\] delivered **10b** in only moderate yields; thus, this synthetic route was abandoned.
Finally, we applied the traditional amination of alkyl halogenides for the preparation of jacaranone amines (method F). For this purpose, alcohol **5** was first converted with tetrabutyl ammonium bromide (TBAB), PPh~3~, and 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) \[[@B36-molecules-23-02902]\] to the corresponding bromide **9**. This intermediate was then coupled with the appropriate secondary amine in the presence of NaI and proton sponge^®^ \[[@B37-molecules-23-02902]\] to obtain the amines, **10b**--**d**, in good to excellent yields. Only the *N*-alkylation of isoindoline (**10a**) led to slightly lower yields under these conditions. Deprotection of the obtained amines, **10a**--**d**, with LiOH in DMF \[[@B38-molecules-23-02902]\] was successful, resulting in the desired derivatives, **11a**--**d**.
Previous studies have demonstrated that isoindolines can be readily converted to tetrahydroisoindoles by palladium hydroxide-catalyzed hydrogenation \[[@B39-molecules-23-02902],[@B40-molecules-23-02902]\]. To broaden the range of usable amines, we examined the reported procedure and observed a quantitative conversion of **11a** to the expected tetrahydroisoindole, **11e**.
Finally, we investigated the oxidative dearomatization of the synthesized *N*-containing phenols into the respective p-alkyl quinols. Such cyclic dienones exhibit not only promising pharmacophores \[[@B3-molecules-23-02902],[@B41-molecules-23-02902]\], but are also attractive intermediates for enantioselective natural product synthesis \[[@B42-molecules-23-02902],[@B43-molecules-23-02902],[@B44-molecules-23-02902]\]. Phenol dearomatization processes are generally mediated by hypervalent iodine reagents, and are well-documented in the literature \[[@B43-molecules-23-02902],[@B45-molecules-23-02902]\]. The commonly used protocol using phenyliodine(III) diacetate (PIDA) in aqueous CH~3~CN \[[@B46-molecules-23-02902]\] appeared to be most suitable for our purpose.
The conversion of the compounds, **7a**--**j** and **12,** with PIDA afforded the respective p-substituted cyclohexadienones, **13a**--**j** and **15**, in satisfactory yields, whereas the oxidation of all tertiary amines (**11a**--**e**) failed. To improve the rate of conversion for these compounds, we examined the impact of varying the pH values on the reaction outcome. The best results were obtained applying a 1 M phosphate buffer that adjusted the pH to 6.4 during the oxidation. This variation led to the availability of a few additional tertiary jacaranone amines (**14a**,**14c**), but the yields still remained far from being satisfactory.
Subsequently, the synthesized dienones were evaluated for their antiproliferative and antiprotozoal activity, following the method described in the Experimental section.
2.2. Physicochemical Properties {#sec2dot2-molecules-23-02902}
-------------------------------
Physicochemical parameters play crucial roles in the selection process of drug candidates for product development. The properties of small molecules, especially those that are orally bioavailable, are concentrated in a relatively narrow range of physicochemical space known as the "drug-like space" \[[@B47-molecules-23-02902]\]. An optimal lipophilicity range, along with low molecular weight and small polar surface area, are major prerequisites that lead to good absorption of chemicals by the intestine through passive diffusion \[[@B48-molecules-23-02902],[@B49-molecules-23-02902]\]. For this reason, an assessment of drug-likeness was made, and various physicochemical properties were calculated for all tested compounds ([Table 1](#molecules-23-02902-t001){ref-type="table"} and [Supplementary Materials](#app1-molecules-23-02902){ref-type="app"}).
All compounds had relatively low molecular weights within the range of 223--352 g·mol^−1^. Their polar surface areas are low and well within the range where good central nervous system (CNS) penetration is plausible \[[@B50-molecules-23-02902],[@B51-molecules-23-02902]\]. The latter parameter is especially important to treat the CNS-persistent second stage of human African trypanosomiasis (HAT) \[[@B52-molecules-23-02902]\]. All derivatives fulfill the Lipinski rule of five \[[@B53-molecules-23-02902]\] and the Veber rule \[[@B54-molecules-23-02902]\]. Except for imides, **13c** and **13g**, the logP data of which lie slightly outside the proposed region, all mentioned compounds also comply with the drug-likeness classifier defined by Ghose et al. \[[@B55-molecules-23-02902]\].
The adequate application of ligand efficiency (LE) metrics is of utmost relevance in guiding lead discovery---and, more importantly, lead optimization---towards drug-like chemical space \[[@B56-molecules-23-02902],[@B57-molecules-23-02902]\]. The ligand efficiency metrics of our synthesized compounds (LE \> \~0.3), lipophilic ligand efficiency (LLE) (LLE \> \~5), and lipophilicity-corrected ligand efficiency (LELP) (−10 \< LELP \< 10) agree closely with the values proposed for drug candidates \[[@B56-molecules-23-02902]\] (see [Supplementary Materials, Table S3](#app1-molecules-23-02902){ref-type="app"}).
In addition, all synthesized dienones were subjected to the BOILED-Egg analysis \[[@B58-molecules-23-02902],[@B59-molecules-23-02902]\], an improvement upon the well-known Egan egg model \[[@B60-molecules-23-02902]\]. This tool utilizes the computed lipophilicity and polarity of small drugs as input, allowing researchers to predict brain and intestinal permeation efficacies. This model is frequently used in industrial and academic contexts for drug discovery and development. All computed substances are within the thresholds of the model and, therefore, are predicted to show good gastrointestinal absorption. Furthermore, compounds, **13d** and **14a**, also lie within the physicochemical space of molecules that have a high probability of permeating the blood-brain barrier (BBB) (see [Supplementary Materials, Figure S1](#app1-molecules-23-02902){ref-type="app"}).
2.3. Biological Evaluation {#sec2dot3-molecules-23-02902}
--------------------------
### 2.3.1. Antiproliferative Activity {#sec2dot3dot1-molecules-23-02902}
All synthesized dienones (**13a***--***j**, **14a**, **14c**, and **15**) were evaluated for their cytotoxic activity against human (cancer) cell lines. To cover a range of different tumor entities, we used a panel of cancer cell lines (CCRF-CEM leukemia, MDA-MB-231 breast cancer, HCT-116 colon cancer, and U251 glioblastoma cells) as well as a non-tumorigenic human cell line (MRC-5 lung fibroblasts). All derivatives were screened for their cytotoxicity at 5 µg/mL and 50 µg/mL to cover a broad concentration range. Cells were exposed to the derivatives for 72 h. As can be seen in [Figure 2](#molecules-23-02902-f002){ref-type="fig"}, the highest cytotoxicity was found for **13b** and **13i**. Both compounds reduced the metabolic activity below 40% of the control at 5 µg/mL in all (**13i**) or almost all (**13b**) cell lines. At 50 µg/mL, almost all tested compounds displayed activities against leukemia and breast cancer cells lines, but the overall cytotoxicity of compounds **13f**, **13g**, **13j**, and **14a** was negligible. Furthermore, the 50 µg/mL dilution corresponds to concentrations in the 140--215 µM range, which is not considered to be active. Interestingly, the morpholine derivative, **14c**, displayed only minor cytotoxicity against most cell lines at 5 µg/mL, but subsequently exhibited the highest antitrypanosomal activity. No clear correlation between cytotoxic and antiprotozoal effects could be drawn. Against human MRC-5 cells, **13f**, **13g**, **13j**, and **14a** did not show any cytotoxicity at 5 µg/mL and only a weak activity at 50 µg/mL. These results essentially match those of the subsequent L6 cytotoxicity assay, which was performed during the antiprotozoal screening. In that series, the highest IC~50~ values (and, therefore, the lowest cytotoxicity) were found for compounds **13b**, **13f**, and **13g** (for detailed results, see [Supplementary Materials, Table S4](#app1-molecules-23-02902){ref-type="app"}).
### 2.3.2. Antiprotozoal Activity {#sec2dot3dot2-molecules-23-02902}
The synthesized dienones were also investigated for their activity against *P. falciparum* NF54 and T. brucei rhodesiense STIB900 as well as for their cytotoxicity against L6 rat skeletal myoblasts ([Table 1](#molecules-23-02902-t001){ref-type="table"}). For each parasite, a selectivity index (SI = IC~50(L6)~/IC~50(parasite)~) was calculated. The TDR (Special Program for Research and Training in Tropical Diseases, World Health Organization) criteria \[[@B61-molecules-23-02902]\] were adopted to interpret antiparasitic activity and selectivity.
All derivatives showed moderate (IC~50~ = 1--10 μM) or high (IC~50~ \< 1 μM) activity towards *T. brucei rhodesiense*, except the inactive pyridine-2,3-dicarboximide, **13f**, and the morpholine-3,5-dione, **13g**, with IC~50~ values \>10 μM. These results were surprising, especially in the case of compound **13f**, as basic, nitrogen-containing compounds often show favorable activities against protozoal parasites. Interestingly, the corresponding morpholine derivative, **14c**, showed, in contrast, the highest antitrypanosomal activity (IC~50~ = 0.27 μM) of all the tested *N*-dienones. Compared to the antitrypanosomal activity, the antiplasmodial effects of all tested compounds against *P. falciparum* NF54 strains were rather weak. Notable in this series, unfortunately, was the lack of selectivity of most compounds, as the compounds showed selectivity indices (SI) of \<13.
### 2.3.3. Structure-Activity Relationships (SAR) of the Antiproliferative and Antiprotozoal Activity {#sec2dot3dot3-molecules-23-02902}
The mechanism of action of compounds with quinoid structural elements is based on redox cycling with excessive generation of reactive oxygen species (ROS) in the intracellular environment \[[@B62-molecules-23-02902]\]. ROS play central roles in cell signaling and are able to activate the intrinsic pathway of cell apoptosis \[[@B63-molecules-23-02902]\]. It is expected that these processes are responsible for the cytotoxic action of quinoids on microorganisms, as well as on tumor cells \[[@B64-molecules-23-02902]\]. Due to the nature of the presented compounds, target specific effects are few and far between. For instance, the antiproliferative effects of the phytoquinoid, jacaranone, are caused by its interactions with the protein kinase B (AKT) and mitogen-activated protein kinase (p38 MAPK) signaling pathways \[[@B13-molecules-23-02902]\].
Nevertheless, a closer examination of the SARs of jacaranone-based nitrogenous cyclohexadienones with regard to their antiproliferative activity ([Figure 2](#molecules-23-02902-f002){ref-type="fig"}) suggests that the most potent compounds, **13b**, **13e**, and **13i**, share an α,β-unsaturated imide as a core structural element ([Figure 3](#molecules-23-02902-f003){ref-type="fig"}).
These compounds showed high activity levels against some (**13b**: CCRF-CEM, MDA-MB-231, HCT-116; **13e**: CCRF-CEM) or all (**13i**) tested cell lines at low concentrations. Compound **13b** also showed a comparably low cytotoxicity against L6 cells with an IC~50~ of 26.8 µM, hinting that it has a target-specific inhibitory effect. In contrast, pyridine-2,3-dicarboximide, **13f**, and the morpholine-3,5-dione, **13g,** exhibited neither cytotoxic nor antiprotozoal activity.
Unfortunately, our antiprotozoal assays revealed no specific effects. However, a certain rank correlation between antiplasmodial activity and logP (r~S~ = −0.772) or ASApho values (r~S~ = −0.711) on one side and antitrypanosomal activity and ASApol (r~S~ = 0.870) on the other side was observed (see also [Supplementary Materials, Table S2](#app1-molecules-23-02902){ref-type="app"}).
3. Experimental Section {#sec3-molecules-23-02902}
=======================
3.1. Chemicals and Instruments {#sec3dot1-molecules-23-02902}
------------------------------
Melting points were obtained on a digital melting point apparatus (Electrothermal IA 9200, Staffordshire, UK). The NMR spectra were measured on a Unity Inova 400 MHz instrument (Varian, Darmstadt, Germany) and a Avance III 300 MHz NMR Spectrometer (Bruker, Rheinstetten, Germany) at 25 °C using 5 mm tubes. Chemical shifts were given in parts per million (ppm), the tetramethylsilane (TMS) resonance (0.00 ppm) was used as an internal standard. Coupling constants (*J*) were reported in hertz (Hz). ^1^H and ^13^C-resonances were assigned using ^1^H,^1^H, and ^1^H,^13^C correlation spectra. ^1^H and ^13^C resonances are numbered as given in the formulae (see [Supplementary Materials](#app1-molecules-23-02902){ref-type="app"}).
High-resolution EI mass spectra (70 eV, source temperature 220 °C) were recorded on an orthogonal TOF spectrometer (Waters GCT Premier, Milford, MA, USA) equipped with a direct insertion (DI) probe. Typically, 0.2 µL of a solution of the sample (c = 0.1 mg/mL) were placed in the glass cup used for DI, dried under atmospheric pressure, and transferred into the vacuum. Mass spectra (50--800 Da; 1 spectrum/s; resolution appr. 7500 FWHM) were continuously acquired while the sample was evaporated rapidly. ESI mass spectra were acquired on an Exactive Orbitrap mass spectrometer equipped with a heated ESI II source (ThermoFisher Scientific, Inc., Bremen, Germany).
HPLC separations were performed on an Agilent HPLC instrument 1200 series (Santa Clara, CA, USA) with quaternary pump, autosampler, autoinjector, column oven, and DAD detection. A Eurospher C18 column (particle size 1.8 μm; 2.0 × 125 mm with guard cartridge) (Knauer, Berlin, Germany) was used for analysis of the compounds at a flow rate of 150 µL/min and at a constant temperature of 25 °C. The chromatographic method was performed with a gradient of acetonitrile (A) in millipore water (B), both with each 0.1% HCOOH, from 10% to 90% A in B within 20 min, then to 100% A within 5 min, followed by returning to starting conditions within 1 min, and re-equilibration for 8 min. 5.0 µL of sample dissolved in methanol were injected and detection was done at 205, 220, and 254 nm. As assayed through HPLC-DAD analysis, all tested compounds possessed a purity higher than 95%.
Materials: TLC was carried out on TLC plates (silica gel 60 *F*~254~ 0.2 mm, 200 × 200 mm) (Merck, Darmstadt, Germany). TLCs were visualized by spraying with cerium(IV) sulfate/ammonium molybdate and subsequent heating with a heat gun. The phosphate buffer (1 M, pH = 6.4) was prepared as follows: 7.1 g (0.05 mmol) Na~2~HPO~4~ and 6.9 g (0.05 mmol) NaH~2~PO~4~ × H~2~O was dissolved in H~2~O and diluted to 100 mL with the same solvent. The pH was controlled using a pH-meter and, if necessary, adjusted to a pH of 6.4. Solvents were concentrated by rotary evaporation below 50 °C. Purity and homogeneity of compounds were assessed by the TLC and HPLC methods.
The intermediates, **6a**--**c**, were prepared via Mitsunobu reaction according to the literature \[[@B22-molecules-23-02902]\], and the subsequent deprotection step was accomplished with TBAF according to the literature \[[@B24-molecules-23-02902]\]. Proton sponge^®^ (1,8-bis(dimethylamino)naphthalene) and other chemicals were purchased from Sigma-Aldrich (Vienna, Austria). All reagents and chemicals were used without any further purification.
3.2. Synthesis {#sec3dot2-molecules-23-02902}
--------------
*2-\[4-(Thexyldimethylsilyloxy)phenyl\]ethanol* (**5**). To a stirred solution of methyl 4-hydroxyphenylacetate **4** (1.2 g, 7.2 mmol) in anhydrous CH~2~Cl~2~ (12 mL), 1.3 mL 1,8-diazabicyclo\[5.4.0\]undec-7-ene (8.7 mmol) and 1.6 mL thexyldimethylsilyl chloride (8.0 mmol) were added successively at 0 °C. The mixture was allowed to reach ambient temperature until TLC showed complete consumption of the starting material (1.5 h). The reaction mixture was diluted with H~2~O and extracted three times with EtOAc. The combined organic layers were dried over Na~2~SO~4~ and evaporated to dryness. The crude product was purified by flash chromatography using cyclohexane (CH)/EtOAc (3:1) to obtain 2-\[4-(thexyldimethylsilyloxy)phenyl\]-acetate in quantitative yield as a colourless oil.
The residual oil was dissolved in 12 mL of anhydrous THF and then slowly treated with 7.2 mL LiAlH~4~ (1 M solution in THF) at 0 °C. After the addition of LiAlH~4~ was completed, the reaction was allowed to reach ambient temperature for 2 h. A 2 M aqueous solution of Na/K tartrate (40 mL) was slowly added at 0 °C to quench the reaction and the mixture was stirred for 1 h. Then, the solution was extracted three times with MTBE, the combined organic layers were dried over Na~2~SO~4~, and concentrated in vacuo to yield 2.0 g (98%) of crude **5** as a clear, colourless oil, which was used without further purification. *R*~f~ = 0.27 (CH:EtOAc = 2:1); ^1^H-NMR (400 MHz, CDCl~3~) δ 7.08 (d, *J* = 8.5 Hz, 2H, H-2/6), 6.78 (d, *J* = 8.5 Hz, 2H, H-3/5), 3.82 (t, *J* = 6.5 Hz, 2H, H-8), 2.80 (t, *J* = 6.5 Hz, 2H, H-7), 1.73 (hept, *J* = 6.9 Hz, 1H, CH-(CH~3~)~2~), 0.94 (d, *J* = 6.9 Hz, 6H, (CH~3~)~2~-CH), 0.94 (s, 6H, (CH~3~)~2~-C), 0.21 (s, 6H, (CH~3~)~2~-Si) ppm; ^13^C-NMR (100 MHz, CDCl~3~) δ 154.1 (C-4), 130.8 (C-1), 129.9 (C-2/6), 120.2 (C-3/5), 63.8 (C-8), 38.4 (C-7), 34.1 (CH-(CH~3~)~2~), 25.0 (C-(CH~3~)~2~), 20.1 ((CH~3~)~2~-C), 18.6 ((CH~3~)~2~-CH), −2.5 ((CH~3~)~2~-Si) ppm; HRMS (ESI) calcd. for C~16~H~29~O~2~Si \[M + H\]^+^ = 281.1937; Found: 281.1931.
### 3.2.1. General Procedure for the Synthesis of the Compounds, **7a**--**7j** {#sec3dot2dot1-molecules-23-02902}
*AcOH-assisted condensation*. A mixture of tyramine **8** (274 mg, 2.0 mmol) and the corresponding anhydride (1.9 mmol) in glacial acetic acid (3 mL) were refluxed for 1.5 h. After cooling of the reaction mixture to ambient temperature, cold H~2~O (10 mL) was added and the resultant precipitate was filtered, washed several times with cold water, and dried under reduced pressure (**7a**, **7e**). When the product did not precipitate from the solution (**7b**--**d**, **7h**--**j**), H~2~O (15 mL) was added, and the aqueous phase was extracted several times with EtOAc. The combined organic layers were washed with 1 M NaHCO~3~, dried over Na~2~SO~4~, and concentrated in vacuo to yield the crude products, which were used without further purification.
*PEG 400-assisted condensation*. A mixture of tyramine **8** (274 mg, 2.0 mmol) and the corresponding anhydride (1.9 mmol) in PEG 400 (0.3 mL) was heated under stirring at 140 °C for 4 h. After cooling to ambient temperature, a large quantity of ice-water (\~30 mL) was added. The resultant precipitate was filtered, washed several times with cold water, and dried under reduced pressure (**7a**, **7e**). For **7b**--**d** and **7f**--**j**, the aqueous phase was extracted several times with EtOAc, the combined organic layers were dried over Na~2~SO~4~, and evaporated to dryness. The crude products were purified by flash chromatography (**7a**--**c** and **7e**--**j**) or recrystallization from EtOAc/acetone/EtOH (30:5:5) (**7d**).
*4-(Thexyldimethylsilyloxy)phenethyl bromide* (**9**). To a stirred solution of PPh~3~ (1.3 g, 5.0 mmol) in anhydrous CH~2~Cl~2~ (10 mL), DDQ (1.1 g, 5.0 mmol) was added slowly at room temperature. Then, (*n*-butyl)~4~NBr (1.6 g, 5.0 mmol) and 1.2 g (4.2 mmol) of alcohol **5** (dissolved in an additional 5 mL of anhydrous CH~2~Cl~2~) were added in 10 min intervals to the thick, beige-coloured mixture. After the addition of **5**, the colour of the reaction mixture immediately changed to deep red. The reaction was stirred for 50 min at an ambient temperature until TLC showed complete consumption of the starting material. The solvent was evaporated to dryness, and the crude product was purified by flash chromatography using CH/EtOAc (1:1) to obtain 1.4 g (81%) of **9** as yellow oil. *R*~f~ = 0.70 (CH:EtOAC = 1:1); ^1^H-NMR (400 MHz, CDCl~3~) δ 7.05 (d, *J* = 8.4 Hz, 2H, H-2/6), 6.77 (d, *J* = 8.5 Hz, 2H, H-3/5), 3.52 (t, *J* = 7.8 Hz, 2H, H-8), 3.08 (t, *J* = 7.8 Hz, 2H, H-7), 1.72 (hept, *J* = 6.9 Hz, 1H, CH-(CH~3~)~2~), 0.94 (d, *J* = 6.9 Hz, 6H, (CH~3~)~2~-CH), 0.94 (s, 6H, (CH~3~)~2~-C), 0.21 (s, 6H, (CH~3~)~2~-Si) ppm; ^13^C-NMR (100 MHz, CDCl~3~) δ 154.4 (C-4), 131.5 (C-1), 129.6 (C-2/6), 120.2 (C-3/5), 38.8 (C-7), 34.1 (CH-(CH~3~)~2~), 33.3 (C-8), 25.0 (C-(CH~3~)~2~), 20.1 ((CH~3~)~2~-C), 18.6 ((CH~3~)~2~-CH), −2.5 ((CH~3~)~2~-Si) ppm; HRMS (EI) Calcd. for C~16~H~27~SiOBr \[M\]^+^ = 342.1014; Found: 342.1017.
### 3.2.2. General Procedure for the Synthesis of the Compounds, **11a**--**11d** {#sec3dot2dot2-molecules-23-02902}
A. Nitrogen alkylation
*Conventional method*. 6 mmol of the respective secondary amine (**11a:** isoindoline, **11b:** pyrrolidine, **11c:** morpholine, **11d:** octahydroisoindole) were dissolved in anhydrous EtOH (3 mL). Then, 206 mg (0.6 mmol) of **9** (dissolved in 1 mL anhydrous EtOH) were added and the mixture was refluxed for 72 h. The solvent was evaporated to dryness to give a residue (**10a**--**10d**), which was used in the following deprotection step without further purification.
*Proton-sponge^®^ method*. 275 mg (0.8 mmol) of **9** (dissolved in 4 mL anhydrous CH~3~CN) were mixed with a stirred solution of 120 mg (0.8 mmol) of NaI and 171 mg (0.8 mmol) of proton-sponge^®^ in anhydrous CH~3~CN (3 mL). Then, 1.6 mmol of the respective secondary amine were added and the mixture was refluxed for 20 h. The solvent was evaporated to dryness to give a residue (**10a**--**10d**), which was used in the following deprotection step without further purification.
B. Removal of the TDS-protecting group
LiOH-hydrate (126 mg, 3.0 mmol) was added to a solution of the TDS ether (**10a**--**d**, 1 mmol) in anhydrous DMF (2 mL) and the mixture was stirred at ambient temperature until TLC showed complete consumption of the starting material (3--17 h). The reaction mixture was then diluted with H~2~O (15 mL), neutralised with phosphate buffer (pH = 6.4), and extracted several times with EtOAc. The combined organic layers were dried over Na~2~SO~4~ and concentrated in vacuo to give a residue, which was purified by flash chromatography.
*N-(4-Hydroxyphenethyl)isoindoline* (**11a**). Compound **11a** was prepared from **9** via **10a** as a white amorphous solid and purified by flash chromatography using CH/EtOAc (1:3). Yield: 60% (proton-sponge^®^ method), 0% (conventional method); *R*~f~ = 0.30 (CH:EtOAC = 1:3); ^1^H-NMR (400 MHz, DMSO-*d*~6~) δ 9.15 (s, 1H, 4-OH), 7.24--7.16 (m, 4H, ArH), 7.05 (d, *J* = 8.4 Hz, 2H, H-2/6), 6.67 (d, *J* = 8.3 Hz, 2H, H-3/5), 3.87 (s, 4H, CH~2~-N), 2.86--2.81 (m, 2H, H-8), 2.69 (t, *J* = 7.7 Hz, 2H, H-7) ppm; ^13^C-NMR (100 MHz, DMSO-*d*~6~) δ 155.9 (C-4), 140.5 (ArC), 130.7 (C-1), 129.9 (C-2/6), 127.0 (ArC), 122.6 (ArC), 115.4 (C-3/5), 58.9 (CH~2~-N), 57.9 (C-8), 34.3 (C-7) ppm; HRMS (EI) calcd. for C~16~H~17~NO \[M\]^+^ = 239.1310; Found: 239.1303.
*N-(4-Hydroxyphenethyl)pyrrolidine* (**11b**). Compound **11b** was prepared from **9** via **10b** as a white amorphous solid and purified by flash chromatography using CHCl~3~/MeOH (1:1). Yield: 81% (proton-sponge^®^ method), 86% (conventional method); *R*~f~ = 0.22 (CHCl~3~:MeOH = 1:1); ^1^H-NMR (400 MHz, CDCl~3~) δ 6.99 (d, *J* = 8.3 Hz, 2H, H-2/6), 6.63 (d, *J* = 8.3 Hz, 2H, H-3/5), 2.75 (s, 4H, H-7/8), 2.69--2.62 (m, 4H, CH~2~-N), 1.88--1.79 (m, 4H, CH~2~-CH~2~-N) ppm; ^13^C-NMR (100 MHz, CDCl~3~) δ 155.2 (C-4), 130.6 (C-1), 129.5 (C-2/6), 115.7 (C-3/5), 58.6 (C-8), 54.0 (CH~2~-N), 34.2 (C-7), 23.3 (CH~2~-CH~2~-N) ppm; HRMS (EI) calcd. for C~12~H~17~NO \[M\]^+^ = 191.1310; Found: 191.1304.
*N-(4-Hydroxyphenethyl)morpholine* (**11c**). Compound **11c** was prepared from **9** via **10c** as a white amorphous solid and purified by flash chromatography using CHCl~3~/MeOH (15:1). Yield: 87% (proton-sponge^®^ method), 87% (conventional method); *R*~f~ = 0.27 CHCl~3~:MeOH (15:1); ^1^H-NMR (400 MHz, DMSO-*d*~6~) δ 9.14 (s, 1H, 4-OH), 6.99 (d, *J* = 8.5 Hz, 2H, H-2/6), 6.65 (d, *J* = 8.5 Hz, 2H, H-3/5), 3.56 (t, *J* = 4.6 Hz, 4H, CH~2~-O), 2.62--2.57 (m, 2H, H-7), 2.44--2.39 (m, 2H, H-8), 2.41--2.35 (m, 4H, CH~2~-N) ppm; ^13^C-NMR (100 MHz, DMSO-*d*~6~) δ 155.9 (C-4), 130.7 (C-1), 129.9 (C-2/6), 115.5 (C-3/5), 66.6 (CH~2~-O), 61.1 (C-8), 53.8 (CH~2~-N), 32.1 (C-7) ppm; HRMS (EI) calcd. for C~12~H~17~NO~2~ \[M\]^+^ = 207.1259; Found: 207.1255.
*N-(4-Hydroxyphenethyl)octahydroisoindole* (**11d**). Compound **11d** was prepared from **9** via **10d** as a white amorphous solid and purified by flash chromatography using CHCl~3~/EtOH (5:2). Yield: 77% (proton-sponge^®^ method), 79% (conventional method); *R*~f~ = 0.19 (CHCl~3~:EtOH = 5:2); ^1^H-NMR (400 MHz, CDCl~3~) δ 6.93 (d, *J* = 8.3 Hz, 2H, H-2/6), 6.77 (d, *J* = 8.3 Hz, 2H, C-3/5), 3.18 (dd, *J* = 10.7, 6.3 Hz, 2H, CH~2(a)~-N), 3.06--3.00 (m, 2H, H-8), 2.93--2.87 (m, 2H, CH~2(b)~-N), 2.86--2.80 (m, 2H, H-7), 2.34--2.24 (m, 2H, CH-CH~2~), 1.67--1.58 (m, 2H, CH~2(a)~-CH), 1.54--1.45 (m, 2H, CH~2(a)~-CH~2~-CH), 1.52--1.43 (m, 2H, CH~2(b)~-CH), 1.39--1.31 (m, 2H, CH~2(b)~-CH~2~-CH) ppm; ^13^C-NMR (100 MHz, CDCl~3~) δ 156.4 (C-4), 129.5 (C-2/6), 128.1 (C-1), 115.9 (C-3/5), 59.0 (C-8), 57.1 (CH~2~-N), 36.7 (CH-CH~2~), 32.3 (C-7), 25.9 (CH~2~-CH), 22.5 (CH~2~-CH~2~-CH) ppm; HRMS (EI) calcd. for C~16~H~23~NO \[M\]^+^ = 245.1780; Found: 245.1772.
*N-(4-Hydroxyphenethyl)-4,5,6,7-tetrahydroisoindole* (**11e**). A mixture of **11a** (239 mg, 1 mmol), ammonium formate (631 mg, 10 mmol), and palladium hydroxide on carbon, 20 wt. % loading (64 mg) in anhydrous MeOH (8 mL) was refluxed for 16 hrs. The mixture was filtered through celite^®^, diluted with H~2~O, and extracted three times with EtOAc. The combined organic layers were dried over Na~2~SO~4~ and concentrated in vacuo to give 241 mg of crude **11e** as a slightly yellow oil in quantitative yields, which can be used without further purification. *R*~f~ = 0.69 (EtOAc); ^1^H-NMR (400 MHz, CDCl~3~) δ 7.00 (d, *J* = 8.2 Hz, 2H, H-2/6), 6.75 (d, *J* = 8.2 Hz, 2H, H-3/5), 6.31 (s, 2H, CH-N), 3.97--3.91 (m, 2H, H-8), 3.01--2.90 (m, 2H, H-7), 2.59--2.52 (m, 4H, CH~2~-C=), 1.76--1.68 (m, 4H, CH~2~-CH~2~-C=) ppm; ^13^C-NMR (100 MHz, CDCl~3~) δ 154.3 (C-4), 130.7 (C-1), 129.8 (C-2/6), 119.4 (C=C(H)-N), 115.9 (CH-N), 115.4 (C-3/5), 51.3 (C-8), 37.6 (C-7), 24.2 (CH~2~-CH~2~-C=), 22.0 (CH~2~-C=) ppm; HRMS (EI) calcd. for C~16~H~19~NO \[M\]^+^ = 241.1467; Found: 241.1465.
### 3.2.3. General Procedure for the Reduction of Heterocyclic N-Imides {#sec3dot2dot3-molecules-23-02902}
The corresponding imide, **7a/7h**, (2 mmol) was dissolved in 8 mL of anhydrous THF and then treated dropwise with 4 mL LiAlH~4~ (1 M solution in THF) at 0 °C. After the addition of LiAlH~4~ was complete, the reaction was allowed to reach an ambient temperature for 2 h. Then, a 2 M aqueous solution of Na/K tartrate (50 mL) was added at 0 °C to quench the reaction and the mixture was stirred for 1 h. The solution was extracted four times with MTBE, the combined organic layers were dried over Na~2~SO~4~, and concentrated in vacuo to give a residue, which was purified by flash chromatography.
*N-(4-Hydroxyphenethyl)isoindoline* (**11a**). Compound **11a** was prepared from **7a** as a white amorphous solid and purified by flash chromatography using CH/EtOAc (1:3). Yield: 72%; *R*~f~ = 0.30 (CH:EtOAC = 1:3).
*3-Hydroxy-N-(4-hydroxyphenethyl)octahydroisoindole-1-one* (**12**). Compound **12** was prepared from **7h** as a white amorphous solid and purified by flash chromatography using CH/EtOAc (1:3). Yield: 88%; *R*~f~ = 0.28 (CH:EtOAc = 1:3); HRMS (EI) calcd. for C~16~H~21~NO~3~ \[M\]^+^ = 275.1521; Found: 275.1527.
### 3.2.4. Procedures for the Synthesis of Dienones, **13a**--**j**, **14a**, **14c**, **15** {#sec3dot2dot4-molecules-23-02902}
*Conventional method*. A solution of the cyclic imide, **7a**--**j,** or amide, **12**, (1.5 mmol) in CH~3~CN (20 mL) and H~2~O (8 mL) at 0 °C was treated with PIDA (644 mg, 2.0 mmol), and stirred for 7 min at this temperature. The reaction mixture was diluted with EtOAc and washed with a 1 M aqueous solution of NaHCO~3~. The aqueous phase was re-extracted three times with EtOAc. The combined organic layers were dried over Na~2~SO~4~ and concentrated in vacuo to give a residue, which was purified by flash chromatography.
*Phosphate buffer method*. 1 mmol of the respective tertiary amine, **11a/11c**, was dissolved in 1.5 mL HCl (1 M in dioxane) and concentrated in vacuo to yield the corresponding hydrochloride. A solution of the hydrochloride in CH~3~CN (12 mL), H~2~O (3 mL) and phosphate buffer (1 M, pH = 6.4, 2 mL) at 0 °C was then treated with PIDA (644 mg, 2.0 mmol) and stirred for 7 min at this temperature. The solvent was evaporated to dryness, and the crude product was purified by flash chromatography.
*N-\[2-(1-Hydroxy-4-oxocyclohexa-2,5-dien-1-yl)ethyl\]phthalimide* (**13a**). Compound **13a** was prepared from **7a** as white crystals and purified by flash chromatography using CH/EtOAc (1:3). Yield: 67%; *R*~f~ = 0.42 (CH:EtOAc = 1:3); m.p.: 161--162 °C; ^1^H-NMR (300 MHz, DMSO-*d*~6~) δ 7.88--7.80 (m, 4H, ArH), 6.97 (d, *J* = 10.2 Hz, 2H, H-2/6), 6.10 (d, *J* = 10.2 Hz, 2H, H-3/5), 5.88 (s, 1H, 1-OH), 3.68--3.50 (m, 2H, H-8), 2.08--1.88 (m, 2H, H-7) ppm; ^13^C-NMR (100 MHz, DMSO-*d*~6~) δ 185.0 (C-4), 167.7 ((CO)N), 152.2 (C-2/6), 134.4 (ArC), 131.7 (ArC), 127.1 (C-3/5), 123.0 (ArC), 67.5 (C-1), 37.8 (C-7), 33.1 (C-8) ppm; HRMS (EI) calcd. for C~16~H~13~NO~4~ \[M\]^+^ = 283.0845; Found: 283.0845.
*N-\[2-(1-Hydroxy-4-oxocyclohexa-2,5-dien-1-yl)ethyl\]maleimide* (**13b**). Compound **13b** was prepared from **7b** as yellow crystals and purified by flash chromatography using CH/EtOAc (1:5). Yield: 17%; *R*~f~ = 0.40 (CH:EtOAc = 1:5); m.p.: 151--152 °C; ^1^H-NMR (300 MHz, DMSO-*d*~6~) δ 6.99 (s, 2H, CH-(CO)N), 6.91 (d, *J* = 10.1 Hz, 2H, H-2/6), 6.08 (d, *J* = 10.1 Hz, 2H, H-3/5), 5.85 (s, 1H, 1-OH), 3.45--3.38 (m, 2H, H-8), 1.93--1.85 (m, 2H, H-7) ppm; ^13^C-NMR (100 MHz, DMSO-*d*~6~) δ 185.0 (C-4), 170.8 ((CO)N), 152.1 (C-2/6), 134.6 (CH-(CO)N), 127.1 (C-3/5), 67.4 (C-1), 37.9 (C-7), 32.8 (C-8) ppm; HRMS (EI) calcd. for C~12~H~11~NO~4~ \[M\]^+^ = 233.0688; Found: 233.0686.
*N-\[2-(1-Hydroxy-4-oxocyclohexa-2,5-dien-1-yl)ethyl\]succinimide* (**13c**). Compound **13c** was prepared from **7c** as a white solid and purified by flash chromatography using CHCl~3~/CH~3~CN (1:3). Yield: 55%; *R*~f~ = 0.51 (CHCl~3~:CH~3~CN = 1:3); m.p.: 128--129 °C; ^1^H-NMR (400 MHz, DMSO-*d*~6~) δ 6.93 (d, *J* = 10.2 Hz, 2H, H-2/6), 6.10 (d, *J* = 10.2 Hz, 2H, H-3/5), 5.86 (s, 1H, 1-OH), 2.57 (s br, 4H, CH~2~-(CO)N), 3.38--3.31 (m, 2H, H-8), 1.89--1.77 (m, 2H, H-7) ppm; ^13^C-NMR (100 MHz, DMSO-*d*~6~) δ 185.5 (C-4), 178.0 ((CO)N), 152.6 (C-2/6), 127.5 (C-3/5), 67.9 (C-1), 37.5 (C-7), 33.9 (C-8), 28.4 (CH~2~-(CO)N) ppm; HRMS (EI) calcd. for C~12~H~13~NO~4~ \[M\]^+^ = 235.0845; Found: 235.0826.
*4,5-Dichloro-N-\[2-(1-hydroxy-4-oxocyclohexa-2,5-dien-1-yl)ethyl\]phthalimide* (**13d**). Compound **13d** was prepared from **7d** as white crystals and purified by flash chromatography using CH/EtOAc (1:1). Yield: 40%; *R*~f~ = 0.22 (CH:EtOAc = 1:1); m.p.: 213--214 °C; ^1^H-NMR (400 MHz, DMSO-*d*~6~) δ 8.17 (s, 2H, ArH), 6.96 (d, *J* = 10.1 Hz, 2H, H-2/6), 6.10 (d, *J* = 10.1 Hz, 2H, H-3/5), 5.89 (s, 1H, 1-OH), 3.62--3.56 (m, 2H, H-8), 2.02--1.95 (m, 2H, H-7) ppm; ^13^C-NMR (100 MHz, DMSO-*d*~6~) δ 185.5 (C-4), 166.4 ((CO)N), 152.6 (C-2/6), 137.7 (C(Cl)=), 132.1 (C=C(CO)N), 127.6 (C-3/5), 125.6 (ArC), 67.9 (C-1), 38.0 (C-7), 34.0 (C-8) ppm; HRMS (EI) calcd. for C~16~H~11~Cl~2~NO~4~ \[M\]^+^ = 351.0065; Found: 351.0090.
*3,4-Dichloro-N-\[2-(1-hydroxy-4-oxocyclohexa-2,5-dien-1-yl)ethyl\]maleimide* (**13e**). Compound **13e** was prepared from **7e** as yellowish crystals and purified by flash chromatography using CH/EtOAc (1:1). Yield: 64%; *R*~f~ = 0.30 (CH:EtOAc = 1:1); m.p.: 168--169 °C; ^1^H-NMR (400 MHz, DMSO-*d*~6~) δ 6.95 (d, *J* = 10.1 Hz, 2H, H-2/6), 6.11 (d, *J* = 10.1 Hz, 2H, H-3/5), 5.91 (s br, 1H, 1-OH), 3.53--3.46 (m, 2H, H-8), 1.95--1.90 (m, 2H, H-7) ppm; ^13^C-NMR (100 MHz, DMSO-*d*~6~) δ 185.4 (C-4), 163.3 ((CO)N), 152.5 (C-2/6), 132.9 (C(Cl)=), 127.6 (C-3/5), 67.8 (C-1), 37.9 (C-7), 34.8 (C-8) ppm; HRMS (EI) calcd. for C~12~H~9~Cl~2~NO~4~ \[M\]^+^ = 300.9909; Found: 300.9914.
*N-\[2-(1-Hydroxy-4-oxocyclohexa-2,5-dien-1-yl)ethyl\]pyridine-2,3-dicarboximide* (**13f**). Compound **13f** was prepared from **7f** as white crystals and purified by flash chromatography using CHCl~3~/CH~3~CN (1:1). Yield: 19%; *R*~f~ = 0.37 (CHCl~3~:CH~3~CN = 1:1); m.p.: 167--168 °C; ^1^H-NMR (400 MHz, DMSO-*d*~6~) δ 8.95 (dd, *J* = 5.0, 1.5 Hz, 1H, ArH), 8.27 (dd, *J* = 7.7, 1.5 Hz, 1H, ArH), 7.77 (dd, *J* = 7.7, 5.0 Hz, 1H, ArH), 6.98 (d, *J* = 10.1 Hz, 2H, C-2/6), 6.11 (d, *J* = 10.1, 2H, H-3/5), 5.88 (s, 1H, 1-OH), 3.69--3.57 (m, 2H, C-8), 2.05--1.94 (m, 2H, H-7) ppm; ^13^C-NMR (100 MHz, DMSO-*d*~6~) δ 185.5 (C-4), 166.6 ((CO)N), 155.2 (ArC), 152.6 (C-2/6), 152.0 (ArC), 131.6 (ArC), 128.3 (ArC), 127.7 (ArC), 127.6 (C-3/5), 68.0 (C-1), 38.1 (C-7), 33.7 (C-8) ppm; HRMS (EI) calcd. for C~15~H~12~N~2~O~4~ \[M\]^+^ = 284.0797; Found: 284.0792.
*N-\[2-(1-Hydroxy-4-oxocyclohexa-2,5-dien-1-yl)ethyl\]morpholine-3,5-dione* (**13g**). Compound **13g** was prepared from **7g** as a yellowish solid and purified by flash chromatography using CH/EtOAc (1:5). Yield: 18%; *R*~f~ = 0.33 (CHCl~3~:EtOAc = 1:5); m.p.: 142--143 °C; ^1^H-NMR (400 MHz, DMSO-*d*~6~) δ 6.94 (d, *J* = 10.1 Hz, 2H, H-2/6), 6.12 (d, *J* = 10.0 Hz, 2H, H-3/5), 4.36 (s, 4H, CH~2~-(CO)N), 3.70--3.56 (m, 2H, H-8), 1.89--1.78 (m, 2H, H-7) ppm; ^13^C-NMR (100 MHz, DMSO-*d*~6~) δ 185.5 (C-4), 170.1 ((CO)N), 152.7 (C-2/6), 127.5 (C-3/5), 68.0 (C-1), 67.4 (CH~2~-(CO)N), 37.8 (C-7), 33.8 (C-8) ppm; HRMS (EI) calcd. for C~12~H~13~NO~5~ \[M\]^+^ = 251.0794; Found: 251.0794.
*N-\[2-(1-Hydroxy-4-oxocyclohexa-2,5-dien-1-yl)ethyl\]hexahydrophthalimide* (**13h**). Compound **13h** was prepared from **7h** as yellow crystals and purified by flash chromatography using CH/EtOAc (1:3). Yield: 79%; *R*~f~ = 0.29 (CH:EtOAc = 1:3); m.p.: 135--136 °C; ^1^H-NMR (400 MHz, DMSO-*d*~6~) δ 6.94 (d, *J* = 10.1 Hz, 2H, H-2/6), 6.10 (d, *J* = 10.1 Hz, 2H, H-3/5), 5.84 (s, 1H, 1-OH), 3.40--3.35 (m, 2H, H-8), 2.93--2.82 (m, 2H, CH-(CO)N), 1.85--1.80 (m, 2H, H-7), 1.71 (s, 2H, CH~2(a)~-CH), 1.60--1.51 (m, 2H, CH~2(b)~-CH), 1.42--1.32 (m, 2H, CH~2(a)~-CH~2~-CH), 1.31--1.21 (m, 2H, CH~2(b)~-CH~2~-CH) ppm; ^13^C-NMR (100 MHz, DMSO-*d*~6~) δ 185.4 (C-4), 179.7 ((CO)N), 152.7 (C-2/6), 127.5 (C-3/5), 67.9 (C-1), 39.3 (CH-(CO)N), 37.6 (C-7), 33.8 (C-8), 23.5 (CH~2~-CH), 21.6 (CH~2~-CH~2~-CH) ppm; HRMS (EI) calcd. for C~16~H~19~NO~4~ \[M\]^+^ = 289.1314; Found: 289.1310.
*N-\[2-(1-Hydroxy-4-oxocyclohexa-2,5-dien-1-yl)ethyl\]-3,4,5,6-tetrahydrophthalimide* (**13i**). Compound **13i** was prepared from **7i** as an orange solid and purified by flash chromatography using CH/EtOAc (1:1). Yield: 88%; *R*~f~ = 0.18 (CH:EtOAc = 1:1); m.p.: 93--94 °C; ^1^H-NMR (400 MHz, DMSO-*d*~6~) δ 6.92 (d, *J* = 10.1 Hz, 2H, H-2/6), 6.08 (d, *J* = 10.1 Hz, 2H, H-3/5), 5.85 (s, 1H, 1-OH), 3.42--3.36 (m, 2H, H-8), 2.24--2.17 (m, 4H, CH~2~-C=), 1.86 (dd, *J* = 8.5, 6.8 Hz, 2H, H-7), 1.69--1.62 (m, 4H, CH~2~-CH~2~-C=) ppm; ^13^C-NMR (100 MHz, DMSO-*d*~6~) δ 185.5 (C-4), 170.9 ((CO)N), 152.6 (C-2/6), 141.5 (C=C(CO)), 127.5 (C-3/5), 67.9 (C-1), 38.6 (C-7), 33.0 (C-8), 21.3 (CH~2~-CH~2~-C=), 19.9 (CH~2~-C=) ppm; HRMS (EI) calcd. for C~16~H~17~NO~4~ \[M\]^+^ = 287.1158; Found: 287.1160.
*N-\[2-(1-Hydroxy-4-oxocyclohexa-2,5-dien-1-yl)ethyl\]-1,2,3,6-tetrahydrophthalimide* (**13j**). Compound **13j** was prepared from **7j** as white crystals and purified by flash chromatography using CH/EtOAc (1:1). Yield: 49%; *R*~f~ = 0.28 (CH:EtOAc = 1:1); m.p.: 145--146 °C; ^1^H-NMR (400 MHz, DMSO-*d*~6~) δ 6.90 (d, *J* = 10.1 Hz, 2H, H-2/6), 6.09 (d, *J* = 10.1 Hz, 2H, H-3/5), 5.87 (s, 1H, 1-OH), 5.85--5.82 (m, 2H, CH=CH), 3.31--3.36 (m, 2H, H-8), 3.11--3.06 (m, 2H, CH-(CO)N), 2.39--2.32 (m, 2H, CH~2(a)~-CH), 2.21--2.13 (m, 2H, CH~2(b)~-CH), 1.79 (td, *J* = 7.5, 1.5 Hz, 2H, H-7) ppm; ^13^C-NMR (100 MHz, DMSO-*d*~6~) δ 185.5 (C-4), 180.3 ((CO)N), 152.5 (C-2/6), 128.1 (CH=CH), 127.6 (C-3/5), 67.8 (C-1), 38.9 (CH-(CO)N), 37.8 (C-7), 34.1 (C-8), 23.5 (CH~2~-CH) ppm; HRMS (EI) calcd. for C~16~H~17~NO~4~ \[M\]^+^ = 287.1158; Found: 287.1154.
*N-\[2-(1-Hydroxy-4-oxocyclohexa-2,5-dien-1-yl)ethyl\]isoindoline* (**14a**). Compound **14a** was prepared from **11a** applying the phosphate buffer method as a brownish solid and purified by flash chromatography using CHCl~3~/EtOH (1:5). Yield: 16%; *R*~f~ = 0.50 (CHCl~3~:EtOH = 1:5); m.p.: 103--104 °C; ^1^H-NMR (400 MHz, DMSO-*d*~6~) δ 7.24--7.12 (m, 4H, ArH), 6.99 (d, *J* = 10.1 Hz, 2H, H-2/6), 6.06 (d, *J* = 10.1 Hz, 2H, H-3/5), 3.81--3.77 (m, 4H, CH~2~-N), 2.70--2.62 (m, 2H, H-8), 1.93--1.85 (m, 2H, H-7) ppm; ^13^C-NMR (100 MHz, DMSO-*d*~6~) δ 185.3 (C-4), 153.2 (C-2/6), 139.8 (ArC), 126.5 (ArC), 126.3 (C-3/5) 122.0 (ArC), 68.0 (C-1), 58.3 (CH~2~-N), 50.0 (C-8), 38.6 (C-7) ppm; HRMS (EI) calcd. for C~16~H~17~NO~2~ \[M\]^+^ = 255.1259; Found: 255.1251.
*N-\[2-(1-Hydroxy-4-oxocyclohexa-2,5-dien-1-yl)ethyl\]morpholine* (**14c**). Compound **14c** was prepared from **11c** applying the phosphate buffer method as a brownish solid and purified by flash chromatography using EtOAc/EtOH (1:1). Yield: 28%; *R*~f~ = 0.37 (EtOAc:EtOH = 1:1); m.p.: 98--99 °C; ^1^H-NMR (400 MHz, DMSO-*d*~6~) δ 6.95 (d, *J* = 10.0 Hz, 2H, H-2/6), 6.04 (d, *J* = 10.0 Hz, 2H, H-3/5), 3.56--3.46 (m, 4H, CH~2~-O), 2.32--2.26 (m, 4H, CH~2~-N), 2.25--2.20 (m, 2H, H-8), 1.79 (t, *J* = 7.6 Hz, 2H, H-7) ppm; ^13^C-NMR (100 MHz, DMSO-*d*~6~) δ 185.8 (C-4), 153.8 (C-2/6), 126.8 (C-3/5), 68.5 (C-1), 66.6 (CH~2~-O), 53.7 (CH~2~-N), 53.4 (C-8), 37.0 (C-7) ppm; HRMS (EI) calcd. for C~12~H~17~NO~3~ \[M\]^+^ = 223.1208; Found: 223.1201.
*3-Hydroxy-N-\[2-(1-hydroxy-4-oxocyclohexa-2,5-dien-1-yl)ethyl\]octahydroisoindole-1-one* (**15**). Compound **15** was prepared from **12** as a beige solid and purified by flash chromatography using EtOAc. Yield: 65%; *R*~f~ = 0.14 (EtOAc); m.p.: 127--128 °C; ^1^H-NMR (400 MHz, DMSO-*d*~6~) δ 6.97--6.91 (m, 2H, H-2/6), 6.08 (d, *J* = 11.0 Hz, 2H, H-3/5), 5.90 (d, *J* = 6.6 Hz, 1H, 9′-OH), 5.82 (s, 1H, 1-OH), 4.55 (d, *J* = 6.6 Hz, 1H, H-9′), 3.39--3.31 (m, 1H, H-8~(a)~), 3.05--2.96 (m, 1H, H-8~(b)~), 2.63--2.56 (m, 1H, H-3′), 2.06--1.98 (m, 1H, H-8′), 1.89--1.82 (m, 1H, H-7~(a)~), 1.83--1.77 (m, 1H, H-4′~(a)~), 1.80--1.72 (m, 1H, H-7~(b)~), 1.72--1.66 (m, 1H, H-7′~(a)~), 1.49--1.35 (m, 3H, H-4′~(b)~/5′~(a)~/6′~(a)~), 1.19--1.06 (m, 1H, H-6′~(b)~), 0.95--0.89 (m, 1H, H-5′~(b)~), 0.91--0.83 (m, 1H, H-7′~(b)~) ppm; ^13^C-NMR (100 MHz, DMSO-*d*~6~) δ 185.6 (C-4), 175.2 (C-2′), 153.2 (C-2/6), 127.3 (C-3/5), 85.6 (C-9′), 68.1 (C-1), 40.8 (C-8′), 38.5 (C-3′), 38.1 (C-7), 35.2 (C-8), 26.3 (C-7′), 23.3 (C-6′), 23.2 (C-4′), 23.1 (C-5′) ppm; HRMS (EI) calcd. for C~16~H~21~NO~4~ \[M\]^+^ = 291.1471; Found: 291.1469.
3.3. Cytotoxicity against Human (Cancer) Cells {#sec3dot3-molecules-23-02902}
----------------------------------------------
### 3.3.1. Cell Culture {#sec3dot3dot1-molecules-23-02902}
Human CCRF-CEM leukemia and MDA-MB-231 breast cancer cells lines were kept in RPMI1640 medium (Gibco^®^, ThermoFisher Scientific Inc., New York, NY, USA), supplemented with 2 mM [l]{.smallcaps}-glutamine (Gibco^®^), 10% heat-inactivated foetal bovine serum (FBS, Gibco^®^), 100 units/mL Penicillin (PAA), and 100 µg/mL Streptomycin (Gibco^®^) (1% Pen/Strep). HCT-116 and U251 cells were cultured in high-glucose Dulbecco's Modified Eagle Medium (DMEM, Gibco^®^) containing 2 mM [l]{.smallcaps}-glutamine, 10% FBS, and 1% Pen/Strep. MRC-5 cells were grown in Minimum Essential Medium (MEM, Gibco^®^) supplemented with 2 mM [l]{.smallcaps}-glutamine, 10% FBS, and 1% Pen/Strep. All cells were kept in a humidified 5% CO~2~ atmosphere at 37 °C and passaged at 90% confluence.
### 3.3.2. XTT Viability Assay {#sec3dot3dot2-molecules-23-02902}
A Cell Proliferation Kit II (XTT) was purchased from Sigma-Aldrich and performed as described previously \[[@B65-molecules-23-02902]\] and in accordance with the manufacturer's protocol. In brief, adherent cell lines were seeded at a density of 50,000 cells/mL or 100,000 cells/mL (MRC-5) in 96 well plates (100 µL, flat bottom) and grown for 24 h before test compounds were added. Suspension cells (CCRF-CEM) were seeded at 100,000 cells/mL and test compounds were added immediately. After 72 h, XTT solution was added for another 90 min or 4 h (CCRF-CEM cells) and absorbance was measured at 490 nm with a reference wave length of 650 nm (Hidex Sense Microplate Reader 425-301, Hidex, Turku, Finland). Results are expressed as a percentage of the vehicle-treated (0.5% DMSO) control cells. Vinblastine served as the positive control (0.01 µg/mL).
3.4. In Vitro Growth Inhibition Assay of Plasmodium Falciparum NF54 {#sec3dot4-molecules-23-02902}
-------------------------------------------------------------------
In vitro activity against erythrocytic stages of *P. falciparum* was determined by a modified \[^3^H\]-hypoxanthine incorporation assay \[[@B66-molecules-23-02902]\] using the drug-sensitive NF54 strain and the standard drug, chloroquine (Sigma C6628). Briefly, parasite cultures incubated in RPMI 1640 medium with 5% AlbuMAX^TM^ (without hypoxanthine) were exposed to serial drug dilutions in microtiter plates. After 48 h of incubation at 37 °C in a reduced oxygen atmosphere, 0.5 μCi \[^3^H\]-hypoxanthine was added to each well of the plate. Cultures were incubated for a further 24 h before they were harvested onto glass-fiber filters and washed with distilled water. The radioactivity was counted using a Betaplate^TM^ liquid scintillation counter (Wallac, Zurich). The results were recorded as counts per minute (CPM) per well at each drug concentration and expressed as a percentage of the untreated controls. IC~50~ values were calculated from the sigmoidal inhibition curves using Microsoft Excel. Chloroquine was used as the control.
3.5. In vitro Growth Inhibition Assay of Trypanosoma Brucei Rhodesiense {#sec3dot5-molecules-23-02902}
-----------------------------------------------------------------------
*Trypanosoma brucei rhodesiense*, STIB 900 strain, and the standard drug, melarsoprol, were used for the assay. Minimum Essential Medium (50 μL) supplemented with 25 mM HEPES, 1g/L additional glucose, 1% MEM non-essential amino acids (100×), 0.2 mM 2-mercaptoethanol, 1 mM Na-pyruvate, and 15% heat-inactivated horse serum was added to each well of a 96-well microtiter plate \[[@B67-molecules-23-02902]\]. Serial drug dilutions of 11 three-fold dilution steps covering a range from 100 to 0.002 μg/mL were prepared. Then, 4 × 10^3^ bloodstream forms of *T. b. rhodesiense* (STIB 900) in 50 μL were added to each well and the plate was incubated at 37 °C under a 5% CO~2~ atmosphere for 72 h. 10 μL Alamar Blue (resazurin, 12.5 mg in 100 mL double-distilled water) was then added to each well and incubation continued for a further 2--4 h \[[@B68-molecules-23-02902]\]. Then, the plates were read with a Spectramax Gemini XS microplate fluorometer (Molecular Devices Cooperation, Sunnyvale, CA, USA) using an excitation wavelength of 536 nm and an emission wavelength of 588 nm. The IC~50~ values were calculated from the sigmoidal inhibition curves using the microplate reader software, Softmax Pro (Molecular Devices Cooperation, Sunnyvale, CA, USA). Melarsoprol was used as the control.
3.6. Cytotoxicity against L6 Cells {#sec3dot6-molecules-23-02902}
----------------------------------
Assays were performed in 96-well microtiter plates, each well containing 100 μL of RPMI 1640 medium supplemented with 1% [l]{.smallcaps}-glutamine (200 mM) and 10% foetal bovine serum, and 4000 L6 cells (a primary cell line derived from rat skeletal myoblasts). Serial drug dilutions of 11 threefold dilution steps covering a range from 100 to 0.002 μg/mL were prepared. After 72 h of incubation, the plates were inspected under an inverted microscope to assure growth of the controls and sterile conditions. 10 μL of Alamar Blue solution was then added to each well and the plates incubated for another 2 h. Then, the plates were read with a Spectramax Gemini XS microplate fluorometer (Molecular Devices Cooperation, Sunnyvale, CA, USA) using an excitation wavelength of 536 nm and an emission wavelength of 588 nm. The IC~50~ values were calculated by linear regression from the sigmoidal dose inhibition curves using the microplate reader software, Softmax Pro (Molecular Devices Cooperation, Sunnyvale, CA, USA). Podophyllotoxin (Sigma P4405) was used as the control.
4. Conclusions {#sec4-molecules-23-02902}
==============
In conclusion, we have synthesized a series of jacaranone imides and amines with promising antiproliferative activities from commercially available methyl hydroxyphenyl acetate (**4**) and tyramine (**8**). Although the substances showed beneficial physicochemical properties, antiprotozoal effects remained comparatively weak. Imide **13i** showed the highest activity against *P. falciparum* NF54 with an IC~50~ of 1.28 µM, while the lowest IC~50~ against *T. b. rhodesiense* was displayed by the morpholine derivate **14c** with 0.27 µM. The conjugated imides, **13b**, **13e**, and **13i**, exhibited the overall highest cytotoxicity against all tested cancer cell lines.
We are aware that some of the performed chemical modifications did not result in druggable chemical entities. However, we consider that the exploration of a multifaceted chemical lead as present in the jacaranone scaffold through systematic derivatizations may open doors to unexpected biological properties.
The authors are grateful to Rudolf Bauer for supporting the XTT experiments and Sara Crockett for help in English editing. The authors acknowledge the financial support by the University of Graz.
**Sample Availability:** Samples of the compounds **13a**--**j**, **14a**, **14c** and **15** are available from the authors.
Supplementary material associated with this article are available online. Contents: Compared overall yields of the key products. Calculated physicochemical parameters and models. Full results of the XTT viability assay. Data and NMR spectra of the prepared compounds.
######
Click here for additional data file.
Conceptualization, A.P.; Data curation, A.P., N.K., W.S., R.S., M.K. and M.-M.K.; Formal analysis, A.P. and R.S.; Investigation, G.L., N.K., W.S. and M.-M.K.; Methodology, A.P., G.L., N.K., W.S., R.S., M.K. and M.-M.K.; Project administration, A.P.; Resources, A.P.; Supervision, A.P.; Validation, A.P., N.K., W.S., R.S. and M.K.; Writing---original draft, A.P. and M.-M.K.; Writing---review & editing, N.K., W.S., R.S. and M.K.
This research received no external funding.
The authors declare no conflict of interest.
Figures, Schemes and Table
==========================
{#molecules-23-02902-f001}
{#molecules-23-02902-sch001}
![Reagents and conditions: (i) Pyrrolidine, \[Cp\*IrCl~2~\]~2~ (5 mol% Ir), NaHCO~3~, toluene, 110 °C, 25 h (method E: **10b**: 45%); (ii) PPh~3~, DDQ, TBAB, CH~2~Cl~2~, RT, 50 min (81%); (iii) secondary amine, NaI, proton sponge^®^, CH~3~CN, 20 h (method F: **10a**: 72%, **10b**: 87%, **10c**: 87%, **10d**: 94%); (iv) LiOH, DMF, RT, 3--17 h (**11a**: 84%, **11b**: 93%, **11c**: 100%, **11d**: 82%); (v) ammonium formate, Pd(OH)~2~/C, MeOH, reflux, 16 h (100%); (vi) LiAlH~4~, THF, 0 °C, 90 min (method D: **11a**: 72%, **11b**: 0%, **11c**: 0%, **11d**: 0%, **12**: 88%); (vii) PhI(OAc)~2~, CH~3~CN/H~2~O/phosphate buffer (12:3:2), pH = 6.4, 0 °C, 7 min (**14a**: 16%, **14b**: 0%, **14c**: 28%, **14d**: 0%, **14e**: 0%); (viii) PhI(OAc)~2~, CH~3~CN/H~2~O (12:5), 0 °C, 7 min (**15**: 65%).](molecules-23-02902-sch002){#molecules-23-02902-sch002}
{#molecules-23-02902-f002}
{#molecules-23-02902-f003}
molecules-23-02902-t001_Table 1
######
In vitro antiparasitic activity, host toxicity, and key physicochemical properties of tested compounds.
Compd. *P. falc.* ^a^ SI ^b^ *T.b.rhod.* ^c^ SI ^b^ Cyt. L6 ^d^ Chemical Structure log*P* tPSA (7.4)
--------- ---------------- -------- ----------------- -------- ------------- ---------------------------------- -------- ------------
Chl. 0.002
Mel. 0.004
Pod. 0.007
**13a** 3.78 1.3 1.58 3.2 5.08  0.85 74.68
**13b** 4.42 6.1 2.15 12.5 26.80  −0.18 74.68
**13c** 8.63 1.1 6.93 1.4 9.90  −0.60 74.68
**13d** 3.24 1.9 5.71 1.1 6.28  1.89 74.68
**13e** 74.38 0.1 2.26 4.5 10.26  −0.38 74.68
**13f** 28.04 5.5 44.75 3.4 153.48  −0.06 87.57
**13g** 11.82 6.6 15.32 5.1 77.54  −1.13 83.91
**13h** 3.04 1.0 1.70 1.7 2.96  0.81 74.68
**13i** 1.28 2.7 0.80 4.4 3.52  0.66 74.68
**13j** 3.93 2.0 0.97 8.3 8.04  0.55 74.68
**14a** 2.91 1.0 0.57 4.9 2.81  1.89 41.74
**14c** 10.93 0.3 0.27 12.9 3.46  0.04 49.77
**15** 6.18 2.0 1.52 8.3 12.63  0.58 77.84
^a^*P. falciparum*, strain NF54, erythrocytic stages; ^b^ SI is the ratio: IC~50~ in L6 cells/IC~50~ in each parasite; ^c^ *T. brucei rhodesiense*, strain STIB900 trypomastigote forms; ^d^ cytotoxicity L6 cells rat skeletal myoblasts. Reference drugs: Chloroquine (chl., IC~50~ = 0.002 ± 0.001), melarsoprol (mel., IC~50~ = 0.004 ± 0.003), podophyllotoxin (pod., IC~50~ = 0.007 ± 0.002). The IC~50~ value of each reference drug is the mean from multiple measurements taken in parallel with the compounds of interest. IC~50~ values of the tested compounds are means of two to three independent assays. The individual IC~50~ values within each assay varied \<25%. The physical properties were predicted by using Marvin 18.10.0, ChemAxon (<https://www.chemaxon.com>).
|
{
"pile_set_name": "PubMed Central"
}
|
Apple Watch
The Apple Watch is a smartwatch which incorporates fitness tracking plus other health-oriented capabilities as well as integration with iOS and other Apple products and services and is developed by Apple Inc. The device is available in four variants which are Apple Watch Sport, Apple Watch, Apple Watch Hermès, and Apple Watch Edition. The Watch is distinguished by different combinations of cases and first or third party interchangeable bands.
The Apple Watch relies on a wirelessly connected iPhone either via Bluetooth or Wi-Fi to perform many of its default functions such as calling and texting. It is compatible with the iPhone 5 or later models running the iOS 8.2 or later.
Design
The Apple Watch comes in four collections and features two case sizes: 38 mm (1.5 in) and 42 mm (1.7 in). The case of the watch includes a mechanism to enable the straps to be interchangeable. The device is designed to withstand splashes of water.
Input
The watch includes a “digital crown” which can be turned to scroll or zoom and pressed to return to the home screen, and a touchscreen that features Force Touch technology, which makes it pressure-sensitive and capable of distinguishing between a tap and a press. The watch also has a side button which can be used to display a list of contacts, or access Apple Pay.
Battery and Charging
The device’s battery can last for 18 hours of mixed usage. Apple Watch is charged by means of inductive charging. The watch will enter a “power reserve” mode if the battery depletes to less than 10% and this allows the user to continue to read the time for an additional 72 hours. The watch reverts to its original mode when recharged.
Hardware
The Apple Watch uses the S1 system-on-chip. It provides haptic feedback when an alert or a notification is received using a linear actuator called the “Taptic Engine” . The watch is also equipped with a built-in heart rate sensor, which uses both infrared and visible-light LEDs and photodiodes.
Storage and Memory
The Apple Watch has 8 GB of storage which allows the user to store up to 2 GB of music and 75 MB of photos. When paired with an iPhone, all music on that iPhone is also available from the Apple Watch.
Software and Support
Apple Watch runs watchOS, which is based around a home screen with circular app icons. The OS can be navigated using the touchscreen or the crown on the side of the watch.
It is capable of receiving notifications, messages, and phone calls via a paired iPhone. “Glances” allow users to swipe between pages containing widget-like displays of information. WatchOS also supports Handoff to send content from Apple Watch to an iOS or OS X device, and act as a viewfinder for an iPhone camera, Siri is also available for voice commands, although it is not capable of responding with voice prompts. Apple Watch also supports Apple Pay, and enables its use with older iPhone models that do not contain near-field communication (NFC) support.
|
{
"pile_set_name": "Pile-CC"
}
|
Twistaplot
Twistaplot is a series of children's gamebooks, that were published by Scholastic from 1982 to 1985. Books #1, #4, #9, and #14 were written by R.L. Stine, who would go on to write the Fear Street series and the Goosebumps series, which in turn spawned the gamebook spin-off series Give Yourself Goosebumps. The remaining books were written by various authors including Louise Munro Foley. They were Scholastic's response to the Choose Your Own Adventure series. After the success of the Goosebumps series, the Twistaplot titles that were written by R. L. Stine were reissued with new covers in 1994 and 1995.
Style and gameplay
Twistaplot covers a wide variety of genres, including science fiction, fantasy, and horror. Similar to the Give Yourself Goosebumps series, they are novels with branching plots. The books are written from the second-person perspective, in present-tense form. The protagonist in each book is never referred to by name, and the protagonist's gender is ambiguous. Thus the reader can easily imagine himself/herself as the protagonist of the storyline. But unlike the Give Yourself Goosebumps series, the books have interior illustrations.
Spin-offs
After the success of Twistaplot, the series spawned a series of computer games for Scholastic's electronic magazine, Microzine. It also spawned another gamebook spin-off titled Pick-a-Path, which was intended for a younger audience.
Books
Twistaplot
The Time Raider
The Train of Terror
The Formula for Trouble
Golden Sword of Dragonwalk
The Sinister Studios of KESP-TV
Crash Landing!
The Video Avenger
Race into the Past
Horrors of the Haunted Museum
Mission of the Secret Spy Squad
Camp-Out on Danger Mountain
Journey to Vernico 5
Midnight at Monster Mansion
Instant Millionaire
Spellcaster
Secrets of the Lost Island
Ghost Riders of Goldspur
Calling Outer Space
Pick-a-Path
The Dandee Diamond Mystery
The Roller Coaster Ghost
The Great Baseball Championship
The Amazing Bubblegum Caper
The Super Trail Bike Race
Mystery at Mockingbird Manor
The Fantastic Journey of the Space Shuttle Astra
The Magic Top Mystery
Jungle Adventure
The Mystery of the Missing Mummy
Dinosaur Adventure
The Ballerina Mystery
The Secret of 13
RIM, The Rebel Robot
The Hot Dog Gang Caper
Adventure at Camp Schoonover
Murf the Monster
See also
R. L. Stine
Give Yourself Goosebumps
Choose Your Own Adventure
Scholastic Corporation
Parachute Press
Louise Munro Foley
External links
Twistaplot at Gamebooks.org
Category:Gamebooks
Category:Series of children's books
Category:Scholastic Corporation books
|
{
"pile_set_name": "Wikipedia (en)"
}
|
#!/usr/bin/env ruby
#
# Put description here
#
#
#
#
#
require 'swig_assert'
require 'friends'
a = Friends::A.new(2)
raise RuntimeError if Friends::get_val1(a) != 2
raise RuntimeError if Friends::get_val2(a) != 4
raise RuntimeError if Friends::get_val3(a) != 6
|
{
"pile_set_name": "Github"
}
|
Tracklist:01. Show Me What You Got02. Do It Till We Drop03. Am I Wrong04. Desperate Love05. Let Me Be The One06. You're Not My Lover07. Jump Into The Fire08. When It Comes From The Heart09. Borrowed Time10. Back To You11. Lucky Tonight12. You're Never Alone13. Is It Too Late?14. Only Love Can Save You15. Lot To Learn16. Round And Round
|
{
"pile_set_name": "Pile-CC"
}
|
Q:
Searching for advices to build a timer for a game
Unfortunately my architecture does not work so i need your help.
The Problem which i want to solve:
I programmed a mini game in which you can select exercises like "run for 1 minute".
showing countdown anywhere in app: fragment, activity, actionbar...
do task after finish
countdown should run ahead if leaving the fragment
countdown should with the right progress again if i go back to the fragment
I tried to solve the Problem while implementing CountDownTimer. But if the countDownTimer is part of the fragment it will be destroyed if i leave the fragment. When i come back the countdowntimer begins from the beginning...
So i thought about a thread... but how can i display the countdown in the fragment and anywhereelse i want?
Will the thread alive until he is done? Even if i close the application?
So can you name please some keywords i can search for to solve the problem. Or instead describing a solution?
Thanks for your advices ;)
A:
You should probably put your counter in a Service which will run as a remote process and bind to that service everywhere you need to display the timer, then use the observer pattern to call a listener callback from you service CountDownTimer's onTick method whenever you you want to update the observers:
mCountDownTimer = new CountDownTimer(startTime, 1000) {
//update after each tick
public void onTick(long millisUntilFinished) {
long seconds = (millisUntilFinished / 1000) % 60;
long minutes = ((millisUntilFinished / 1000) / 60) % 60;
long hours = (((millisUntilFinished / 1000) / 60) / 60) % 24;
long days = (((millisUntilFinished / 1000) / 60) / 60) / 24;
if(listeners!=null){
Log.d(TAG, "days:"+days + "hours:"+ hours + "minutes:"+ minutes + "seconds:"+ seconds);
listeners.onTimeChanged(days, hours, minutes, seconds);
}
}
public void onFinish() {
if(listeners!=null){
Log.d(TAG, "timer finished");
listeners.onTimerFinish();
}
}
}.start();
|
{
"pile_set_name": "StackExchange"
}
|
This page provides one-point access to all collected information concerning
Croatia.
The information includes information about specialized institutions, hate crime legislation,
reports from inter-governmental organizations, State reports, action plans and other
national initiatives.
Latest - Action plans
Report on the implementation of the EU framework for national Roma integration strategies
European Commission. Directorate-General for Justice
Published: Brussels : European Commission, 2 April 2014
|
{
"pile_set_name": "Pile-CC"
}
|
/*
Copyright (C) 2013-2020 Expedia Inc.
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 com.hotels.styx.client.netty.connectionpool;
import com.google.common.annotations.VisibleForTesting;
import com.hotels.styx.api.Buffers;
import com.hotels.styx.api.HttpMethod;
import com.hotels.styx.api.HttpVersion;
import com.hotels.styx.api.LiveHttpRequest;
import com.hotels.styx.api.LiveHttpResponse;
import com.hotels.styx.api.Requests;
import com.hotels.styx.api.exceptions.TransportLostException;
import com.hotels.styx.api.extension.Origin;
import com.hotels.styx.client.OriginStatsFactory;
import com.hotels.styx.common.format.HttpMessageFormatter;
import com.hotels.styx.common.logging.HttpRequestMessageLogger;
import io.netty.buffer.ByteBuf;
import io.netty.channel.Channel;
import io.netty.channel.ChannelFuture;
import io.netty.channel.ChannelFutureListener;
import io.netty.channel.ChannelPipeline;
import io.netty.handler.codec.http.DefaultHttpContent;
import io.netty.handler.codec.http.DefaultHttpRequest;
import io.netty.handler.codec.http.HttpObject;
import io.netty.handler.timeout.IdleStateHandler;
import org.slf4j.Logger;
import reactor.core.publisher.BaseSubscriber;
import reactor.core.publisher.Flux;
import reactor.core.publisher.FluxSink;
import java.util.NoSuchElementException;
import java.util.Objects;
import java.util.Optional;
import java.util.concurrent.atomic.AtomicInteger;
import java.util.concurrent.atomic.AtomicReference;
import static com.hotels.styx.api.HttpHeaderNames.HOST;
import static io.netty.handler.codec.http.LastHttpContent.EMPTY_LAST_CONTENT;
import static java.lang.String.format;
import static java.util.Objects.requireNonNull;
import static java.util.concurrent.TimeUnit.MILLISECONDS;
import static org.slf4j.LoggerFactory.getLogger;
/**
* An operation that writes an HTTP request to an origin.
*/
public class HttpRequestOperation {
private static final String IDLE_HANDLER_NAME = "idle-handler";
private static final Logger LOGGER = getLogger(HttpRequestOperation.class);
private final LiveHttpRequest request;
private final Optional<OriginStatsFactory> originStatsFactory;
private final int responseTimeoutMillis;
private final AtomicInteger terminationCount = new AtomicInteger(0);
private final AtomicInteger executeCount = new AtomicInteger(0);
private final boolean requestLoggingEnabled;
private volatile long requestTime;
private final HttpRequestMessageLogger httpRequestMessageLogger;
/**
* Constructs an instance.
* @param request HTTP request
* @param originStatsFactory OriginStats factory
* @param responseTimeoutMillis response timeout in milliseconds
* @param requestLoggingEnabled
*/
public HttpRequestOperation(LiveHttpRequest request, OriginStatsFactory originStatsFactory,
int responseTimeoutMillis, boolean requestLoggingEnabled, boolean longFormat, HttpMessageFormatter httpMessageFormatter) {
this.request = requireNonNull(request);
this.originStatsFactory = Optional.ofNullable(originStatsFactory);
this.responseTimeoutMillis = responseTimeoutMillis;
this.requestLoggingEnabled = requestLoggingEnabled;
this.httpRequestMessageLogger = new HttpRequestMessageLogger("com.hotels.styx.http-messages.outbound", longFormat, httpMessageFormatter);
}
@VisibleForTesting
static DefaultHttpRequest toNettyRequest(LiveHttpRequest request) {
HttpVersion version = request.version();
HttpMethod method = request.method();
String url = request.url().toString();
DefaultHttpRequest nettyRequest = new DefaultHttpRequest(toNettyVersion(version), toNettyMethod(method), url, true);
request.headers().forEach((name, value) ->
nettyRequest.headers().add(name, value));
return nettyRequest;
}
private static io.netty.handler.codec.http.HttpMethod toNettyMethod(HttpMethod method) {
return io.netty.handler.codec.http.HttpMethod.valueOf(method.name());
}
private static io.netty.handler.codec.http.HttpVersion toNettyVersion(HttpVersion version) {
return HttpVersion.HTTP_1_0.equals(version)
? io.netty.handler.codec.http.HttpVersion.HTTP_1_0
: io.netty.handler.codec.http.HttpVersion.HTTP_1_1;
}
private static boolean requestIsOngoing(RequestBodyChunkSubscriber bodyChunkSubscriber) {
return bodyChunkSubscriber != null && bodyChunkSubscriber.requestIsOngoing();
}
public Flux<LiveHttpResponse> execute(NettyConnection nettyConnection) {
AtomicReference<RequestBodyChunkSubscriber> requestRequestBodyChunkSubscriber = new AtomicReference<>();
requestTime = System.currentTimeMillis();
executeCount.incrementAndGet();
Flux<LiveHttpResponse> responseFlux = Flux.create(sink -> {
if (nettyConnection.isConnected()) {
RequestBodyChunkSubscriber bodyChunkSubscriber = new RequestBodyChunkSubscriber(request, nettyConnection);
requestRequestBodyChunkSubscriber.set(bodyChunkSubscriber);
addProxyBridgeHandlers(nettyConnection, sink);
new WriteRequestToOrigin(sink, nettyConnection, request, bodyChunkSubscriber)
.write();
if (requestLoggingEnabled) {
httpRequestMessageLogger.logRequest(request, nettyConnection.getOrigin());
}
} else {
sink.error(new TransportLostException(nettyConnection.channel(), nettyConnection.getOrigin()));
}
});
if (requestLoggingEnabled) {
responseFlux = responseFlux
.doOnNext(response -> {
httpRequestMessageLogger.logResponse(request, response);
});
}
return responseFlux.map(response ->
Requests.doFinally(response, cause -> {
if (nettyConnection.isConnected()) {
removeProxyBridgeHandlers(nettyConnection);
if (requestIsOngoing(requestRequestBodyChunkSubscriber.get())) {
LOGGER.warn("Origin responded too quickly to an ongoing request, or it was cancelled. Connection={}, Request={}.",
new Object[]{nettyConnection.channel(), this.request});
nettyConnection.close();
requestRequestBodyChunkSubscriber.get().dispose();
}
}
}));
}
private void addProxyBridgeHandlers(NettyConnection nettyConnection, FluxSink<LiveHttpResponse> sink) {
Origin origin = nettyConnection.getOrigin();
Channel channel = nettyConnection.channel();
channel.pipeline().addLast(IDLE_HANDLER_NAME, new IdleStateHandler(0, 0, responseTimeoutMillis, MILLISECONDS));
originStatsFactory.ifPresent(
originStatsFactory -> channel.pipeline()
.addLast(RequestsToOriginMetricsCollector.NAME,
new RequestsToOriginMetricsCollector(originStatsFactory.originStats(origin))));
channel.pipeline().addLast(
NettyToStyxResponsePropagator.NAME,
new NettyToStyxResponsePropagator(sink, origin, responseTimeoutMillis, MILLISECONDS, request));
}
private void removeProxyBridgeHandlers(NettyConnection connection) {
ChannelPipeline pipeline = connection.channel().pipeline();
terminationCount.incrementAndGet();
try {
pipeline.remove(IDLE_HANDLER_NAME);
if (originStatsFactory.isPresent()) {
pipeline.remove(RequestsToOriginMetricsCollector.NAME);
}
pipeline.remove(NettyToStyxResponsePropagator.NAME);
} catch (NoSuchElementException cause) {
long elapsedTime = System.currentTimeMillis() - requestTime;
LOGGER.error("Failed to remove pipeline handlers from pooled connection. elapsedTime={}, request={}, terminationCount={}, executionCount={}, cause={}",
new Object[]{elapsedTime, request, terminationCount.get(), executeCount.get(), cause});
}
}
@Override
public int hashCode() {
return Objects.hash(request);
}
@Override
public boolean equals(Object obj) {
if (this == obj) {
return true;
}
if (obj == null || getClass() != obj.getClass()) {
return false;
}
HttpRequestOperation other = (HttpRequestOperation) obj;
return Objects.equals(this.request, other.request);
}
@Override
public String toString() {
return new StringBuilder(32)
.append(this.getClass().getSimpleName())
.append("{httpRequest=")
.append(this.request)
.append('}')
.toString();
}
private static final class WriteRequestToOrigin {
private final FluxSink<LiveHttpResponse> responseFromOriginFlux;
private final NettyConnection nettyConnection;
private final LiveHttpRequest request;
private final RequestBodyChunkSubscriber requestBodyChunkSubscriber;
private WriteRequestToOrigin(FluxSink<LiveHttpResponse> responseFromOriginFlux, NettyConnection nettyConnection, LiveHttpRequest request,
RequestBodyChunkSubscriber requestBodyChunkSubscriber) {
this.responseFromOriginFlux = responseFromOriginFlux;
this.nettyConnection = nettyConnection;
this.request = request;
this.requestBodyChunkSubscriber = requestBodyChunkSubscriber;
}
public void write() {
Channel originChannel = this.nettyConnection.channel();
if (originChannel.isActive()) {
io.netty.handler.codec.http.HttpRequest httpRequest = makeRequest(request);
originChannel.writeAndFlush(httpRequest)
.addListener(subscribeToRequestBody());
} else {
responseFromOriginFlux.error(new TransportLostException(originChannel.remoteAddress(), nettyConnection.getOrigin()));
}
}
private ChannelFutureListener subscribeToRequestBody() {
return headersFuture -> {
if (headersFuture.isSuccess()) {
headersFuture.channel().read();
Flux.from(request.body())
.map(Buffers::toByteBuf)
.subscribe(requestBodyChunkSubscriber);
} else {
String channelIdentifier = String.format("%s -> %s", nettyConnection.channel().localAddress(), nettyConnection.channel().remoteAddress());
LOGGER.error(format("Failed to send request headers. origin=%s connection=%s request=%s",
nettyConnection.getOrigin(), channelIdentifier, request), headersFuture.cause());
responseFromOriginFlux.error(new TransportLostException(nettyConnection.channel().remoteAddress(), nettyConnection.getOrigin()));
}
};
}
private io.netty.handler.codec.http.HttpRequest makeRequest(LiveHttpRequest request) {
DefaultHttpRequest nettyRequest = toNettyRequest(request);
Optional<String> host = request.header(HOST);
if (!host.isPresent()) {
nettyRequest.headers().set(HOST, nettyConnection.getOrigin().hostAndPortString());
}
return nettyRequest;
}
}
private static final class RequestBodyChunkSubscriber extends BaseSubscriber<ByteBuf> {
private final NettyConnection nettyConnection;
private final LiveHttpRequest request;
private final Channel channel;
private volatile boolean completed;
private RequestBodyChunkSubscriber(LiveHttpRequest request, NettyConnection nettyConnection) {
this.request = request;
this.channel = nettyConnection.channel();
this.nettyConnection = nettyConnection;
}
@Override
public void hookOnComplete() {
channel.writeAndFlush(EMPTY_LAST_CONTENT)
.addListener(future -> completed = true);
}
@Override
public void hookOnError(Throwable e) {
completed = true;
}
@Override
public void hookOnNext(ByteBuf chunk) {
HttpObject msg = new DefaultHttpContent(chunk);
channel.writeAndFlush(msg)
.addListener((ChannelFuture future) -> {
request(1);
if (future.isSuccess()) {
future.channel().read();
} else {
String channelIdentifier = String.format("%s -> %s", nettyConnection.channel().localAddress(), nettyConnection.channel().remoteAddress());
LOGGER.error(format("Failed to send request body data. origin=%s connection=%s request=%s",
nettyConnection.getOrigin(), channelIdentifier, request), future.cause());
this.onError(new TransportLostException(nettyConnection.channel().remoteAddress(), nettyConnection.getOrigin()));
}
});
}
boolean requestIsOngoing() {
return !completed;
}
}
}
|
{
"pile_set_name": "Github"
}
|
Q:
Mangling sk_buff data in a Netfilter module
I am building a module that does massive mangling of the protocol contained within. I am only mangling Layer 4 packets. I convert them back on the other end to how they should be. The packet size is still 1:1, so there really isn't a need to reallocate skb...
That said, I change skb->data, and then return NF_ACCEPT from my NF_IP_LOCAL_OUT hook. I have another hook that shows me that the sk_buff is passed to NF_IP_POST_ROUTING, but the packet never actually leaves the host (as in I don't see it in Wireshark). I can't figure out what is going on. Is the packet being dropped somewhere? I am not using any other kernel hooks other than the netfilter hooks and I am not manipulating the destination, so it should leave the machine without question.
Any ideas what might be causing it? Do I need to register my custom IPPROTO with the kernel? I have it in /etc/protocols I figured that would be enough. Or am I just going down the wrong path entirely? I tried working with the ESP and AH code that's in the kernel for IPsec, since it also mangles the packets, but all the transform code is more complicated than I need for what I am doing.
A:
Resolution
It would seem I was doing everything correctly with a single exception. I wasn't recalculating the IP header's checksum (since I was changing the protocol id itself, this is mandatory).
Code
iph->check = 0;
iph->check = ip_fast_csum(iph, iph->ihl);
And presto it worked.
|
{
"pile_set_name": "StackExchange"
}
|
Szadek
Szadek is a town in Zduńska Wola County, Łódź Voivodeship, Poland, with 1,976 inhabitants (2016).
History
In 1921, there were 535 Jews out of the total 3,058 residents in Szadek. At that time, the Jewish population was concentrated mostly along Sieradzka Street, where they constituted almost 90% of inhabitants.
During World War II, 410 Jews were imprisoned in a ghetto. On 14 August 1942, all of its inhabitants were deported to the Chełmno extermination camp.
References
External links
Official town website
Category:Cities and towns in Łódź Voivodeship
Category:Zduńska Wola County
Category:Kalisz Governorate
Category:Łódź Voivodeship (1919–1939)
Category:Holocaust locations in Poland
|
{
"pile_set_name": "Wikipedia (en)"
}
|
In Autharium's original Terms and Conditions, the company made an incredibly blatant rights grab that put the NY BPHs to shame. Basically, even if you remove your book from their database, they would still own all licencing and ancillary rights to your IP property.
Well instead of addressing the matter directly with PG, these slimy bottom-feeders filed a bad faith DMCA notice claiming copyright violation in an effort to shut up PG's revelation. Ironic considering their own method for stealing any meaningful copyright from authors, huh?
As PG noted, if you're going to pick a fight, you should know who your up against. Which is frankly what makes the folks running Autharium a bunch of dumbasses.
The best we can do as writers is to watch each others backs from slimeball organization like Autharium. If you're a writer, spread this story as far and wide as possible. Information is power, and we need to arm our fellows.
|
{
"pile_set_name": "Pile-CC"
}
|
[unreadable] The HIV Evolution and Dynamics Meeting is a small annual HIV meeting with a 15 year history. This meeting has given people who perform data analysis, mathematician modeling, and HIV evolutionary analysis a specific opportunity to come together to discuss new research, both in terms of new studies and their implications, and new analysis tools and methods that can be applied to HIV. Mathematical and statistical aspects of the work can be discussed in greater depth than is possible in the larger HIV meetings, which primarily focus on experienial and clinical presentations. Historically this meeting has alternated venues between Europe and the US, to allow greater access to the meeting for researchers on both sides of the Atlantic. It can be one of the most important meetings of the year for HIV Scientists directly involved in the analysis of data. The meeting draws individuals who model in vivo dynamics and disease progression, global variation of HIV with considerations of the epidemic history, immunology and vaccine strategies, and individuals that study the emergence of drug resistance. The talks and posters range from important new studies that have complex aspects that may be presented more from a traditional view, but are discussed from an analysis perspective; mathematical oriented talks from scientists outside the HIV field who develop new analysis methods that might usefully be brought into the sphere of HIV research. On the order of 100 to 150 scientists attend, this number has depended on the venue in the past. There is ample time for discussion and developing contacts to facilitate and extend ongoing studies, and to initiate new collaborative efforts. The meeting has traditionally been supported by the OAR and the CDC with supplemental funding coming in through industry and the fund raising efforts of the primary organizer in any given year. We are requesting a continuation of the invaluable support received this grant for past 5 years which has permitted the attendance of junior investigators and participants from under developed countries. The UCSD Office of Continuing Medical Education has offered to support the financial and organizational infrastructure of the conference for the 3 year period for which we are requesting funding, and will work directly with the primary scientific organizer regardless of his or her home institution. The HIV Evolution and Dynamics Meeting is a small, intensive, annual HIV meeting with a 15 year history. This meeting has given people who perform data analysis, mathematical modeling, and HIV evolutionary analysis an opportunity to come together to discuss new research, both in terms of new studies and their implications, and new analysis tools and methods that can be applied to HIV. The information presented and generated by this meeting has potential important implications regarding HIV transmission, prevention, disease progression and treatment. [unreadable] [unreadable] [unreadable] [unreadable]
|
{
"pile_set_name": "NIH ExPorter"
}
|
MK Demands Public Inquiry Into the Duchy of Cornwall
Mebyon Kernow has re-iterated its call for a full Public Inquiry into the Duchy of Cornwall and Cornwall’s ambiguous constitutional relationship with the Crown.
|
{
"pile_set_name": "OpenWebText2"
}
|
Mind-body medicine in primary care. Implications and applications.
A growing body of research in basic and clinical science confirms that psychological states and interventions affect physiologic and pathophysiologic processes and the outcome of clinical illness. This evidence is reviewed in detail, with special attention paid to those findings that have particular relevance for primary care physicians. Specific guidelines are offered for incorporating mind-body principles and techniques into primary care practice.
|
{
"pile_set_name": "PubMed Abstracts"
}
|
INTRODUCTION
============
Gene therapy showed great potential in the treatment of various diseases, including infertility, HIV, cancer, etc. ([@R1]). The success of gene therapy, e.g., in cancer treatment, is mainly dependent on the development of an efficient gene delivery vector ([@R2]). During the delivery process, the gene carrier must cross multiple biological barriers and the cell membrane, as well as escape endosomal entrapment and degradation by nucleases ([@R3]). Compared with virus-based delivery strategies, nonviral gene delivery approaches face substantial challenges not only regarding the loading and release of DNA/RNA, targeted delivery, and intracellular uptake but also with respect to the issues of biocompatibility and immune response ([@R4], [@R5]).
Currently, the vigorous effort in nanotechnology provides great potential in engineering more stable and efficient vehicles for gene transfer to cancer cells. Owing to their unique physical-chemical properties, numbers of nanomaterials have emerged and been used in gene delivery ([@R6]--[@R8]). Among them, gold nanoparticles (Au NPs) with specific size and surface functionalization can overcome obstacles associated with cellular, local, and systemic delivery of gene sequences, which has become one of the most studied gene carrier systems in vitro and in vivo ([@R3], [@R9]). One important approach was introduced by Mirkin and colleagues in 2006 ([@R10]). They reported a type of spherical nucleic acid, in which Au NPs improve the stability of oligonucleotides and prevent their degradation by nucleases, meanwhile exhibiting more than 99% cellular uptake to reach a high effective concentration. Inspired by their work, our group previously selected ultrasmall (\~2 nm) Au NPs to deliver triplex-forming oligonucleotides into a nucleus, directly interfering with gene transcription process without using any nuclear targeting sequence ([@R11]). In subsequent work, we demonstrated that variation of particle core size (\<10 nm) and surface functionalization could be used synergistically to control the cellular uptake processes ([@R12]).
However, these strategies still face some shortcomings. On one hand, the net uptake amount of ultrasmall NPs is still low because of cell exocytosis, which resulted in little therapeutic effect ([@R13]). On the other hand, efficient clearance of the particles from the body represents a critical requirement of safe translation of NPs to clinical practice for disease treatment ([@R14]). To take advantage of both enhanced nuclear internalization of small-sized NPs and enhanced tumor accumulation/retention of large-sized NPs ([@R15]), stimuli-responsive drug delivery systems were developed ([@R16]), which shrink their size by responding to internal tumor microenvironments \[e.g., enzymes ([@R17]), low pH ([@R18]), etc.\] or external stimuli \[e.g., ultraviolet (UV) ([@R19]), near-infrared (NIR) irradiation ([@R20]), magnetic field ([@R21]), etc.\]. Most representatively, Fukumura and colleagues proposed a multistage NP system composed of a gelatin core with amino--polyethylene glycol quantum dots conjugated to the rim, in which the engineered 100-nm NPs can shrink to 10 nm after they extravasated from leaky regions of the tumor vasculature and being exposed to the overexpressed protease (matrix metalloproteinase-2) in the tumor microenvironment ([@R17]). Similarly, Tan and colleagues assembled a DNA-based nuclear-uptake nanodrug system carrying a cell-targeted NIR-responsive nanotruck for drug-resistant cancer therapy ([@R22]). By using this size-photocontrollable nanodrug delivery system, anticancer drugs were efficiently accumulated in the nuclei to effectively kill cancer cells. In a recent publication, Wang and colleagues reported a smart polymeric clustered nanoparticle (iCluster), which exhibits an initial size of ∼100 nm ([@R23]). Once iCluster accumulated at tumor sites, the intrinsic tumor extracellular acidity triggered the discharge of platinum prodrug-conjugated poly(amidoamine) dendrimers (diameter, ∼5 nm) to kill cancer cells. Most recently, an effective surface-to-core drug delivery strategy was reported by Kim *et al.* ([@R24]), in which small Au NPs (\~15 nm) with programmable DNA were located in the interconnected channels of silica NPs (\~150 nm). This "nanoparticle-loaded nanoparticle" exhibited better accumulation in tumor tissue, and the small Au NPs were subsequently released for deep penetration into the three-dimensional tumor environment. Although those examples are conceptually impressive, there are still plenty of challenges to developing smarter nanosystems simultaneously realizing enhanced tumor retention and cellular uptake, especially realizing controlled therapeutic efficacy. Specifically, it is imperative to establish an efficient delivery system for enhanced and controlled gene interference--based therapeutics.
Inspired by nature's ability to hybridize DNA, DNA-mediated self-assembled gold-DNA nanostructures (\~200 nm) were designed and fabricated in this work. As illustrated in [Fig. 1](#F1){ref-type="fig"}, the sunflower-like nanostructures exhibited strong NIR absorption and photothermal conversion ability. Upon NIR irradiation, the large-sized nanostructure could disassemble and liberate ultrasmall Au NPs. The released 2-nm NPs modified with the *c-myc* oncogene silencing sequence improved the NPs nucleus permeability and thus enhanced the transfection efficiency. By synergistically controlling the preincubation time in vitro, circulation time in vivo, and the time point of irradiation, we achieved increased cellular uptake amount, tunable gene silencing efficacy, and controlled tumor inhibition effect. The transformable nanosunflowers provide an excellent model for the design of nanovehicle, and the system has great potential in biomedical applications.
{#F1}
RESULTS
=======
Self-assembly and characterization of the large-sized nanostructures
--------------------------------------------------------------------
We first synthesized 2-nm Au NPs with tiopronin coverage (Au-TIOP NPs) ([@R25]) and then modified them with thiol-oligonucleotides (SH-POY2T) through a well-established ligand exchange method ([@R26]). Here, POY2T is a 23-nt (nucleotide) oligonucleotide that can bind with the P2 promoter of the *c-myc* oncogene to form a triplex structure and down-regulate *c-myc* expression of cancer cells ([Fig. 1B](#F1){ref-type="fig"}, step ④) ([@R27]). Meanwhile, another single-stranded sequence was designed and named as CA to complementarily hybridize with the tail part of POY2T sequence, thus blocking the ability of the POY2T binding with the *c-myc* oncogene. Furthermore, the 2-nm Au-POY2T NPs and CA sequence self-assemble into large-sized sunflower-like structures, as schematically shown in [Fig. 1A](#F1){ref-type="fig"}.
First, the morphology of the self-assembled nanostructures was investigated using electron microscopy techniques. As shown in [Fig. 2A](#F2){ref-type="fig"}, uniform sunflower-shaped nanostructures were identified under the transmission electron microscope (TEM) observation. The size of an individual self-assembled structure was measured to be approximately 200 nm with highly uniform morphology. It was found that nanostructures formed with a thinner center (light in color) and thicker edges (dark in color). It should be pointed out that most of the ultrasmall inorganic NPs were distributed around the outer rim of the nanostructures resulting in the sunflower-like shape ([Fig. 1A](#F1){ref-type="fig"}). At the same time, the bio-TEM with lower voltage (80 kV) captured the same view ([Fig. 2B](#F2){ref-type="fig"}), revealing more details of the polymer constituents representing the DNA moieties of the "sunflower" nanostructures. Moreover, high-resolution TEM images verified the particular edge distribution of small NPs (black dots) at the rim of the sunflower ([Fig. 2C](#F2){ref-type="fig"}). Furthermore, the scanning electron microscope (SEM) confirmed the uniform and unique morphology of the self-assembled nanostructures. As shown in [Fig. 2D](#F2){ref-type="fig"}, the different magnifications of the monodispersed nanostructures indicated the high yield and reliability of the DNA-mediated self-assembly process. Last, enlarged SEM images demonstrated that the center and the edge of the nanostructures was distinctly different, which was consistent with the TEM observations.
{#F2}
Surface plasmon resonance and photothermal characterization of the self-assembled nanostructures
------------------------------------------------------------------------------------------------
Previous studies have demonstrated that the surface plasmonic effect of Au NPs could be changed as a result of self-assembly or agglomeration ([@R28]). Hence, we next examined the UV-Vis absorption spectra of the ultrasmall Au NPs before and after DNA-mediated self-assembly. As shown in [Fig. 3A](#F3){ref-type="fig"} (blue curve), monodispersed individual 2-nm Au-POY2T NPs (TEM image shown in fig. S1A) did not exhibit significant absorption in the range from 400 to 1000 nm, which is the characteristic spectrum of ultrasmall Au NPs. However, after the DNA-mediated self-assembly process, the obtained nanostructures exhibited a broad and strong absorption in the NIR region (red curve). The surface plasmon resonance absorption band was found from 740 to 810 nm, and the maximum absorption wavelength was centered at 767 nm, which means that the self-assembled nanostructures have significant NIR absorption and could generate heat under NIR irradiation ([@R29]). The strong NIR absorbance observed of the self-assembled nanostructure could be attributed to the close interparticle spacing and the nonuniform spatial distribution of the individual ultrasmall particles within the large-sized nanostructure ([@R30]).
{#F3}
We next tested the heat response of the self-assembled nanostructures under NIR irradiation ([@R31]). According to a formula ([@R32], [@R33]), the melting point (*T*~m~) of the complementary DNA sequences (POY2T and CA) selected in this work was calculated to be about \~41°C, which means that half of the duplex structure between POY2T and CA dissociates when the local temperature reaches 41°C. To this end, the photothermal effect of the self-assembled nanostructures was studied. Compared with the control group, as shown in [Fig. 3B](#F3){ref-type="fig"}, the temperature of a solution containing 200-nm nanostructures increased significantly from 30° to ∼38°C only after 4-min NIR irradiation (808 nm, 1 W/cm^2^), and the temperature reached a stable plateau at \~50°C after 10-min irradiation. In contrast, the temperature rise of the pure water was less than 5°C even after 14-min irradiation ([Fig. 3C](#F3){ref-type="fig"}). Meanwhile, we also measured the heat response of nanostructures dispersed in cell culture medium. A similar photothermal effect was observed. Thus, we chose 10 min as the optimal time for NIR irradiation in the following study.
Disassembly behavior of the self-assembled nanostructures
---------------------------------------------------------
Triggered by melting dissociation, we hypothesized that the self-assembled nanostructures could shrink and disassemble into individual ultrasmall Au-POY2T NPs ([@R20], [@R22]). We found that the maximum absorption (767 nm) of the self-assembled nanostructures decreased markedly upon 10-min NIR irradiation ([Fig. 3D](#F3){ref-type="fig"}), which indicated the disassembly of the sunflower-like nanostructure. To support this explanation, the NIR-induced disassembly process was followed by TEM observation before and after NIR irradiation. Briefly, 5-μl solution of self-assembled nanostructures was dripped onto a copper mesh and then was irradiated by NIR light for 10 min and dried before TEM observation. Compared with the original morphology of nanostructures shown in [Fig. 3E](#F3){ref-type="fig"}, the self-assembled sunflower-like nanostructures changed significantly after NIR irradiation, as shown in [Fig. 3F](#F3){ref-type="fig"}. The 200-nm self-assembled structure was completely destroyed, and the size was largely reduced (\<100 nm) as well. Meanwhile, the ultrasmall particles (2-nm Au-POY2T NPs) were restored into the dispersed state and spread throughout on the grid surface (enlarged image shown in fig. S1B). These TEM images directly confirmed the dissociating response of the self-assembled gold-DNA nanostructures upon NIR irradiation, which indicated that the generated heat in proximity of the self-assembled nanostructure could reach the melting temperature of the NP network consisting of the complementary part of POY2T and CA sequence.
In addition to TEM observation, the disassembly process and size transformation of large-sized nanostructures were monitored by a particle size analyzer. Briefly, the dynamic light scattering size of self-assembled nanostructure was recorded before and after continuous NIR irradiation. As shown in [Fig. 3Ga](#F3){ref-type="fig"}, after a ligand exchange reaction from the original synthesized Au-TIOP NPs (fig. S1C), the hydrodynamic size of 2-nm Au-POY2T NPs was increased to \~5 nm with narrow size distribution. After DNA-mediated self-assembly, the obtained nanostructures exhibited a hydrodynamic size approximately 208 nm ([Fig. 3Gb](#F3){ref-type="fig"}), which was consistent with the electron microscopy characterization above. Upon NIR irradiation for 3 min, the hydrodynamic size of the larger nanostructure decreased and separated into three principal distributions, mainly appearing at \~62, \~150, and \~6 nm ([Fig. 3Gc](#F3){ref-type="fig"} and table S1), which demonstrated that the large-sized nanostructure began to disassemble as triggered by NIR irradiation. Apparently, with the continuous NIR irradiation up to 10 min, most of the ultrasmall particles (\>70%, peak approximately \~6 nm) were generated, and the larger particles visibly decreased ([Fig. 3Gd](#F3){ref-type="fig"}). As expected, irradiation with longer time (12.5 or 15 min) more completely disintegrated the large structures (table S1). However, long-time NIR irradiation (\>10 min, e.g., 12.5 min) induced significant thermal toxicity to the cells (viability, \<70%; fig. S2). Therefore, again, 10 min was confirmed as an optimized NIR irradiation time for the following study. It is reasonable that all the size changes of the self-assembled nanostructure could be attributed to the heat-induced dissociation of the nanostructure under NIR irradiation, which was consistent with the result discussed above.
Together, uniform large-sized nanostructures were self-assembled with sunflower-like morphology, which exhibited significant NIR absorption and photothermal disassembly properties. Triggered by heat-inducing NIR irradiation, the large-sized structures dissociated into smaller parts and generated ultrasmall treatment units (Au-POY2T NPs).
Enhanced cellular uptake of the self-assembled nanostructures
-------------------------------------------------------------
We then tried to apply the NIR irradiation to MCF-7 cells treated with the self-assembled gold-DNA nanostructures and evaluated their cellular uptake level in vitro. Before that, we challenged the stability of the self-assembled nanostructures both in water and 10% fetal bovine serum (FBS)--containing cell culture medium. Compared with dispersing in water, the hydrodynamic diameter of self-assembled nanostructures showed a slight increase (fig. S3), which could be explained by protein adsorption on the surface of nanostructures through electrostatic interaction ([@R34]). The formed protein corona thus may protect the nanostructures from degradation by deoxyribonucleases in the cytoplasm ([@R35]). The result indicated that the self-assembled nanostructure was kept quite stable when dispersed in cell culture medium even after 24-hour incubation.
Afterward, the cellular internalization of 2-nm Au-POY2T NPs and 200-nm self-assembled nanostructures was studied for different incubation times. The cellular uptake was quantified using inductively coupled plasma mass spectrometry (ICP-MS), and the mass of gold amount was calculated and converted to the number of 2-nm Au NPs using a previously reported method ([@R36], [@R37]). As shown in fig. S4A, the uptake amount of both nanomaterials was increased after each incubation period. Apparently, at the first 3 hours of incubation, the internalization of individual 2-nm Au-POY2T NPs was faster than the larger counterpart. However, after 6-hour incubation, MCF-7 cells contained more self-assembled nanostructures. The total internalization amount of Au-POY2T NPs contained in larger nanostructures was almost 1.7-fold higher compared to the individual Au-POY2T NP treatment after 24-hour incubation (fig. S4B). The cellular uptake results strongly suggested that different mechanisms could be involved in the cell internalization of both 2-nm Au-POY2T NPs and 200-nm self-assembled nanostructures. Moreover, this could also be explained by the cell exocytosis effect on small-sized NPs ([@R13]).
We next compared the effects of various endocytosis inhibitors on the cellular uptake process (fig. S4C) ([@R12]). Low temperature and adenosine triphosphate (ATP) depletion can suppress the energy-dependent pathway for NP internalization ([@R38]). Cooling cells to 4°C only had limited effects on the uptake of individual 2-nm Au-POY2T NPs but suppressed largely the internalization of the 200-nm self-assembled nanostructures. Similar results were observed by pretreatment of cells with sodium azide (NaN~3~)/2-deoxyglucose (DOG) to deplete ATP, followed by particle treatment at 4° or 37°C. The results indicated that the cellular uptake of large-sized nanostructures was strongly temperature and energy dependent. To understand the cellular uptake pathway in detail, we studied the effects of dynasore, nystatin, methyl-β-cyclodextrin (MβCD), chlorpromazine (CPM), and sucrose, which inhibit dynamin-mediated endocytosis, lipid raft/caveolae--dependent endocytosis, and clathrin-mediated endocytosis, respectively ([@R12]). Significantly, all of the inhibitors suppressed the cellular uptake of self-assembled nanostructures, indicating that several endocytosis pathways are involved in the internalization of large-sized nanostructures. Meanwhile, none of the inhibitors showed a notable influence of the uptake on 2-nm Au-POY2T NPs, strongly suggesting that a different pathway, i.e., membrane fusion, was involved in the uptake of 2-nm NPs, which was also consistent with our previous findings ([@R12]). Combined with the cellular uptake results and the known cell exocytosis of small-sized NPs ([@R39]), we conclude that the self-assembled nanostructures deliver more Au-POY2T NPs into cells than the individual ultrasmall ones for a long time incubation.
Controlled nucleus localization and gene silencing study of the self-assembled nanostructures
---------------------------------------------------------------------------------------------
Having demonstrated the enhanced cellular uptake of self-assembled nanostructures in vitro, the quantitative distribution of small-sized Au-POY2T NPs in nucleus was thus determined to investigate the controllable "standby" and "attack" ([Fig. 1B](#F1){ref-type="fig"}) strategy after the NIR triggering. As the schematic route shown in [Fig. 4A](#F4){ref-type="fig"}, cell nuclei were extracted for ICP-MS analysis after incubation of individual 2-nm Au-POY2T NPs, self-assembled nanostructures, and self-assembled nanostructures with NIR irradiation after different periods of preincubation time (1, 3, 6, and 12 hours). The results indicated that cell preincubation time largely affected the small-sized Au-POY2T NP internalization in the cell nucleus ([Fig. 4B](#F4){ref-type="fig"}). For example, when applying NIR irradiation after 12-hour preincubation, the number of particles in the nucleus (for a total of 24 hours of incubation) was 7.5 times higher than without NIR irradiation and 1.6 times higher than irridation after 1-hour preincubation. Compared with the control group (treated with individual 2-nm Au-POY2T NPs), the number of particles in the nucleus increased to \~170% when treated with self-assembled nanostructures and irradiated after 12-hour preincubation time (fig. S4D). These results demonstrated that the distribution of Au-POY2T NPs in the cell nucleus can be well controlled by regulating the cell preincubation time and the time point of NIR irradiation.
{#F4}
At the cellular level, with increasing preincubation time, more self-assembled nanostructures were endocytosed and standby in the cytoplasm, which was further observed by a confocal and Bio-TEM study ([Fig. 4, C and D](#F4){ref-type="fig"}) ([@R40]). After applying NIR irradiation, the produced heat dissociated the gold-DNA structures and released the small-sized Au-POY2T NPs, which can directly enter the cell nucleus. These results obviously indicated that the large-sized assemblies have much higher selectivity and efficiency to transport these small-sized Au-POY2T NPs into the cell cytoplasm and the nucleus than simple treatment with pristine small Au-POY2T NPs.
Thereafter, the NIR irradiation--controlled therapeutic effect of the nanosunflowers was evaluated by cell viability tests. As shown in [Fig. 4E](#F4){ref-type="fig"}, the anticancer activity (oncogene silencing effect) of the nanosunflowers increased markedly (\>80%) when NIR irradiation was applied after 12-hour preincubation time. Compared with the treatment of individual 2-nm Au-POY2T (30%), the self-assembled nanostructure killed more than double the cancer cells. The therapeutic effect can be controlled efficiently and accurately by changing the cell preincubation time and the irradiation time point. It is worth noting that insufficient irradiation time (e.g., 3 min) did not liberate enough small Au-POY2T NPs to achieve significant gene silencing. This behavior can be explained by the photothermal response results ([Fig. 3](#F3){ref-type="fig"}) as discussed above. Moreover, *c-myc* gene expression and protein levels were determined by reverse transcription polymerase chain reaction (PCR) and Western blots, respectively, to confirm the controllable gene regulation process. As shown in [Fig. 4F](#F4){ref-type="fig"}, the pristine POY2T sequence and the self-assembled nanostructures exhibited limited *c-myc* gene silencing ability. Treatment with individual Au-POY2T NPs decreased the *c-myc* mRNA level to about 74.9%. However, NIR irradiation at time points of 1, 3, 6, and 12 hours after the incubation with self-assembled nanostructures displayed 62.0, 45.5, 25.4, and 12.6% of *c-myc* gene suppression, respectively. Separate *c-myc* mRNA level evaluation in cytoplasm and nucleus (fig. S5) also confirmed that the nanosunflowers process better knockdown of *c-myc* in nucleus versus cytoplasm in the presence of NIR irradiation. Further determination of the *c-myc* protein levels in the different treatment groups supported the NIR-controlled protein silencing by the nanosunflowers ([Fig. 4, G and H](#F4){ref-type="fig"}). Together, these results demonstrated a superior ability of the transformable nanostructure in silencing of the *c-myc* oncogene and oncoprotein compared with the free POY2T sequence and individual Au-POY2T NPs. Moreover, the effectiveness of *c-myc* silencing can be precisely controlled by tuning cell preincubation time before applying NIR irradiation.
Controlled tumor growth inhibition study of the self-assembled nanostructures
-----------------------------------------------------------------------------
Before testing the controllable antitumor efficiency of nanosunflowers in vivo, we investigated blood compatibility of the assembled nanostructures. As shown in fig. S6A, nanosunflowers with concentrations ranging from 1 nM to 20 μM (at an equivalent POY2T dose) did not show obvious hemolysis of mouse red blood cells. Further blood biochemistry analysis (fig. S6B) also confirmed the good blood compatibility of nanosunflowers obtained in this work. Then, the MCF-7 tumor model was established by using BALB/c nude mice at day 0. After tumor volumes reached about 50 mm^3^, the animals were randomly divided into nine groups. Then, the mice were treated with 100 μl of various formulations (equivalent to 10 μM in POY2T) at days 9, 12, and 15 ([Fig. 5A](#F5){ref-type="fig"}). After each intravenous injection, the tumor-bearing mice in groups ③, ④, ⑤, and ⑥ were irradiated with a NIR laser for 10 min (to reach a local temperature above \~41°C) at 1, 3, 6, and 12 hours. During the animal experiment, no obvious body weight altering was observed ([Fig. 5B](#F5){ref-type="fig"}), indicating good biocompatibility of nanosunflowers. As shown in [Fig. 5C](#F5){ref-type="fig"}, mice treated with NIR showed no effect on tumor growth, demonstrating that light irradiation is safe and does not contribute to tumor inhibition. Noteworthy, mice treated with POY2T, Au-POY2T NPs, nanosunflowers, or nanosunflowers with NIR irradiation at 1 or 3 hours showed a slight decrease of tumor volume. Meanwhile, mice treated with nanosunflowers and irradiated at 6 hours after intravenous injection induced significant suppression of tumor growth. The most notable antitumor effect was shown in the nanosunflower-treated group irradiated at 12 hours after intravenous injection, and the tumor volume was about ^1^/~10~ compared to the control group, indicating the efficient delivery of gene silencing units into the tumor site. In addition, the NIR-triggered penetration enhancement of nanosunflowers was further demonstrated by an MCF-7 multicellular spheroid model (fig. S7) ([@R17]), which well explained the notable antitumor consequence of these nanoagents. After the mice were sacrificed at day 24, all tumors were isolated and weighted ([Fig. 5, D and E](#F5){ref-type="fig"}), together demonstrating that the nanosunflowers showed a NIR-controlled tumor growth inhibition in vivo. The quantified gold amounts inside tumors (fig. S8) also correlate to the tumor uptake of NPs very well with the therapeutic efficacy. In addition, the hematoxylin and eosin (H&E) staining slides and semiquantitative scoring results ([Fig. 5F](#F5){ref-type="fig"} and table S2) showed no histological morphology change of organs, including the heart, liver, spleen, lung, and kidney, after different treatments, indicating that nanosunflowers and NIR therapy have no remarkable side effect on normal tissues. In contrast, there was serious structure damage, a large number of inflammatory cell infiltrations, and a significant cell death in the tumor tissues, especially in groups ⑤ and ⑥, exhibiting the excellent theranostic capability of nanosunflowers.
{#F5}
DISCUSSION
==========
For a long time, the therapeutical effect of nanomedicine has been greatly challenged by complicated tumor microenvironments. As discussed above, it is almost impossible for nanoagents with a fixed size to achieve long time blood circulation, effective accumulation in tumor through the enhanced permeability and retention effect, deep tumor penetration, and efficient cell uptake at the same time. Recently, more and more attention has been paid on this "size relativity" rule by the nanomedicine community. To overcome the multiple biological barriers during the drug delivery, nanodrugs should be rationally designed. In this work, self-assembled sunflower-like nanostructures act as multiparticle carriers, which are loaded with numerous ultrasmall therapeutic units. At the cellular level, the endocytosis pathway of the large-sized nanostructure transports more small NPs inside the cells compared to a membrane fusion process of individual ultrasmall NPs. When applying NIR irradiation as a trigger, self-assembled nanostructures dissociate and disassemble, thereby releasing a large number of small NPs to target the nucleus. In tumor-bearing mice models, large-sized nanosunflowers passively target the tumor site at the first stage. With the NIR triggered transformation and shrinkage, those particles penetrate into the deeper tumor tissue and were taken up by cells ([@R15], [@R17], [@R20]). As a result, the efficient and controllable gene down-regulation was achieved, and the tumor growth was significantly inhibited as well.
The nanosunflower-based gene delivery system could be as follows: (i) A safe and controllable gene delivery tool. Gene silencing can only be activated by NIR irradiation, which occurs only at tumor sites and without side effects to normal tissues. (ii) An effective nuclear delivery vehicle. Genes/drugs can be protected by nanosunflowers from degradation/inactivation in cytoplasm and be delivered to the nucleus directly permeating the nuclear pore complex by as-released ultrasmall carriers. (iii) A switchable/tunable architecture for selective activation of nanomedicine. By NIR-triggered disassembly, the prodrugs were converted into active moieties switching "on" their properties for disease treatment.
In summary, a DNA-mediated self-assembled nanostructure was designed and fabricated in this work. The uniform sunflower-like nanostructure exhibited strong NIR absorption and showed a sensitive photothermal response. By synergistically controlling both the preincubation time in vitro (or circulation time in vivo) and the NIR irradiation time point, the transfection efficiency can be gradually controlled down to a minimum level. The obtained results of this study provide a blueprint for constructing transformable gene interference carriers with intricate functionality to adjust expression levels of genes with external control.
MATERIALS AND METHODS
=====================
Preparation of 2-nm Au-POY2T NPs
--------------------------------
First, 2-nm Au-TIOP NPs were synthesized using a previously reported method ([@R25]). Typically, 6 ml of methanol, 1 ml of acetic acid, and 5 ml of 1% HAuCl~4~ were mixed and kept stirring for 5 min, and 64 mg of tiopronin powder was added under vigorous stirring. After the solution changed color to nearly colorless, NaBH~4~ solution (100 mg in 500 μl of ice-cold water) was added into the above mixture under vigorous stirring. The reaction was terminated after 3 hours, and the resulting mixture was dialyzed (dialysis membrane, Solarbio; molecular weight cutoff, 8000 to 14,000 Da) against Milli-Q water for 72 hours, which was changed every 8 hours. Two-nanometer Au-POY2T NPs were obtained by replacing the tiopronin on the surface of Au-TIOP NPs with thiol-modified oligonucleotides (SH-POY2T: SH-C6-AAAAAATGGGT GGGTGGTTTGTTTTTGGG) through a ligand exchange method ([@R26]). SH-POY2T sequence was first treated by 5 mM Tris-(2-carboxyethyl)-phosphine (TCEP) for 30 min in phosphate-buffered saline (PBS) buffer. Then, 2-nm Au-TIOP NPs were added and kept stirring at room temperature for 24 hours. The exchange efficiency was determined by gel electrophoresis, and the intensity of the band indicates that \~50% POY2T were conjugated to the 2-nm Au NPs.
Self-assembly of the larger-sized nanostructures
------------------------------------------------
Thiol-modified CA sequence (10 μM; SH-C6-CCCAAAAACAAACCAC) was first treated by 5 mM TCEP for 30 min in PBS buffer, followed by addition of 3 × PBS, 5 mM MgCl~2~, 10 mM NaHPO~4~, and kept stirring for 3 min. Then, the freshly prepared 2-nm Au-POY2T NPs was added to the above solution, was heated to 60°C, and was reacted for 10 min. Last, the reaction was kept stirring at 35°C for another 2 hours, then cooled down to room temperature. Before further use, the obtained solution was washed twice by PBS at 5000 rpm for 5 min to remove the free particles, unbounded sequences, and excess molecules. The gold concentration of assembled nanostructures was determined by the ICP-MS method, calculated and converted to the 2-nm Au NPs.
Heat response study of the self-assembled nanostructures under the NIR irradiation
----------------------------------------------------------------------------------
Briefly, aqueous solution and cell culture medium containing self-assembled nanostructures (equivalent to 20 μM in POY2T sequence) were irradiated by using an 808-nm NIR laser at 1 W/cm^2^ for 14 min. The temperature of solutions was measured by a digital thermometer and recorded at different time points. Water and cell culture medium were used as blank controls, and each measurement was done in triplicate. The theoretical melting temperature (*T*~m~) of DNA was calculated by the formula: *T*~m~ = (*w*A + *x*T) × 2 + (*y*G + *z*C) × 4, where *w*, *x*, *y*, and *z* are the number of the bases A, T, G, and C in the sequence, respectively ([@R32]).
Cell culture
------------
MCF-7 cells (human breast cancer cell line) were purchased from the American Type Culture Collection (Manassas, VA) and maintained in low-glucose Dulbecco's modified Eagle's medium with 10% FBS and 1% antibiotic \[penicillin (100 U/ml) and streptomycin (100 μg/ml)\]. The cells were cultured in a water-jacketed CO~2~ incubator (Forma Series II 3110, Thermo Fisher Scientific Inc., USA) providing a humidified atmosphere with 5% CO~2~ at 37°C.
Cell uptake study
-----------------
MCF-7 cells were seeded in a 48-well plate at a density of ∼ 2 × 10^4^ cells per well 24 hours a day before the experiment. At the day of incubation, cells were washed three times with PBS, and as-synthesized 2-nm Au-POY2T NPs and self-assembled nanoflowers (calculated as the number of Au-POY2T NPs from the gold element amount) were added at a concentration of 100 nM and incubated at different times (1, 3, 6, 12, and 24 hours) at 37°C. After each incubation, the cells were washed three times with PBS buffer. Cell lysis buffer (250 μl per well) was used to lyse the cells, and the culture plate was kept at room temperature on a vibrator for 30 min. In addition, a freeze/thaw cycle was adopted to further facilitate the cell lysis process before the ICP sample preparation step.
Cell uptake inhibition study
----------------------------
MCF-7 cells were seeded in a 48-well plate at a density of ∼2 × 10^4^ cells per well 24 hours in advance. At the day of experiment, cells were washed three times with PBS and preincubated with the following endocytic inhibitors in complete medium for 2 hours at 37°C: MβCD (10 mM), nystatin (180 nM), sodium azide (NaN~3~, 10 mM) + DOG (50 mM), dynasore (80 μM), CPM hydrochloride (20 nM), and sucrose (450 mM). For temperature- and energy-dependent pathway study, cells were pretreated with 10 mM NaN~3~ and 50 mM DOG at 4°C for 2 hours. The concentrations of the inhibitors were used according to previous reports ([@R12]). After 2 hours, Au-POY2T NPs and self-assembled nanoflowers were added at a concentration of 100 nM of Au-POY2T NPs and incubated for another 22 hours at 37°C in the presence of the inhibitors. Untreated cells were used as a negative control, and cells treated with only NPs in the absence of inhibitors were used as a positive control. After incubation, cells were washed three times with PBS buffer, and cell lysis buffer (250 μl per well) was used to lyse the cell. The cell culture plate was kept at room temperature on a vibrator for 30 min. In addition, a freeze/thaw cycle was adopted to further facilitate the cell lysis process before the ICP sample preparation step.
Cell nucleus localization study
-------------------------------
The experimental setup of the cell nucleus localization study was schemed as shown in [Fig. 4A](#F4){ref-type="fig"}. For each 96-well plate, a number of \~10^4^ MCF-7 cells were seeded 24 hours in advance. Afterward, 100 nM 2-nm Au-TIOP NPs or self-assembled nanoflowers (equal concentration calculated as 100 nM of Au-POY2T NPs from the gold element amount) were suspended in fresh media and added to the wells. After each preincubation point, the cells were irradiated by a NIR laser for 10 min and ready for ICP-MS analysis after further incubation. Before ICP-MS sample preparation, nuclear extraction of the cells was processed. Briefly, the cells were washed with PBS, trypsinized, and centrifuged for 3 min at 179*g*. The treated cells were resuspended in 1 ml of PBS and were handled for cell nucleus extraction using a nuclear extraction kit (SN000, Solarbio, Shanghai, China). Briefly, the sample was ground in lysis buffer for 3 min, centrifuged at 700*g* for 5 min, resuspended in lysis buffer, precipitated in medium buffer, and stored in a store buffer. All the procedures were carried out at 4°C quickly to keep nucleus integrity. The extracted nuclei were analyzed by ICP-MS after a nitrolysis procedure.
Cell viability study with NIR laser irradiation
-----------------------------------------------
MCF-7 cells (10^4^ cells per well) were seeded in 96-well plates for 24 hours in advance. Afterward, 2-nm Au-POY2T NPs, self-assembled nanoflowers, and other control groups (POY2T sequence, CA sequence, and 2-nm Au-TIOP NPs) were suspended in fresh media and added to the wells. All the treated concentrations were at or equal to 1 μM in POY2T. For self-assembled nanostructure-treated groups, the cells were irradiated by an 808-nm NIR laser at 1 W/cm^2^ for 3 or 10 min after each preincubation (1, 3, 6, and 12 hours). After each irradiation, the cells were continued for incubation until 24 hours. Last, the cell viability was determined by an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Briefly, the medium was replaced with 100 μl of MTT (0.5 mg/ml), and after a 3-hour incubation, the MTT solution was replaced with 150 μl of dimethyl sulfoxide solution. The absorbance at 570 nm of each well was measured by a plate reader. Untreated cells in the medium were used as a control. All SDs were calculated from three replicates.
Tumor inhibition study
----------------------
BALB/c nude mice (6 weeks, female) were obtained from Beijing Charles River Laboratory Animal Technology Co. Ltd. (Beijing, China) and raised in a specific pathogen--free grade laboratory. All animal experiments were performed in accordance with the *Guide for the Care and Use of Laboratory Animals* proposed by the National Institutes of Health (NIH). All animal experiments were conducted with the approval of the Institutional Animal Care and Use Committee, Institute of Process Engineering, Chinese Academy of Sciences. Briefly, the MCF-7 tumor model was established by subcutaneous injection of 10^6^ MCF-7 cells into the right flank of BALB/c nude mice (about 20 g) at day 0. After tumor volumes reached about 50 mm^3^, the animals were randomly divided into nine groups (four mice per group). Then, the mice were treated with 100 μl of various formulations (equivalent to 10 μM in POY2T sequence) at days 9, 12, and 15 by intravenous injection. In groups ③, ④, ⑤, and ⑥ (as labeled in [Fig. 5](#F5){ref-type="fig"}), the tumors were irradiated with an 808-nm NIR laser (1 W/cm^2^) for 10 min (to reach the local temperature above 41°C) at 1, 3, 6, and 12 hours after each intravenous injection. In day 24, the mice were sacrificed, and all tumors were isolated and weighted.
### Statistical analysis
All data are expressed as means ± SD. Statistical differences were determined by two-tailed Student's *t* test; \**P* \< 0.05, \*\**P* \< 0.01, and \*\*\**P* \< 0.001. The density of Western blot bands was quantified using ImageJ software (NIH Image).
Supplementary Material
======================
###### http://advances.sciencemag.org/cgi/content/full/5/10/eaaw6264/DC1
###### Download PDF
###### Gold-DNA nanosunflowers for efficient gene silencing with controllable transformation
**Funding:** This work was supported by the Natural Science Foundation key project (31630027 and 31430031), NSFC-DFG project (31761133013), and a National Distinguished Young Scholars grant (31225009). The authors also appreciate the support by the "Strategic Priority Research Program" of the Chinese Academy of Sciences (grant no. XDA09030301) and support by the external cooperation program of BIC, Chinese Academy of Sciences (grant no. 121D11KYSB20130006), and the National Natural Science Foundation of China (31570968 and 81201194). A.H. is grateful to the EU for funding through an ERC Advanced Grant (694616). **Author contributions:** S.H., N.G., and X.-J.L. conceived and designed the experiments. S.H., N.G., F.C., H.G., and Y.G. performed the experiments. S.H., N.G., Y.J., and X.-J.L. analyzed the results. S.H., N.G., Z.W., A.H., and X.-J.L. wrote and revised the manuscript. S.H. and X.-J.L. supervised the entire project. **Competing interests:** The authors declare that they have no competing interests. **Data and materials availability:** All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.
Supplementary material for this article is available at <http://advances.sciencemag.org/cgi/content/full/5/10/eaaw6264/DC1>
Fig. S1. Characterization of the as-synthesized NPs.
Fig. S2. Cytotoxicity evaluation of MCF-7 cells with NIR irradiation at different times.
Fig. S3. Stability test of self-assembled nanostructures.
Fig. S4. Cellular uptake and intracellular distribution of NPs.
Fig. S5. *C-myc* mRNA level determined in cytoplasm and nucleus separately by real-time PCR.
Fig. S6. Safety evaluation of the nanosunflower structure.
Fig. S7. Penetration behavior study of fluorescein isothiocyanate--labeled nanosunflowers in multicellular spheroid model.
Fig. S8. Quantitative biodistribution of average Au content in tissues including the heart, liver, spleen, lung, kidney, and tumor after different treatments.
Table S1. Hydrodynamic size distribution of Au-POY2T NPs and nanosunflowers before and after NIR irradiation for 3, 10, 12.5, or 15 min, respectively.
Table S2. Histopathological scoring results of the H&E staining images.
[^1]: These authors contributed equally to this work.
|
{
"pile_set_name": "PubMed Central"
}
|
Q:
How to load a java.util.Set with snakeYAML
I try to load the following yaml sequence :
- Person(paul):
firstName: Paul
lastName: Lumbergh
children :
- Person(bill)
- Person(jane)
which i tried to load in the following bean :
public class Person {
private long id;
private String firstName;
private String lastName;
private Person father;
private Set<Person> children;
}
I got this error which is due to the fact that snakeYaml load my sequence in a java.util.List instead of java.util.Set.
Is it a way to force snakeYAML to load a sequence in a java.util.Set ?
org.yaml.snakeyaml.error.YAMLException: org.yaml.snakeyaml.error.YAMLException: Cannot set property='children' with value='[Person [firstName=Bill, secondName=Lumbergh], Person [firstName=Jane, secondName=Lumbergh]]' (class java.util.ArrayList) in Person [firstName=Paul, secondName=Lumbergh]
at org.yaml.snakeyaml.extensions.compactnotation.CompactConstructor$ConstructCompactObject.construct(CompactConstructor.java:163)
at org.yaml.snakeyaml.constructor.BaseConstructor.constructObject(BaseConstructor.java:183)
at org.yaml.snakeyaml.constructor.BaseConstructor.constructSequenceStep2(BaseConstructor.java:277)
at org.yaml.snakeyaml.constructor.BaseConstructor.constructSequence(BaseConstructor.java:248)
at org.yaml.snakeyaml.constructor.SafeConstructor$ConstructYamlSeq.construct(SafeConstructor.java:440)
at org.yaml.snakeyaml.constructor.BaseConstructor.constructObject(BaseConstructor.java:183)
at org.yaml.snakeyaml.constructor.BaseConstructor.constructDocument(BaseConstructor.java:142)
at org.yaml.snakeyaml.constructor.BaseConstructor.getSingleData(BaseConstructor.java:128)
at org.yaml.snakeyaml.Yaml.loadFromReader(Yaml.java:480)
at org.yaml.snakeyaml.Yaml.load(Yaml.java:411)
at com.pearson.fixy.Fixy.loadEntities(Fixy.java:105)
at com.pearson.fixy.Fixy.load(Fixy.java:126)
at com.dvidea.TestFixy.test(TestFixy.java:24)
at sun.reflect.NativeMethodAccessorImpl.invoke0(Native Method)
at sun.reflect.NativeMethodAccessorImpl.invoke(NativeMethodAccessorImpl.java:39)
at sun.reflect.DelegatingMethodAccessorImpl.invoke(DelegatingMethodAccessorImpl.java:25)
at java.lang.reflect.Method.invoke(Method.java:597)
at org.junit.runners.model.FrameworkMethod$1.runReflectiveCall(FrameworkMethod.java:44)
at org.junit.internal.runners.model.ReflectiveCallable.run(ReflectiveCallable.java:15)
at org.junit.runners.model.FrameworkMethod.invokeExplosively(FrameworkMethod.java:41)
at org.junit.internal.runners.statements.InvokeMethod.evaluate(InvokeMethod.java:20)
at org.junit.runners.BlockJUnit4ClassRunner.runChild(BlockJUnit4ClassRunner.java:76)
at org.junit.runners.BlockJUnit4ClassRunner.runChild(BlockJUnit4ClassRunner.java:50)
at org.junit.runners.ParentRunner$3.run(ParentRunner.java:193)
at org.junit.runners.ParentRunner$1.schedule(ParentRunner.java:52)
at org.junit.runners.ParentRunner.runChildren(ParentRunner.java:191)
at org.junit.runners.ParentRunner.access$000(ParentRunner.java:42)
at org.junit.runners.ParentRunner$2.evaluate(ParentRunner.java:184)
at org.junit.runners.ParentRunner.run(ParentRunner.java:236)
at org.eclipse.jdt.internal.junit4.runner.JUnit4TestReference.run(JUnit4TestReference.java:50)
at org.eclipse.jdt.internal.junit.runner.TestExecution.run(TestExecution.java:38)
at org.eclipse.jdt.internal.junit.runner.RemoteTestRunner.runTests(RemoteTestRunner.java:467)
at org.eclipse.jdt.internal.junit.runner.RemoteTestRunner.runTests(RemoteTestRunner.java:683)
at org.eclipse.jdt.internal.junit.runner.RemoteTestRunner.run(RemoteTestRunner.java:390)
at org.eclipse.jdt.internal.junit.runner.RemoteTestRunner.main(RemoteTestRunner.java:197)
A:
According to the yaml specification the set syntax is the following one :
- Person(paul):
firstName: Paul
lastName: Lumbergh
children : !!set ? Person(bill) ? Person(jane) –
|
{
"pile_set_name": "StackExchange"
}
|
RpoN of the fish pathogen Vibrio (Listonella) anguillarum is essential for flagellum production and virulence by the water-borne but not intraperitoneal route of inoculation.
To investigate the involvement of RpoN in flagellum production and pathogenicity of Vibrio (Listonella) anguillarum, the rpoN gene was cloned and sequenced. The deduced product of the rpoN gene displayed strong homology to the alternative sigma 54 factor (RpoN) of numerous species of bacteria. In addition, partial sequencing of rpoN-linked ORFs revealed a marked resemblance to similarly located ORFs in other bacterial species. A polar insertion or an in-frame deletion in the coding region of rpoN abolished expression of the flagellin subunits and resulted in loss of motility. Introduction of the rpoN gene of V. anguillarum or Pseudomonas putida into the rpoN mutants restored flagellation and motility. The rpoN mutants were proficient in the expression of other proposed virulence determinants of V. anguillarum, such as ability to grow under low available iron conditions, and expression of the LPS O-antigen and of haemolytic and proteolytic extracellular products. The infectivity of the rpoN mutants with respect to the wild-type strain was unaffected following intraperitoneal injection of fish but was reduced significantly when fish were immersed in bacteria-containing water. Thus, RpoN does not appear to regulate any factors required for virulence subsequent to penetration of the fish epithelium, but is important in the infection of fish by water-borne V. anguillarum.
|
{
"pile_set_name": "PubMed Abstracts"
}
|
Contact
Early Childhood Mental Health: What Can I Do?
Early Childhood Mental Health: What Can I Do?
Objectives
Participants will learn fundamental concepts in early childhood mental health
Participants will increase their understanding of how to intervene with challenging behaviors
Participants will improve their knowledge of how to differentiate between typical development an d atypical
Registration is closed. This event has already been held.
Early Childhood Mental Health: What Can I Do?85 Sigourney Street, Hartford, CT, 06105, US
|
{
"pile_set_name": "Pile-CC"
}
|
Q:
jQuery UI Combobox clear selection event
I have a combo box of which the HTML looks like this:
<select id="myCombo">
<option value=""></option> <!-- Not shown in jQuery UI Combobox because empty value -->
<option value="1">Option 1</option>
<option value="2">Option 2</option>
<option value="3">Option 3</option>
</select>
I've attached the jQuery UI Combobox to I as such:
$("#myCombo").combobox({
select: function () {
if ($("#myCombo").val() == "") {
//DO SOMETHING
}
else {
//DO SOMETHING ELSE
}
}
});
When I select an option by either typing and/or selecting an option, the "DO SOMETHING ELSE" part is triggered like it should, so no issue there.
However, when I clear the selection (this selects the first option of my original combo) by deleting the text or clicking the "x", nothing get's triggered, so I can't execute the "DO SOMETHING" part of my function.
How can I trigger this part? Is there maybe another event that is triggered when clearing a selection?
I have searched and found lots of topic on selecting an item, but none on clearing/deselecting something(that were answered at least).
A:
After looking further into it I've found a way to trigger an event when clearing the text.
For this I had to edit the original custom.combobox widget JS, provided by the example on the jQuery UI site
In this js look for the _removeIfInvalid function and edit it like so
_removeIfInvalid: function (event, ui) {
// Selected an item, nothing to do
if (ui.item) {
return;
}
// Search for a match (case-insensitive)
var value = this.input.val(),
valueLowerCase = value.toLowerCase(),
valid = false;
this.element.children("option").each(function () {
if ($(this).text().toLowerCase() === valueLowerCase) {
this.selected = valid = true;
return false;
}
});
// Found a match, nothing to do
if (valid) {
//**ADD this piece of code**
this._trigger("change", event, {
item: null
});
return;
}
// Remove invalid value
this.input
.val("")
.attr("title", value + " didn't match any item")
.tooltip("open");
this.element.val("");
this._delay(function () {
this.input.tooltip("close").attr("title", "");
}, 2500);
this.input.data("ui-autocomplete").term = "";
//**ADD this piece of code**
this._trigger("change", event, {
item: null
});
}
The added piece of code (I know it's added 2 times, but the code would otherwise jump out of the function before it was ran), will add a change event to the combobox that can be used in your own script. This change event, I can use to run any code I want when the selection is cleared.
$("#myCombo").combobox({
select: function () {
//DO SOMETHING ON SELECT
//IMPORTANT: The other function can't be triggered before the combobox loses focus!!
$(".custom-combobox-input").blur();
},
change:function () {
//DO SOMETHING ON CLEAR
}
});
The removeIfInvalid function is always called by default when an option can't be found and by adding an event to the control when this function is invoked is invoked, we finally have a place to execute our algorithmns.
Hopefully, more people are helped with this small fix.
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Särskilda badtider för kvinnor – politiker vill inte kommentera
Publicerad: 08 maj 2016 kl. 07.12
Uppdaterad: 18 juli 2019 kl. 14.19
1 av 3 | Foto: Jimmy Wixtröm Yusuf Aydin (KD) är den enda som vill träffa Aftonbladets Peter Kadhammar för att diskutera separata tider för kvinnor på Fittjabadet utanför Stockholm.
Den här kolumnen handlar om separata badtider för kvinnor men mest om Sverige.
På bilden till den här artikeln borde det ha varit två personer till, en från Socialdemokraterna och en från Miljöpartiet. Men den ende som hade tid och lust att träffa Aftonbladet och diskutera separata tider för kvinnor på Fittjabadet utanför Stockholm var kristdemokraten Yusuf Aydin.
Han är emot. Att kvinnor ska simma för sig cementerar gamla unkna patriarkala system från Mellanöstern och Nordafrika, anser han. Sådana normer och värderingar hör inte hemma i Sverige.
Aydin är själv invandrare, från sydöstra Turkiet. Kanske bidrar det till att han med sådan självklarhet törs uttala sig i denna fråga.
12-årig kom han för 22 år sedan hit med mamma och syskon. De tillhörde syrianska minoriteten.
– I Sverige försökte vi släppa en del av våra gamla värderingar. För oss var det inte svårt att anpassa oss. Jag lärde mig svenska på sex månader.
Fittjabadet erbjuder bad för kvinnor och flickor över 13 år lördagar 9-10 och söndagar 15.30–17. Då tjänstgör heller ingen manlig personal.
Badtiden utvidgades med lördagstimmen i vintras efter ett medborgarförslag till kultur- och fritidsnämnden från Shakhlo Altieva. Hon är miljöpartist men lämnade förslaget som privatperson. Varför har jag inte lyckats utröna, jag har genom Miljöpartiet i Botkyrka kommun bett att få tala med henne men hon har inte hört av sig.
Altieva ville också att åldersgränsen på 13 år för flickor skulle slopas:
"Har ni inte tänkt på att de flesta flickor mognar mycket tidigare nu och redan från 9 års ålder börjar känna sig obekväma att bada/simma med män och pojkar?!"
Den politiska majoriteten bestående av Socialdemokraterna, Miljöpartiet och Vänsterpartiet gick med på förslaget, bortsett från resonemanget om småflickor.
Jag söker Fredrik Olsson, politisk sekreterare för Miljöpartiet i Botkyrka. Han vill ha mina frågor skriftligt. Sedan svarar han per sms:
"Särskilda badtider har funnits i Botkyrka i över tio år och MP-Botkyrka har aldrig drivit frågan... Shakhlo skrev ett medborgarförslag om att återgå till två timmar särskilda badtider efter att det minskats till en timme."
Men ni var väl för kvinnotiderna? frågar jag i ett sms tillbaka.
"Hela majoriteten var för", svarar Olsson.
Jag söker Robert Aslan, socialdemokratisk ordförande i kultur– och fritidsnämnden i Botkyrka. Han har inte tid att träffas. I ett mail skriver han att han inte har något att tillägga som inte redan står i de skrivelser han vet att jag fått från fritidsnämndens kansli.
Socialdemokraternas politiske sekreterare i Botkyrka svarar inte när jag påminner om att jag bett att få tala med en företrädare för partiet.
Så nu sitter jag i solskenet utanför Fittjabadet med bara Yusuf Aydin från Kristdemokraterna. Det låga, röda badhuset smälter fint in i parken som sluttar ner mot Albysjön.
– Särskilda tider för kvinnor kan vara motiverat. Det beror på sammanhang och syfte, säger Aydin. Vi har varit positiva till speciella tider för att ge tjejer mer utrymme på fritidsgårdar och inom idrotten. Men när det gäller badet är syftet att upprätthålla normer och värderingar som inte hör hemma i Sverige.
Han lägger fritidsnämndens handlingar framför sig på bordet.
– Det är inte så konstigt att sådana förslag förs fram. Invandrare från Mellanöstern och Nordafrika kommer från utpräglade grupp- och klansamhällen där kontrollen av kvinnor är en viktig del. De kommer till Sverige som är ett av världens mest individualistiska och sekulära samhällen.
I ett av pappren Aydin har framför sig ställer de borgerliga partierna frågan varför "feministiska" partier som Socialdemokraterna, Miljöpartiet och Vänsterpartiet inte betonar att jämställdhet ska gälla för alla oavsett bakgrund och religion.
– Vi måste vara tydliga med vad som är självklara normer och rättigheter i Sverige. Jämställdhet. Tolerans och respekt för varandras olikheter. Att man inte tar med sig konflikterna man flytt från hit. Är vi inte tydliga med sådant skapas parallellsamhällen i vårt land.
En äldre herre går förbi med Dajmstrut i handen. Jag följer honom med blicken och funderar på vad som är typiskt svenskt.
En Dajmstrut.
Det fina badet.
Den välordnade parken.
Politiska partier som självklart tycker en viss sak och sedan står chockade inför en svängning i opinionen, eller kanske inte ens en svängning utan att vissa saker plötsligt blir fria för diskussion.
Det vällustiga skallet från mobben på internet när den finner ett nytt offer på skolgården, som det offentliga samhället allt oftare påminner om. Ena dagen går mobben i ena riktningen, nästa dag har den vänt. Inte konstigt att politiker blir strykrädda, oroliga för att säga fel, tycka fel.
Jag frågar Yusuf Aydin vad det mångkulturella samhället är, frågan är inget skämt, jag har aldrig fattat vad som avses. Han ler och säger att han vill se ett samhälle där kulturer samverkar i stället för att existera sida vid sida.
Sedan säger han att han vill läsa sina citat för han vill ju inte att det ska bli bråk om vad han sagt. Och det är ju också typiskt svenskt.
Botkyrka: Långt ifrån lagom
■ ■ ■ Botkyrka kommun mellan Stockholm och Södertälje har 89 000 invånare. De beräknas bli över 100 000 år 2021.
■ ■ ■ 56 procent av invånarna är födda i ett annat land eller har båda sina föräldrar födda utomlands. Det talas 100 olika språk i kommunen. Botkyrka och Haparanda är de enda kommunerna i Sverige där en majoritet av invånarna har utländsk bakgrund.
■ ■ ■ Botkyrkas paroll är nog Sveriges mest kända: "långt ifrån lagom". Den ser alla som kör E4:an till eller från Stockholm.
Källa: Botkyrka kommun och Wikipedia.
Av: Peter Kadhammar
KOPIERA LÄNK
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Effects of N6-cyclohexyl adenosine (CHA) on isolation-induced aggression in male mice.
Several studies have suggested adenosine receptor involvement in the modulation of aggressive behavior; however, the influence of adenosine A1 agonists on aggression is scarcely known. In this study, we examined the effect of N6-cyclohexyl adenosine (CHA; 0.025-0.4 i.p.), a selective adenosine A1 receptor agonist, on agonistic behavior elicited by isolation in male mice. Individually housed mice were exposed to anosmic standard opponents 60 min after drug administration, and the encounters were videotaped and evaluated using an ethologically based analysis. CHA exhibited an ethopharmacological profile characterized by a selective decrease of offensive behaviors (threat and attack) at the intermediate dose (0.1 mg/kg), without impairment of motor activity. In contrast, the antiaggressive action of the highest doses used (0.2 and 0.4 mg/kg) was accompanied by a marked increase of immobility. It is concluded that the behavioral effects observed in this study could be related to an adenosine modulatory action on other neurotransmitter systems (dopamine/serotonin).
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Thursday, June 13, 2013
Sissy School - Panty Check
Alright Sissies said the headmistress bend over and pull down your panties for inspection.
Amid considerable giggling the sissies all complied.
"Sissy Kaaren" snapped the headmistress, "where are your panties?"
"I um...I think I left them in my room..." said Sissy Kaaren
As the other sissies giggled one said, "Or maybe they're in the janitors room."
"Or at the boys locker room" said another .
"Maybe the postman knows where they are" another said laughing
"Or the school bus driver might have seen them earlier today." said the fouurth.
"Sissy Kaaren!" the headmistress shouted, "I want to see you in my office at the end of the school day to discuss this. Now go to your next class and at the earliest opportunity retrieve your panties and don't let me catch you without them again!"
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Q:
Is it advisable to have many clickable hyperlinks in an academic CV?
I have recently been updating my academic CV. I realise that some items are not as internationally recognised as to that every reader will be aware of their importance without googling them. Hence, I am thinking about inserting hyperlinks to those items lest the reader wish to learn more.
Now, many items on my CV are clickable, and a reader particularly interested in one item may now just click on it to see a webpage with more details to pop up.
However, I rarely see a CV with many hyperlinks behind those words/phrases. Is this a taboo, or I am OK to do so?
A:
I agree: most academic CVs do not have a festival of hyperlinks. I don't see a problem with it, unless -- as @Taladris says -- the large amount of hyperlinking creates clutter in the document. For something like a CV, where the spacing on the page is highly adjustable, I would think that you could probably have even a highly hyperlinked CV and take a little care to make sure that it does not look too busy to the eye.
I can tell you though why I don't feel the need to hyperlink my CV (and I imagine the reason holds more generally). It's simple: I also have a webpage, and anything which appears on my CV which could get linked to also appears on my webpage. Further, the translation between the two is straightforward: I have a section of my CV listing papers, and I also have an immediately visible link to a subpage containing papers from my main webpage (which, as you can see, is no frills to say the least, but it seems to get the job done).
Although I am certainly no expert on the visual display of information, webpage design (you'll know that immediately if you clicked on the above link) or anything like that, it is my opinion that a webpage is a more natural medium to have clickable content than a CV.
I think every young academic should have a professional webpage. If they do have one, I'm not sure that a heavily hyperlinked CV is necessary, although again I see no harm in it.
A:
General advise would be, yes, include links but do not rely on them for key information. You do not necessarily know if the recipients read the electronic version or a printout. If it is a printout, it is very unlikely that people will key in URLs to look up information, unless they are interested. In for, example a job application, your application may be one of a large number and there may not be time to spend on looking up information that should have been included directly in the first place. Remember it is you responsibility to yourself to provide everything the reader of the CV may want, not the other way around.
So although, there is no problem with including links, think twice about what information you link to and what you actually put in your CV.
A:
As long as it does not reduce readability, I don't see any reason for not including hyperlinks.
Readability is of course about format. As a personal preference, I would not like to read a document where all words are in blue and underlined, or equation numbers in a red square. So you have to find a way to make the links discreet (but still easily noticeable by the reader).
Readability is also, and mainly, about the content. Be sure your content is still clear when your CV is printed (or in case links are broken). Also, try to keep links meaningful. In particular, keep all your links high-quality: if links to your publications or to the diploma system of your home country will help for your evaluation, you would ruin all your effect if these links are "drowned" in a sea of meaningless links.
Did you consider about tool-tips instead of some links? It will still provide some information, but with the drawback of having to load a new page.
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Smallville Season 9 Episode 1
Smallville Season 9 Episode 1,Watch Clark Kent as he soars again in the Smallville season 9 episode 1, entitled “Savior” on Friday night, September 25. Kent will return in this season confused of choosing between Kryptonian heritage and his human past while protecting Metropolis from even more powerfull past and new villains.
Smallville season 9 sypnosis:
“Clark (Tom Welling) tells Jor-El he’s ready to start his training, but Jor-El sends him back to Metropolis to cut ties with Lois before he can begin. Chloe (Allison Mack) is shocked when Lois (Erica Durance) suddenly reappears after having been missing for weeks, but Lois has no recollection of vanishing into thin air with the Legion ring. While investigating a monorail crash, Lois meets John Corben (guest star Brian Austin Green), a new reporter at The Daily Planet, with a negative attitude toward the Red-Blue Blur. Chloe begs Clark to use the Legion ring to go back in time to save Jimmy, but he refuses, driving a wedge into their friendship. Meanwhile, Oliver (Justin Hartley) continues down a dark road, and Zod (Callum Blue) arrives at the Luthor mansion. Kevin Fair directed the episode written by Brian Peterson & Kelly Souders.”
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838 F.2d 466Unpublished Disposition
NOTICE: Fourth Circuit I.O.P. 36.6 states that citation of unpublished dispositions is disfavored except for establishing res judicata, estoppel, or the law of the case and requires service of copies of cited unpublished dispositions of the Fourth Circuit.
Wayne Edward HAILEY, Plaintiff-Appellant,v.Paul Safford, # 121633; Henry E. Ponton, Cpl.; Larry C.Childress, Sgt.; Albert G. Spradley, Sgt.;Raymond M. Muncy, Warden; BuckinghamCorrectional Center,Defendants-Appellees.
No. 86-7317.
United States Court of Appeals, Fourth Circuit.
Submitted: Nov. 24, 1986.Decided Jan. 22, 1988.
Wayne Edward Hailey, pro se.
Richard Francis Gorman, III, Office of the Attorney General, for appellees.
Before WIDENER, WILKINSON and WILKINS, Circuit Judges.
PER CURIAM:
1
A review of the record and the district court's opinion discloses that this appeal from its order denying relief under 42 U.S.C. Sec. 1983 is without merit. Because the dispositive issues recently have been decided authoritatively, we dispense with oral argument and affirm the judgment below on the reasoning of the district court. Hailey v. Safford, C/A No. 85-0848-AM (E.D. Va. Sept. 16, 1986).
2
AFFIRMED.
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/**
* Storage keeps quantities for HUs.
*/
package de.metas.handlingunits.storage;
/*
* #%L
* de.metas.handlingunits.base
* %%
* Copyright (C) 2015 metas GmbH
* %%
* 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, see
* <http://www.gnu.org/licenses/gpl-2.0.html>.
* #L%
*/
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{
"pile_set_name": "Github"
}
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Q:
Why is there nothing in the Materials tab?
Where'd everything go? I'm just starting with Blender and I thought I was doing everything as in tutorial i watched yesterday, i mean there are like three steps, but clearly something's wrong.
A:
Just scroll up. I know its weird I don't know why it does that.
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As you head to the bar for New Year's Eve, or to a friend's party, there may be alcohol involved, making it impossible to drive home safely.
A new California state law that takes effect Jan. 1 is hoping to change that for the sake of public safety.
Under Assembly Bill 711, alcohol manufacturers and licensed sellers can offer free or discounted rides through ride-sharing services like Uber or Lyft, or taxicabs. This is to ensure drinkers are transported home safely.
Codes or vouchers can be given to alcohol sellers or directly to alcohol consumers. However, they cannot be offered as incentives to buy a company's product.
Lyft has publically stated support for the bill.
Uber sent a statement to NBC 7 Wednesday saying they were in favor of the legislation, “We are always supportive of efforts to reduce drunk driving. That is why we have partnered with MADD over the past few years to promote safety and getting a designated driver.”
Current California law prohibits alcohol licensees from giving discounts to consumers.
There are some exceptions to this rule, wine and liquor manufacturers have been allowed on a temporary basis to pay for rides for drinkers attending private, invitation-only events.
This new initiative would relax those rules, allowing alcohol manufacturers to give out free or discounted rides in all cases to keep drunk drivers off the road.
The measure was introduced by Assemblyman Evan Low, D-Cupertino.
Proponents of the bill said forty-four other states and the District of Columbia allow liquor manufacturers to pay for free or discounted rides during legislative analysis.
But some are against the measure. Alcohol Justice, a nonprofit based in San Rafael, stated, "While drunk driving is a serious concern to public safety, and efforts to reduce it should generally be applauded, this bill implicitly allows for beer manufacturers to promote the overconsumption of alcohol."
Alcohol Justice goes on to say, "It will negatively impact public health and safety and increase the potential for alcohol-related problems."
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Thank you so much for the helpful information that you sent! We are so thankful we avoided an induction and could do a natural childbirth!
H., J. & A. W., Arlington, VA
Motherhood is everything I ever wanted and so much more. Thank you for helping make my dreams come true.
M.G., Charlottesville, VA
Thank you for your healing listening, therapeutic space, and healing touch. You are truly and healer, and one I will recommend.
Liz Hagerman, Takoma Park, MD
I returned to Angela… after having my daughter … I continue to remain ‘hospital free’, and my OB/GYN and specialist now say I don’t need a hysterectomy because the tumor has not progressed any further in growth … This is just a small part of what the massage time with Angela means to my family and me.
We are truly thankful for her compassionate, caring and healing hands. You have the power to heal yourself from within, but sometimes you need someone else’s hands to guide you in the right direction.
Ashley T., Germantown, MD
Your visit last week really helped… and me, too! Last week ended up being incredibly stressful, and I can’t imagine how we would have fared without your calming influence.
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Well, whatever you did… was amazing: she was in a fabulous mood all day and LAUGHED FOR THE FIRST TIME!!!
F.J., Riverdale, MD
Your visit seems to have done…a lot of good! We’ve had several very successful breastfeeding sessions, which is a lot more than I was able to say just a few days ago!
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Am I the only one around here who farts as loud as i can when i am alone
26,125 shares
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The public could read anonymously posted reviews and complaints of assisted-living facilities and owners of such facilities would face higher fines for repeated serious violations under a measure passed unanimously by the Senate on Tuesday.
Senate Bill 248 also requires increased licensing for homes that handle mentally impaired residents and requires a rating system be in place for assisted-living facilities by March 2015.
“Whatever comfort we can give to families who are looking for a home for a relative, we should give it,” said state Sen. Eleanor Sobel, D-Hollywood. This is the third year in a row a measure aimed at enhancing rules for assisted-living facilities has been introduced, Sobol pointed out.
She said that by eliminating some of the smaller violations that can lead to expensive fines even though they don’t endanger or discomfort a patient, “we got these groups on board,” including the AARP and the Florida Health Care Association.
Those smaller violations include a facility worker assisting a resident with self-medication or treatment, such as measuring vital signs or checking blood-sugar levels. Under the new measure, a worker would be able to assist in those smaller tasks without fear of sanction.
The public posting site would be part of a consumer guide page administered by the state that would also include information on each licensed facility in the state, including its size, date of opening and violations. The comments section would be monitored, and employees of a facility would be prohibited from posting although facility management could respond to comments as part of the online conversation.
The association had fought against the public comments page being part of the state’s website, arguing that the setting provides “an officialness to it,” Robert Asztalos, who represented the health care association as the legislation was being developed, said last month. “It should be part of a private page.”
Still, enough concessions to the supporters of the assisted-living facility industry have so far made the measure palatable.
“The good facilities want to see this kind of bill,” Sobel said. “They want the bad ones to be gotten rid of.”
There are 3,000 assisted-living homes in Florida that provide intermediate care and provide limited supervision to 80,000 people. Lawmakers in recent years have sought to reduce the oversight of assisted-living facilities, although Gov. Rick Scott vetoed one of the most comprehensive measures reducing regulation of the homes in 2011.
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forever ahead of their time
From a press release:
“Amazon.com today announced that Prime members in the greater Washington, D.C. area can now enjoy delivery from 150 popular restaurants, including Maketto, Ben’s Next Door, Hill Country Barbecue Market, Kapnos, b DC Penn Quarter, and many more. Amazon Restaurants is expanding its delivery territory from Northern Virginia to customers in the Capitol Hill, Georgetown, Adams Morgan, H Street, Shaw, and Downtown neighborhoods, to name a few.
“The hustle and bustle in the nation’s capital can make it difficult to try all the amazing restaurants around town,” said Gus Lopez, general manager of Amazon Restaurants. “Now, Amazon Restaurants makes it easy to skip traffic and get delicious meals from top restaurants conveniently delivered to your office or home in an hour or less.”
Using the Amazon or Prime Now mobile apps or by visiting www.amazon.com/restaurants, Prime members in D.C. can order from participating restaurants, browse menus, track the status of their delivery, and watch as their delivery driver travels from the restaurant to the delivery address in real time.
Once an order is placed, the food will be delivered in one hour or less. Amazon Restaurants offers customers transparent pricing—there are no menu markups. If a customer finds a restaurant item on Amazon Restaurants that is priced higher than the regularly priced item on the restaurant’s current online menu within 24 hours of placing the order, Amazon will refund that customer the price of the item.
“Who doesn’t love being a Prime member and all the benefits that come with it?” said Jesse Hiney, general manager of Osteria Morini DC. “Now my customers will be able to get our delicious pasta delivered right to their doors. Sounds dangerous in a delicious way!”
New Participating Restaurants in Washington, D.C. include:
Absolute Noodle
Acacia Bistro
Addis Ethiopian Restaurants
Al Volo DC
Amsterdam Falafelshop
Appioo African Bar & Grill
Arepa Zone
b DC Penn Quarter
Banana Leaves Asian Restaurant & Sushi Bar
Bangkok Joes
Bar Deco
Bolt Burgers
Bozzelli’s
Cafe of India
Coppi’s Organic Restaurant
Das Ethiopian
DC Pizza
DC Wisey’s
DCity Smokehouse
District Doughnut and Coffee
Duffy’s Irish Restaurant and Pub
Dupont Pizza
Espita Mezcaleria
Hill Country Barbecue Market
Indique
I-Thai Restaurant & Sushi Bar
Johnny Pistola’s
Kapnos
Khepra’s Raw Food Juice Bar
Kogod Liquors & Deli
Le Caprice DC Cafe Bakery
Lore Lounge
Maketto
Masala Art
Mayur Kabob House
Merzi
Moe’s Southwest Grill
Moxie’s
Mythology
Nazca Mochica
Nerds & Nibblers
New Dynasty Chinese Restaurant
New Heights Restaurant
Osteria Morini
Panda Gourmet
Pasha’s Kitchen
Pizza Mart
Pow Pow
Prescription Chicken
Quara Ethiopian Fusion Restaurant
Rakuya
Rasoi Indian Kitchen
Rice Bar
Rito Loco
San Antonio Bar & Grill
Shanghai Tokyo Cafe
Shawafel
Simply Banh Mi
Sloppy Mamas
Thai Chili
The Chickery
The Deli
Toku Japanese and Asian Cuisine
Tono Sushi
Uni Bistro
Uprising Muffin Company
Ventnor Sports
West Wing Cafe
Zorba’s Cafe
Prime members can download the Amazon or Prime Now apps or visit www.amazon.com/restaurants to enter their ZIP code and see if the service is available in their area. In ZIP codes where restaurant delivery is available, customers will see Restaurants on the home page.”
But how are they going to fit all that food from Maketto in these tiny robots? Kidding, it’ll probably soon arrive by flying drones…
Photo by PoPville flickr user Joe Flood
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Baharestan (newspaper)
Baharestan ( lit. "The Spring Garden") is an Iranian newspaper in the Fars region. The Concessionaire of this newspaper was Habibollah Noubakht and it was published in Shiraz since 1920.
See also
List of magazines and newspapers of Fars
References
Category:Newspapers published in Iran
Category:Persian-language newspapers
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Q:
What is the best design for an inquiry system (email to database) automatically filtered by some category?
We are working on an inquiry management system using J2EE. We're looking at a feature, allowing users to send inquiries to particular mail-id and entering into the database. Catch is to automatically allocate it to some categories.
A:
For handling external email, I would look into using a Bayesian filter to categorize them. This is how many of the most successful spam filters work, and that technique can be adapted for classifying content other than spam. I haven't used it, but try NClassifier. If that doesn't work, search for Bayesian filter and see what turns up.
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Xia Yuting
Xia Yuting (; born 29 May 2000) is a Chinese badminton player from Jiangsu. She was part of the national junior team that won the mixed team title at the 2017 and 2018 World Junior Championships and also at the 2018 Asian Junior Championships. In the individual junior event, she was the girls' doubles champion at the 2018 World Junior Championships partnered with Liu Xuanxuan.
Achievements
World Junior Championships
Girls' doubles
Asian Junior Championships
Girls' doubles
BWF World Tour (1 title, 1 runner-up)
The BWF World Tour, announced on 19 March 2017 and implemented in 2018, is a series of elite badminton tournaments, sanctioned by Badminton World Federation (BWF). The BWF World Tour are divided into six levels, namely World Tour Finals, Super 1000, Super 750, Super 500, Super 300 (part of the HSBC World Tour), and the BWF Tour Super 100.
Women's doubles
BWF International Challenge/Series (1 title)
Women's doubles
BWF International Challenge tournament
BWF International Series tournament
References
External links
Category:2000 births
Category:Living people
Category:Badminton players from Jiangsu
Category:Chinese female badminton players
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Liverpool At 7 a.m. outside Café 407 in Liverpool, Reverend Carrie Schofield-Broadbent of St. Matthew’s Episcopal Church dished out an early dose of spirituality, free of charge.
In a technological era emphasizing immediacy and instant gratification, fitting in Sunday mass poses a challenge to the workingman’s overtime schedule. Finding the moments for spiritual reflection on a Wednesday can be even more difficult.
Ashes To Go brings spirituality to the streets, allowing Christians to commemorate the holiday while maintaining their busy schedules.
“People were very excited to see us out there,” said Reverend Garrett Anderson of Liverpool Presbyterian Church. “We gave ashes to a lot of people who weren’t going to make it into church that day.”
In 2010, three Chicago-based Episcopal congregations faithfully carried out Ash Wednesday services beyond the confines of their stained-glass church windows. According to ashestogo.org, by 2012 the practice gained national attention in more than 80 churches across 21 states.
On Ash Wednesday of last year, Anderson and Broadbent decided to plan and bring the practice to Liverpool.
Forty-six days before Easter, Ash Wednesday marks the beginning of lent for Methodists, Catholics, Episcopalians and Lutherans alike, among other denominations of Christianity.
“I ran into a lot of people from different Christian traditions who were interested in having ashes and a little prayer,” said Broadbent. “They really liked their experience.”
Rev. Anderson said he gave ashes to more than 25 people outside Nichols Market.
“It’s for people who are going about their daily lives and might not have been able to make it to church,” said Anderson. “So we mark people’s foreheads or hands with the cross in ashes out on the streets.”
Ash Wednesday is a time of self-reflection and prayer through the remembrance of the death of Jesus Christ.
While the message of the holiday remains the same, the method of outreach brings on new spiritual encounters.
“We met up with a lot of different people in the community,” said Broadbent. “Some of them who probably don’t have a church or who were interested in connecting with the tradition of ashes, maybe from their childhood.”
|
{
"pile_set_name": "Pile-CC"
}
|
Q:
Use the browser cookie in fetch in a WebExtension
I’m currently porting an addon from the jetpack to the WebExtension API. I need to continuously update a browser action (toolbar button) with data (e.g. set its badge text).
For this, I would like to do a request from a background script in my extension to an API of the page, which is accessible when the user is logged in (i.e. a cookie is set). What I did so far:
I gave myself host permissions, which is mentioned to be necessary for request from content scripts.
However, content scripts are for injecting JS into pages the user visits.
I created a background script that uses fetch to do a request to the API.
However, when queried from the background script, the API tells me that nobody is logged in, while I can access it with the browser flawlessly.
This is the relevant part of the manifest.json:
{
"background": {
"scripts": ["background.js"]
},
"permissions": [
"*://subdomain.domain.com/*"
]
}
How can I have a continuously running background script that can use the user’s cookie to access this API?
A:
Firefox has stricter cors restrictions for cookies. I solved this by doing the api call from a content-script injected on the page with the same domain. That api call generated an auth token that was used for api calls from the background page, and enabling cors on backend for requests containing token in auth header.
|
{
"pile_set_name": "StackExchange"
}
|
Arablu, Hamadan
Arablu (, also Romanized as ‘Arablū) is a village in Sangestan Rural District, in the Central District of Hamadan County, Hamadan Province, Iran. At the 2006 census, its population was 430, in 123 families.
References
Category:Populated places in Hamadan County
|
{
"pile_set_name": "Wikipedia (en)"
}
|
Emotional adjustment among parents of adolescents and young adults with cancer: the influence of social constraints on cognitive processing and fear of recurrence.
Parents of adolescents and young adults (AYAs) with cancer experience distress comparable to other caregiver populations, but remain understudied. This study tested the social cognitive processing model of emotional adjustment to cancer. We hypothesized that social constraints on emotional disclosure would inhibit cognitive processing and be related to greater fear of cancer recurrence (FCR), potentially negatively influencing psychological adjustment. Data were collected through an online cross-sectional survey study of 66 parents of AYAs with cancer (aged 15-39) and analyzed using bootstrapping techniques for ordinary least squares regression. One-third of the parents reported moderate to severe depressive symptoms. Serial mediation analyses indicated that greater social constraints were related to poorer cognitive processing and higher FCR, and, ultimately, greater depressive symptoms. Alternative models were tested and were not significant. Future psychosocial interventions for parents of AYAs with cancer should include improving cancer-related communication between parents and their social network.
|
{
"pile_set_name": "PubMed Abstracts"
}
|
We released Fennec 1.0 Beta 1 for Maemo! Go read Stuart’s announcement for a good overview of the release. Be sure to watch Madhava’s video walkthrough too. Like Stuart, I am now using Fennec as the default browser on my N810 tablet. We have reached a solid milestone for performance and stability.
What’s New
Most of the work for this release was not visible UI features. Getting the Flash plugin to render onto Fennec’s canvas display surface was a big step. We also added the ability to pan any scrollable list in the chrome UI. So the bookmark list, add-on list, download list, preference list – and so on – now support scrolling/panning just like the main web content. We still need to add support for iframes and web content lists, which are trickier since they kind of conflict with panning the content itself.
Another area that has seen a lot of work is the rendering mechanism – the code that takes the content of the hidden browser element and renders it to the visible canvas display surface. Fennec Beta 1 has better pageload times and much better panning performance because of this work. For more background on what I’m talking about, read this post and the referenced article.
We did add some visible UI features. A big one is the new bookmark list. Fennec now supports bookmark folders and has capabilities for managing your bookmarks and folders. We still have some polish work to do, but the basics are all functional.
The default font size is a bit larger too, making it easier to read text content when Fennec auto-zooms web pages.
I almost forgot – JavaScript JIT is on by default for web content. It makes a big difference. The ARM related fixes to the JIT code made that possible.
What’s Notable
Our never ending struggle to make Fennec (and the Mozilla platform in general) as fast as possible on mobile devices has yielded a few more nuggets. Vlad and Taras have been hammering away on the rendering mechanism. Some parts of the process we can control better than others. The actual drawWindow call still dominates the time to render. We still try to improve the drawWindow performance, but there is only so much we can do. Instead, we try to limit the calls to drawWindow and limit the size of area we need to render.
Another area we can make improvements is overhead of XPConnect – the bridge between JavaScript and C++. On mobile devices, the overhead from XPConnect is non-trivial so we are reducing the XPConnect-able calls. We might also try adding more “quickstubs” – code that short circuits the XPConnect bridge, making the call faster.
Finally, we are noticing slowdowns related to the Places (bookmarks and history) system. Likely to be SQLite file I/O related. Two examples are: during startup the Places system is initialized, and when Fennec loads the bookmark list. I’ll note that neither of these examples is noticeable at all on desktop machines.
The startup issue is caused by a XPCOM component being initialized and in turn, initializes the Places core system. It results in a 250 ms speed bump during startup. We are currently working on a fix for this issue. The bookmark list load time is slowed by accessing the bookmark system for information used to display in the list, for each bookmark. In a simple test using just 10 bookmarks, it can take almost 3 seconds to load the list. Luckily, we were able to avoid some of the calls to the bookmark system and have improved load time by almost 40%.
We already have several performance related patches ready to land for the next release. Also, just about all the performance improvements we make for Fennec on Maemo are directly applicable to Fennec on Windows Mobile – win/win!
|
{
"pile_set_name": "OpenWebText2"
}
|
1908–09 Rangers F.C. season
The 1908–09 season is the 35th season of competitive football by Rangers.
Overview
Rangers played a total of 41 competitive matches during the 1908–09 season. The team finished fourth in the league, six points behind champions Celtic, after only winning 19 of there 34 matches.
The Scottish Cup campaign was thrown out against the league champions after a 2-2 draw at Hampden Park. The final was replayed a week later at the national stadium and finished 1-1, the competition was abandoned and trophy withheld following a riot after the replay.
Results
All results are written with Rangers' score first.
Scottish League Division One
Scottish Cup
Appearances
Source: Fitbastats
See also
1908–09 in Scottish football
1908–09 Scottish Cup
Category:Rangers F.C. seasons
Rangers
|
{
"pile_set_name": "Wikipedia (en)"
}
|
WASHINGTON ― One of the ways the White House brushed aside the first three indictments in the Russia investigation was by noting they weren’t directed at anyone serving in the administration. George Papadopoulos and Paul Manafort were on the campaign ― in limited roles, officials claimed ― and Rick Gates was simply Manafort’s business partner.
Special counsel Robert Mueller’s latest announcement hits closer to home. On Friday, he charged former national security adviser Michael Flynn with lying to the FBI about his contacts with the Russian government.
In the campaign, Flynn was one of the first people to give Donald Trump some national security credibility, at a time when the rest of the foreign policy establishment was running away from him. He became one of Trump’s most outspoken campaign surrogates, and in return, Trump made him his national security adviser when he became president.
The president, often known for feuding with and discarding his employees, remained extremely loyal to Flynn ― even when he was warned that Flynn could be a liability.
“A lot of people in the White House don’t want anything to do with Flynn,” a White House official told Politico in May. ”But Trump loves him. He thinks everyone is out to get him.”
White House lawyer Ty Cobb, nevertheless, tried his best to spin and downplay Flynn’s plea Friday, by saying he wasn’t national security adviser for very long, and he was an “Obama administration official”:
Today, Michael Flynn, a former National Security Advisor at the White House for 25 days during the Trump Administration, and a former Obama administration official, entered a guilty plea to a single count of making a false statement to the FBI. The false statements involved mirror the false statements to White House officials which resulted in his resignation in February of this year. Nothing about the guilty plea or the charge implicates anyone other than Mr. Flynn. The conclusion of this phase of the Special Counsel’s work demonstrates again that the Special Counsel is moving with all deliberate speed and clears the way for a prompt and reasonable conclusion.
Story continues
Two days after the November election, President Barack Obama warned Trump not to hire Flynn. Obama had fired him from his job as head of the Defense Intelligence Agency. Trump appointed Flynn to the high-ranking job anyway.
So Cobb is right that Flynn served in the Obama administration. But even when Obama tried to help his successor out by urging him to cut ties with Flynn, Trump refused to listen.
Then shortly after Trump took office, on Jan. 26, acting Attorney General Sally Yates became concerned that Vice President Mike Pence was publicly denying that Flynn had discussed U.S. sanctions on Russia with that country’s ambassador before Trump was inaugurated.
Yates told the White House official that Flynn was lying to them; federal officials had evidence that he had, indeed, discussed sanctions. She warned them that he could be subject to blackmail from the Russians and therefore a national security risk.
Nevertheless, the White House kept him on board as national security adviser. Trump fired him only after the news of Yates’ warning became public. Trump later fired Yates for refusing to defend his travel ban.
Despite knowing about Flynn’s lying, Trump continued to defend him. Former FBI Director James Comey said when he met with Trump on Feb. 14, the president asked him to ease up on Flynn.
“I hope you can see your way clear to letting this go, to letting Flynn go. He is a good guy. I hope you can let this go,” Comey recalled Trump saying.
Trump later fired Comey and has hinted that it was because he was upset the FBI director wouldn’t stop the Russia investigation.
Trump has held out hope that Flynn will be able to come back to him, and even told aides that he thinks firing him was a mistake.
“Trump feels really, really, really bad about firing him, and he genuinely thinks if the investigation is over Flynn can come back,” a White House official told The Daily Beast in May.
The fact that Flynn pleaded guilty to a relatively small charge seems to indicate that he is cooperating with Mueller ― and perhaps has given information that is far more damaging about people in Trump’s circle. The Associated Press reported Friday that Flynn admitted in his plea deal that Trump transition officials directed his contact with the Russians.
Love HuffPost? Become a founding member of HuffPost Plus today.
This article originally appeared on HuffPost.
|
{
"pile_set_name": "OpenWebText2"
}
|
form=七律
tags=
十里烟笼一径分，
故人迢递久离群。
白云明月皆由我，
碧水青山忽赠君。
浮世宦名浑似梦，
半生勤苦谩为文。
北邙坡上青松下，
尽是锵金佩玉坟。
|
{
"pile_set_name": "Github"
}
|
telugudesifuckvideo
Gentle and gorgeous goddess Shyla Jennings could be fashion model, but this babe knows that her body is so fascinating, especially in beautiful lingerie or even naked. chubby black girl porn Backstage scenes with magnetic female pornstars Erica Fontes, Paige Turnah and Tiana would make you aroused! Watch all of these scenes collected in one video clip.
X
Y
Parents: Fuq.com uses the "Restricted To Adults" (RTA) website label to better enable parental filtering.
Protect your children from adult content and block access to this site by using these programs:
|
{
"pile_set_name": "Pile-CC"
}
|
/*============================================================================
The Medical Imaging Interaction Toolkit (MITK)
Copyright (c) German Cancer Research Center (DKFZ)
All rights reserved.
Use of this source code is governed by a 3-clause BSD license that can be
found in the LICENSE file.
============================================================================*/
#ifndef mitkCLPolyToNrrd_cpp
#define mitkCLPolyToNrrd_cpp
#include "time.h"
#include <sstream>
#include <mitkIOUtil.h>
#include <vtkPolyData.h>
#include <vtkCellArray.h>
#include <mitkSurface.h>
#include "mitkCommandLineParser.h"
#include <mitkSurfaceToImageFilter.h>
#include <vtkSmartPointer.h>
#include <vtkLinearExtrusionFilter.h>
#include <mitkSurfaceToImageFilter.h>
#include <mitkConvert2Dto3DImageFilter.h>
typedef itk::Image< double, 3 > FloatImageType;
typedef itk::Image< unsigned char, 3 > MaskImageType;
int main(int argc, char* argv[])
{
mitkCommandLineParser parser;
parser.setArgumentPrefix("--", "-");
// required params
parser.addArgument("polydata", "p", mitkCommandLineParser::Directory, "Input Polydata", "Path to the input VTK polydata", us::Any(), false, false, false, mitkCommandLineParser::Input);
parser.addArgument("image", "i", mitkCommandLineParser::Directory, "Input Image", "Image which defines the dimensions of the Segmentation", us::Any(), false, false, false, mitkCommandLineParser::Output);
parser.addArgument("output", "o", mitkCommandLineParser::File, "Output file", "Output files. Two files are create, a .nrrd image and a 3d-vtk.", us::Any(), false, false, false, mitkCommandLineParser::Input);
// Miniapp Infos
parser.setCategory("Classification Tools");
parser.setTitle("2D-Polydata to Nrrd Segmentation");
parser.setDescription("Creates a Nrrd segmentation based on a 2d-vtk polydata.");
parser.setContributor("German Cancer Research Center (DKFZ)");
std::map<std::string, us::Any> parsedArgs = parser.parseArguments(argc, argv);
if (parsedArgs.size()==0)
{
return EXIT_FAILURE;
}
if ( parsedArgs.count("help") || parsedArgs.count("h"))
{
return EXIT_SUCCESS;
}
mitk::BaseData::Pointer data = mitk::IOUtil::Load(parsedArgs["polydata"].ToString())[0];
mitk::Image::Pointer image = mitk::IOUtil::Load<mitk::Image>(parsedArgs["image"].ToString());
//MITK_INFO << data;
mitk::Surface::Pointer surf = dynamic_cast<mitk::Surface*>(data.GetPointer());
vtkSmartPointer<vtkPolyData> circle = surf->GetVtkPolyData();
vtkSmartPointer<vtkLinearExtrusionFilter> extruder =
vtkSmartPointer<vtkLinearExtrusionFilter>::New();
extruder->SetInputData(circle);
image->GetGeometry()->GetSpacing()[2];
extruder->SetScaleFactor(1.);
extruder->SetExtrusionTypeToNormalExtrusion();
extruder->SetVector(0, 0, image->GetGeometry()->GetSpacing()[2]);
extruder->Update();
surf->SetVtkPolyData(extruder->GetOutput());
mitk::SurfaceToImageFilter::Pointer surfaceToImageFilter = mitk::SurfaceToImageFilter::New();
surfaceToImageFilter->MakeOutputBinaryOn();
surfaceToImageFilter->SetInput(surf);
surfaceToImageFilter->SetImage(image);
surfaceToImageFilter->Update();
mitk::Image::Pointer resultImage = surfaceToImageFilter->GetOutput();
mitk::Convert2Dto3DImageFilter::Pointer multiFilter = mitk::Convert2Dto3DImageFilter::New();
multiFilter->SetInput(resultImage);
multiFilter->Update();
resultImage = multiFilter->GetOutput();
std::string saveAs = parsedArgs["output"].ToString();
MITK_INFO << "Save as: " << saveAs;
saveAs = saveAs + ".vtk";
mitk::IOUtil::Save(surf.GetPointer(),saveAs);
saveAs = parsedArgs["output"].ToString();
MITK_INFO << "Save as: " << saveAs;
saveAs = saveAs + ".nrrd";
mitk::IOUtil::Save(resultImage,saveAs);
return 0;
}
#endif
|
{
"pile_set_name": "Github"
}
|
Cookies on the Allens Caravans Website
We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we'll assume that you are happy to receive all cookies on the yourname website. However, if you would like to, you can change your cookie settings at any time.
visit us
location
Park alert
Send me updates on this park
Your Name
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01386 870244
Abbot's Salford Holiday Park sits in the Heart of England, just a short distance from Stratford-upon-Avon and Broadway. The Park's pretty village location and its culturally-rich Shakespearean surroundings make Abbot's Salford Park a wonderful place to spend a holiday or short break. Not only does the Park benefit from the stunning natural backdrop of the Cotswolds and the Malvern Hills, but it is also within easy reach of Warwickshire's finest historical towns and villages.
The impressive and attractive 40 acres of riverside meadow of Abbot's Salford Park is characteristic and provides a wonderful, natural backdrop for a peaceful holiday in the heart of the British countryside. The park also offers amenities like a Clubhouse, Lounge Bar and Café, as well as a heated outdoor swimming pool and fishing amenities.
Bookings are taken directly with Hoseasons click below for more information
In a peaceful Cotswold village, on the doorstep to Stratford-upon-Avon
|
{
"pile_set_name": "Pile-CC"
}
|
Former Yahoo CEO Marissa Mayer Creates Tech Startup Incubator - utopcell
https://finance.yahoo.com/news/former-yahoo-ceo-marissa-mayer-010100774.html
======
hknd
I really like how this appears on the yahoo frontpage (:
~~~
utopcell
Yahoo news are not biased!
|
{
"pile_set_name": "HackerNews"
}
|
# Additional ClusterShell group source config file
#
# Please see `man 5 groups.conf` for further details.
#
#
# SLURM partition bindings
#
[slurmpart,sp]
map: sinfo -h -o "%N" -p $GROUP
all: sinfo -h -o "%N"
list: sinfo -h -o "%R"
reverse: sinfo -h -N -o "%R" -n $NODE
#
# SLURM state bindings
#
[slurmstate,st]
map: sinfo -h -o "%N" -t $GROUP
all: sinfo -h -o "%N"
list: sinfo -h -o "%T" | tr -d '*~#$@+'
reverse: sinfo -h -N -o "%T" -n $NODE | tr -d '*~#$@+'
cache_time: 60
#
# SLURM job bindings
#
[slurmjob,sj]
map: squeue -h -j $GROUP -o "%N"
list: squeue -h -o "%i" -t R
reverse: squeue -h -w $NODE -o "%i"
cache_time: 60
#
# SLURM user bindings for running jobs
#
[slurmuser,su]
map: squeue -h -u $GROUP -o "%N" -t R
list: squeue -h -o "%u" -t R
reverse: squeue -h -w $NODE -o "%u"
cache_time: 60
|
{
"pile_set_name": "Github"
}
|
/*
* jPSXdec: PlayStation 1 Media Decoder/Converter in Java
* Copyright (C) 2016-2019 Michael Sabin
* All rights reserved.
*
* Redistribution and use of the jPSXdec code or any derivative works are
* permitted provided that the following conditions are met:
*
* * Redistributions may not be sold, nor may they be used in commercial
* or revenue-generating business activities.
*
* * Redistributions that are modified from the original source must
* include the complete source code, including the source code for all
* components used by a binary built from the modified sources. However, as
* a special exception, the source code distributed need not include
* anything that is normally distributed (in either source or binary form)
* with the major components (compiler, kernel, and so on) of the operating
* system on which the executable runs, unless that component itself
* accompanies the executable.
*
* * Redistributions must reproduce the above copyright notice, this list
* of conditions and the following disclaimer in the documentation and/or
* other materials provided with the distribution.
*
* THIS SOFTWARE IS PROVIDED BY THE COPYRIGHT HOLDERS AND CONTRIBUTORS "AS
* IS" AND ANY EXPRESS OR IMPLIED WARRANTIES, INCLUDING, BUT NOT LIMITED
* TO, THE IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A
* PARTICULAR PURPOSE ARE DISCLAIMED. IN NO EVENT SHALL THE COPYRIGHT OWNER
* OR CONTRIBUTORS BE LIABLE FOR ANY DIRECT, INDIRECT, INCIDENTAL, SPECIAL,
* EXEMPLARY, OR CONSEQUENTIAL DAMAGES (INCLUDING, BUT NOT LIMITED TO,
* PROCUREMENT OF SUBSTITUTE GOODS OR SERVICES; LOSS OF USE, DATA, OR
* PROFITS; OR BUSINESS INTERRUPTION) HOWEVER CAUSED AND ON ANY THEORY OF
* LIABILITY, WHETHER IN CONTRACT, STRICT LIABILITY, OR TORT (INCLUDING
* NEGLIGENCE OR OTHERWISE) ARISING IN ANY WAY OUT OF THE USE OF THIS
* SOFTWARE, EVEN IF ADVISED OF THE POSSIBILITY OF SUCH DAMAGE.
*/
package jpsxdec.i18n.exception;
import javax.annotation.CheckForNull;
import javax.annotation.Nonnull;
import jpsxdec.i18n.ILocalizedMessage;
/** Parsing of serialized text failed.
* Localized message can be displayed to the user. */
public class LocalizedDeserializationFail extends LocalizedException {
public LocalizedDeserializationFail(@Nonnull ILocalizedMessage msg) {
super(msg);
}
public LocalizedDeserializationFail(@Nonnull ILocalizedMessage msg, @CheckForNull Throwable cause) {
super(msg, cause);
}
}
|
{
"pile_set_name": "Github"
}
|
Q:
What is the meaning of the phrase »aber klar« and »aber klar doch«?
What is the meaning of the phrase »aber klar« and »aber klar doch«? Also, do they mean the same or do they differentiate from each other?
Thank you for answering my question :)
A:
Both phrases mean the same. Also, only »klar« means the same, it literally means
clearly
But you better translate it as
surely
yes, of course
So, why don't the words »aber« and »doch« change the meaning? What are they good for?
Both words are modal particles. Modal particle is a word class, that is often used in German, but doesn't exist in most other languages, among them English.
Modal particles do not change the statement of a sentence, they just add some mood or feeling to the sentence. Here in this case, both modal particles try to strengthen the meaning of »klar«.
There is no way to directly translate modal particles. Most translators just ignore them, because modal particles have no influence to the statement that is transported with the sentence. If the mood, that is encoded in the modal particles, is important, then the translator has to be creative and needs to add something to the translation.
Read more about modal particles here: Modal Particle (in German) or in English Wikipedia.
|
{
"pile_set_name": "StackExchange"
}
|
Veden päällä käveleminen on seurakuntapastori Benjamin Sandellin mielestä kiehtova haaste. Siksi hän antoi tiiminsä kanssa tänään alkavalle Disciple17-tapahtumalle teemaksi ”Walk on the water”.
‒ Teema viittaa siihen, että voimme antaa Jumalan määritellä, missä on mahdollista kävellä. Se on vertauskuva elämäntavasta, joka tekee meistä rohkeasti vaikuttavaa suolaa ja valoa, Sandell innostaa.
Ulos veneestä
Helsingin Munkkivuoren kirkolle kokoontuu tänään satoja nuoria aikuisia, joita kutkuttaa astua ulos veneestä ja kävellä Jeesuksen luokse.
Petruksen ja Opiskelija- ja koululaislähetyksen yhdessä järjestämän tapahtuman tarkoituksena on innostaa nuoria aikuisia vastaamaan Jeesuksen kutsuun: Menkää ja tehkää kaikki kansat minun opetuslapsikseni.
‒ Jeesus perusti kirkon ja pyysi meitä tekemään opetuslapsia. Teemme kuitenkin usein päinvastoin: perustamme kirkkoja, mutta opetuslasten kasvattaminen jää vähemmälle, Benjamin Sandell sanoo.
Hän toimii Helsingin ruotsinkielisen Petruksen seurakunnan seurakuntapastorina ja Opiskelija- ja koululaislähetyksen ruotsinkielisen työn vastaavana työntekijä.
Identiteettiä rakentamassa
Sandellin mielestä opetuslapseuttaminen alkaa identiteetin rakentamisesta Jumalan rakkaana lapsena.
‒ Keskiössä on Jeesus ja hänen seuraamisensa. Olemme Jeesuksen työn kautta Jumalan rakkaita lapsia, mutta myös työntekijöitä hänen valtakunnassaan. Kukaan ei pysty tavoittamaan kaikkia, mutta jos jokainen tavoittaa jonkun, syntyy ketju, jossa voimme tavoittaa koko maan ja maailman.
Disciple17-kanavien kirjo näyttää, miten erilaisia asioita opetuslapsen arkeen kuuluu. Esillä ovat esimerkiksi talous, ihmissuhteet, seksi ja maailmankatsomukset.
Opetuslapseuttaminen on sana, joka saa jotkut rypistämään otsaa. Ei kai vaan rakenneta eliittiuskovaisten lahkoa, jonka johtajat sitovat ihmisiä seuraamaan itseään?
‒ Sen, joka ottaa vastaan kutsun tehdä opetuslapsia, on muistettava, että hänen oma elämänsä on Jumalan ensimmäinen intressi. Jokainen päivä alkaa siitä, että Jumala haluaa näyttää armonsa minulle, Sandell sanoo.
Hänen mielestään Jeesuksen kaltaiseksi kasvaminen on palvelijaksi kasvamista.
‒ Jokaisen vanhemman toive on, että lapsi pääsee pidemmälle kuin on itse päässyt. Hengellisen lapsen astuminen kypsyyteen on se, mihin opetuslapseuttamisessa pyritään.
Sandellin mukaan Raamatun sana ja elämä Jumalan lähellä mahdollistavat sen, että Pyhä Henki ohjaa molempien kasvua kaikessa.
‒ Ihminen ei ole vastuussa prosessista, vaan Jumala.
Brittivieraita Sheffieldistä
Kolmikielisen Disciple17-tapahtuman lauantai-ilta on avoin kaikille yli 18-vuotiaille viiden euron hintaan. Ohjelmassa on klo 19:30 alkaen talkshow, raamattuopetusta, esirukousta ja ylistystä.
Mukana ovat tapahtuman brittivieraat, Sheffieldin St. Thomas’ Crookes -seurakunnan apulaiskirkkoherra Tom Finnemore ja opiskelijatyöntekijä James Brown.
Myös jumalanpalvelukseen Munkkivuoren kirkolle sunnuntaina 29.1. klo 11 ovat kaikki tervetulleita. Saarnan pitää Tom Finnemore ja se tulkataan suomeksi.
Lue lisää: disciple.fi
|
{
"pile_set_name": "OpenWebText2"
}
|
Q:
Part identification
Can you help me identify which part numbers these parts are? I can't find them on Lego's site or on brickset.com:
Edit:
I've found the two dark grey bricks in the left photo, so that just leaves the yellow one, and the other two photos.
Thanks!
Ben
A:
I'd say the yellow part is listed on BrickSet as "Lamp Holder" or "Plate, Modified 1 x 1 with Clip Light - Thick Ring", 4081 on BrickLink, Peeron, etc.
The light grey piece is from the Flick Missiles, and is listed on Brickset as "3 M.Arch W.Knob And Shaft ظ3.2" or "Technic, Pin 1/2 with 2L Bar Extension (Flick Missile)", 61184.
The final piece is "Mini Fig. Back Palte W. Knob" or "Minifig, Neck Bracket with Back Stud", 42446
For completeness, the other two are:
"Angular Plate 1.5 Bot. 1X2 1/2" on Brickset or "Bracket 1 x 2 - 1 x 2 Inverted", 99780
The tile I couldn't find on Brickset other than in Rebrickable inventories where it's listed as "Tile 1 x 2 with Joystick and Vehicle Control Panel Pattern" (3069bpr0090) or on BrickLink as "Tile 1 x 2 with Vehicle Control Panel Pattern", 3069bpc1
|
{
"pile_set_name": "StackExchange"
}
|
Saturday, February 15, 2014
Trainboy turns 9 (December 2013)
My sweet little boy is growing up. We celebrated that he has been part of our family now for 9 years in December.
Breakfast in bed. Didn't know I had started a tradition there. Oops.
Cute brother helped me out by holding baby.
After much deliberation, he decided a peppermint chocolate ice cream cake was what he wanted. So I set out to make my first ice cream cake.
My cake is huge!
Lots of candles
Picture showing the inside of the giant cake.
I followed a recipe, but the ice cream layer was just too thick for us. I think that yummy fudgey layer that you get from store bought cakes would have been a nice addition. When you add in that it had to be kept in the freezer also, this cake wasn't completely consumed until mid January.
Favorite present: A calculator
So earlier in the month, Trainboy had an abscess in his mouth and had to get a tooth pulled after a round of antibiotics. While he was at the dentist, his dad made a video to show me later of what happened. In it Trainboy is asked what he wants for Christmas and his immediate answer is "a calculator". Hah! Love it! That was an easy birthday present to get him. He was thrilled! (I should note that part of that desire probably comes from the fact that I am protective of my calculator that I use for tutoring work. He has gotten in trouble for "playing" with my calculator before.)
This kid is really growing up to be an awesome person. I can't believe he is already 9. It doesn't seem like that much time could have already passed. I still remember trying to get him to sleep and how much time I spent worrying about making sure he got his naps. Now he tells me how busy he is trying to fit in all the books he wants to read.
Trainboy as a baby with a beautiful head of hair.
My oldest two boys in 2005
The older ladies who stop you at the store to tell you to cherish the baby stages because you'll miss it and it'll be gone so quickly - I know what they mean now. But in those moments of not getting enough sleep it seemed like every day was never ending in length and I don't have enough memories of cuddling him. I wish I could go back and just hold Trainboy as a baby again. Since I can't, I guess I'll hold his baby brother extra and try to pack in the memories of joy of now. Because Trainboy is an awesome kid with a big heart full of love. He is sweet and caring and helpful. He is inquisitive and a stickler for following the rules. He has a quick temper when he perceives injustice. He loves to watch the birds and grow plants. He is observant and thoughtful. He is wonderful. I am glad he is part of my family.
1 comment:
Happy late birthday Trainboy:)Time really does fly and kiddos really do grow so fast, your post is a good reminder for me to take more notice of each moment and appreciate it, even when things are really hard. <3 thanks for that reminder :)
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The present invention relates to dollies, or carts, adapted to transport large sheets of material across floors and the like.
It has long been a problem to move single large sheets of metal, glass, stone and ceramic about in manufacturing plants and in the field. As an example, a conference table may have a large stone or glass sheet top, for instance, a 5xc3x9710 foot rectanguloid or 6 foot diameter disk weighing 300 or more pounds. Typically, such a top rests on a detachable base, to facilitate transport. When such a large table top is be carried into an office building lobby, up an elevator, and through a finished office, care is needed to protect the top and things along the path. The same problems obtain when glaziers transport large sheets of glass any distance. As another example, in a fabrication shop, a sheet of steel or other material might need to be casually moved from one work station to another. Not only are such large sheet objects awkward to handle, but particularly in the field, it is important that the sheet be handled in a safe way which damages neither the sheet nor other things.
A common way to handle a large sheet is to have at least two or more workers manually carry the sheet. Other times, a conventional flat dolly is employed, even though the sheet tends to be unstable and prone to come off such a type unit. Lashing the sheet to the dolly is awkward and inconvenient.
Prior inventors have addressed the problem in various ways by designing special dollies. Many such dollies have xe2x80x9cAxe2x80x9d frames or other sloped structures mounted on their surface, to support the sheet. The angle at which the sheet is carried is fixed. The prior art dollies are often not suited for carrying round or oval sheets, as characterize many table tops. In general, the prior art A-frame type dollies are bulky and heavy; and, they are costly. They may be suited for certain factory settings. But, in the field it is inconvenient to transport such dollies due to their bulk and weight. The bottom line is that the dollies taught by the prior art tend to not be used because they are unsuitable for applications where a fragile environment, e.g., a finished office or living space, must be traversed.
Thus, there is a continuing need for a dolly which stably carries both rectangular and flat sheets, and which dolly is light, transportable, and economic to produce. And, experience shows that this may not be easy, because a large sheet mounted on a dolly can easily comprise an unstable combination.
An object of the invention is to provide means for transporting both large rectangular and large circular sheet objects. A further object of the invention is that such means be light in weight, convenient to use, easy to transport, and economic to fabricate.
In accordance with the invention, a sheet to be transported is placed edgewise on the base of a rectangular frame dolly base having four wheels, preferably swivel caster wheels. The frame of the dolly base is formed of two lengthwise running side beams and two opposing end members; and, it has a central rectangular opening. A sheet being transported leans against the vertical surfaces of a stanchion comprised of spindles and a horizontal top bar. The stanchion is mounted offset from the longitudinal centerplane of the base. As a rectangular sheet is being carried, it rests along a plane defined by the top surfaces of the front and rear members. When a circular sheet is transported it is cradled within the space between the front and rear members, and its lower edge is at an elevation less than said plane.
For stability during transport, the sheet center of gravity lies within the vertical projection of a no-contact zone, as preferably do the lower and upper parts of a sheet which contacts respectively the base and the stanchion. The no-contact zone is a region defined by the innermost portions of circles of rotation of swivel caster wheels where they touch the floor and swivel around their pivot axes. The inner surfaces of the stanchion which contacts the sheet lie along a vertical plane. That vertical plane is located within bounds of the no-contact zone, called Zone Z herein. Likewise, on the opposing side of the base, the inside of the frame hole of the base is also located within the no-contact zone vertical projection, to desirably position the bottoms of circular sheets placed on the dolly. More preferably, the stanchion and interior of the base frame are located within a sub-portion of the Zone Z, which is called Zone Y. Zone Y is defined by the innermost portions of the circles of rotation of the outer circumferences of the swivel wheels. In the preferred invention, the sheet lies against the stanchion at an angle with the horizontal of 75-90 degrees, preferably 75-85 degrees, most preferably 80-85 degrees.
Preferably, there a retention bar sticking up from the base surface at said opposing side, within the no-contact zone bounds, to position the bottom edge of a rectangular sheet. The retention bar serves the same purpose as the interior of the base frame does for circular sheets; and, when the retention bar extends across the opening of the base frame, it is substitutional for the inner edge of the base frame in determining where a circular sheet bottom will rest. The top surfaces of the end members comprises a resilient frictional material, e.g., rubber underlain by wood. Since the sheet weight is concentrated at two spaced apart points, local deformation of the resilient surface helps stop sideways slipping of the sheet. More preferably, the stanchion, frame hole and retention bar components of the dolly are analogously positioned with respect to a smaller zone, called the no-wheel zone, which lies within the no-contact zone. The no-wheel zone is defined by the innermost circumferential points of the wheels themselves, as compared to where they contact the floor.
In further accord with the invention a second horizontal bar, which is vertically adjustable, runs between the spindles of the stanchion. This provides an adjustable support which is particularly useful for small circular sheets. Preferably, the stanchion is removable from the base, by having the spindles mounted in sockets, or clamped to the base. Alternatively, the stanchion is hinged to the base, so it can be folded flat along the top surface. These features facilitate transport of the dolly to the point of use.
The dolly of the invention is useful for stably transporting a variety of shapes of sheets and economic to construct. The dolly configuration minimizes chance for damage to the sheet edges or by bending fracture during use. And even while providing these advantages, the dolly is light weight, adapted to easy transport, and economically made.
The foregoing and other objects, features and advantages of the invention will become more apparent from the following description of the best mode of the invention and accompanying drawings.
|
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|
Q:
Piping http.Response to http.ResponseWriter
I'm trying to pipe a file that I receive from an API back to the user without having to store it all in memory.
I've come across different concepts/ideas across my search, such as io.Copy, io.Pipe(), etc. I'm not sure which one is the correct solution.
For example, io.Pipe() seems like it's for if someone is creating a new reader and writer on the spot, not ones that already exist.
A:
io.Copy is the way to go for that, something along the lines of:
func pipeReq(rw http.ResponseWriter, req *http.Request) {
resp, err := http.Get(".....")
if err != nil{
//handle the error
return
}
rw.Header().Set("Content-Type", resp.Header.Get("Content-Type"))
rw.Header().Set("Content-Length", resp.Header.Get("Content-Length"))
io.Copy(rw, resp.Body)
resp.Body.Close()
}
//edit: misread the question, fixed the code now.
|
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Episode 3: Whip It!
Can you even handle all the “this bitchhhh” looks the ladies were tossin’ around when Nick announced that he “had sex with Liz”…
Since these ladies are “all dating the same person” this was very rich news for them to hear. I’m like wait, you guys know he’s “had sex” with other women before…right? This situation just makes polygamy seem even less appealing that it already was, amirite? All these ladies are in the race for Nick’s dick, and knowing that one of their own (Liz) already sort of won, is really taking it’s emotional toll on the fam.
Wait, also, the hand games happening during the rose ceremony at the start of this ep was just so HANDSUAL (handsy-sexual). If they could kiss/fuck and talk on TV at the same time, they would, but they can’t so they have hand sex- which honestly looks really fun.
UPDATE: Nick is intrigued ON Danielle L. Or is he intrigued IN Danielle L. Actually, Nick, it’s neither. You are intrigued by. BYE. BYE. BYE.
“If he sleeps with someone before the fantasy I don’t know what I am going to do.” Good thing you won’t have to trouble yourself with such trifling games because you, my forgettable, yellow dressed blondie, are not gonna survive the next fifteen minutes of this episode.
Who else vomited when Corinne used the word “intercourse”? Oh all of you? Great. Don’t know what’s worse: intercourse or an expression often used to describe consensual sexual relations that rhymes with shmake shlove. Meanwhile Corinne is getting ready to shmake shlove with Nick and ABC gifts us our THIRD black out ass box as Corinne adorns and then promptly removes her flasher coat in front of a mirror.
“I miss you so much!!!” says the forgettable “24” year old with a fashion forward black dress with an adventurous neckline and bold leg slit. You’re about to get sacked. But enjoy your s’mores.
Alright ABC slow down with the blackout boxes over the cleavage. Corinne likes Nick ALOT and he makes her really happy, you guys. Her authentic emotions are convincingly relayed through droopy eyes and slurred words. I really feel for the girls wiping the tears from their eyes as they are emotionally drained and feeling sad that a superprivileged narcissist is getting attention by whoring herself out. Brutal.
Corinne’s flasher coat games are sort of making Nick uncomfortable but she’s hot so he leans in. This whole sacks/pillows in the driveway as a stage for Corinne’s drunk winking and whipped creaming her own boobs is a real treat. Some questions I have: How did the conversation go between Corinne and the producers about this situation? Whose idea was it? How many takes did they have to do? Was it low fat whipped cream? Does Nick typically try to stick to a dairy free diet?
Of course she was drunk sleeping during the rose ceremony. Taylor says “She’s been up there all night.” This reminds us just how long these goddamn rose ceremonies are. HOURS upon HOURS. If Nick spends 20-30 minutes with each of these girls that’s a 6-8 hour situation. Yeah, no thanks.
Ok…so Group Date #1 was the only reason that you should have watched this episode. The fucking BACKSTREET BOYS show up, they sing a snippet of “I Want It That Way” a cappella to the squad, these girls are DEAD. As am I. Some thoughts on this….most of these women are at least ten years younger than Nick. They grew up with BSB. Nick, however, is almost the same age as Nick Carter. When he was a teeny bopper he was probably listening to CRISS CROSS and TLC and MOTOWN PHILLY. Nick was never the target audience for BSB. He is a BSB peer.
Nick Viall – September 29, 1980 = 36 going on 37
Nick Carter – January 28th, 1980 = almost 37
Brian Littrell – February 20, 1975 = 42
Howie Dorough – August 22, 1973 = 44
Kevin Richardson – October 3, 1971 = 46
AJ McLean – January 9, 1978 = 39 #hbd
Alright back to business. The ladies are in full face and sexual athlesiure for their BSB group date. They are READY. This date is stressing Corinne out because she is not so great at “planned dancing” because she has “very bad short term memory.” Honestly, I was surprised that our resident dancer Jasmin didn’t get super obnoxious with the choreo, but you know she was thirsty as hell during that performance making eye contact with precious Brian from BSB whilst dancing.
YAS Danielle L I am so into her winning this group date challenge and I am even more into BSB gifting us with another a cappella performance. It was very savage to have the other girls stay on stage while Nick and Danielle slow danced and made out to BSB. Sucks to suck!
Corinne finally revealed to the squad that she has a nanny named Raquel. Raquel makes Corinne’s bed every morning, she prepares Corinne’s cucumber snack and vegetable slices, and she apparently NAILS cheese pasta. Honestly, I want Raquel’s cheese pasta. Whatever that means, I want in.
This week, I wasn’t reminded of the fact that my teeth aren’t white enough, or I that I have undiagnosed depression during the commercial breaks. Nope, instead I am welcomed into an advertisement for SECRET RESORT which is definitely shades of hedonism. The ad features a sultry blonde wearing a ROCK for all ages. A nearby less attractive friend ponders…how was your honeymoon? The ad then takes the viewer on flashbacks to a sensual resort for white elites. Balconies with billowing, white curtains, hidden corners to “make a secret.” FUN!
All I have to say is, this bitch is gonna win. Nick literally cried over her and said “You have made me feel very optimistic.” Translation: you da ONE.
Also, I would puke everyday for the rest of my life if it means I will be treated with such comfort and tenderness. Wow. I have never felt more alone. Also- this moment was very reminiscent of Officer And A Gentleman. Do me, Richard Gere.
As usual Group Date Number 2 was a hot friggin’ mess. What is with Bach Nation always doin’ track events? BOOORRRRIIINNNGGGG. I’m not going to even dignify this date with my valuable opinions.
The pool party…
Wait, getting make-up on was just such a curious course of action to take before being surrounded by water. At least Corinne’s middle-aged sunspotted chest was out to play. All her conversations with Nick are just whispers of “It’s so good to see you. I feel so comfortable with you.”
Last but not least, I don’t know what made me feel more second hand embarrassment: Corinne’s desperate boobie trap or Josephine/Josie singing an original song to Nick after the credits rolled. She had the nerve to call her jingle about how he should take her on a 1:1 a “sales pitch.” Dream on, whatever you’re selling we’re not buying, and stop singing.
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Complete tour to North Ethiopia with all transfers by surface, allowing a complete experience of the variety and width of unique Ethiopian plateau sceneries. It’s the ideal combination for slow-travel lovers enjoying [...]
Three days extension that offers to the trekking lovers the opportunity to live an intense experience with the local community: Tesfa organizes several trekking circuits using guesthouses managed by the community. They [...]
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|
Q:
How to edit a user ID comment or set a new default user ID in GnuPG?
I would like to either remove a user ID or update its comment or at least make another one the default. This is because it contains a comment that has a stupid typographic error. Like:
gpg> list
pub 4096R/xxxxxxxx created: yyyy-mm-dd expires: yyyy-mm-dd usage: SCEA
trust: ultimate validity: ultimate
sub 4096R/xxxxxxxx created: yyyy-mm-dd expires: yyyy-mm-dd usage: SEA
[ultimate] (1). My Name (comment with a stupid typo) <my-primary@email-address>
[ultimate] (2) My Name <my-primary@email-address>
[ultimate] (3) My Name <my-second@email-address>
How can I remove (1) or make (2) the main and default user ID. Everyone that imports my key sees (1). I tried to use --edit-key with primary 2, but all I get is
Please select exactly one user ID.
What to do?
A:
You have to select the user ID to edit before running those commands. If you want to remove the first user ID, press 1return, which will highlight the first user ID with a star * between the number and user ID:
[ultimate] (1)* My Name (comment with a stupid typo) <my-primary@email-address>
[ultimate] (2) My Name <my-primary@email-address>
[ultimate] (3) My Name <my-second@email-address>
Now run deluid to delete it. You can also select multiple user IDs to delete at once. Similarly, to change the default user ID, select the new default (in the unmodified user ID list of your question, by pressing 2return) and run primary.
Use 2return again to deselect.
You cannot edit a user ID (including it's comment). Deleting it also might not be what you want to achieve, if the key was already sent to the key server network, it will simply be merged again next time your receive the key from there (also, others will still see it). Instead, revoke it running revuid (not revkey as indicated in the first revision of this post), which will not delete it but mark it as superseded (which is something that will be synchronized throughout the key server network).
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{
"pile_set_name": "StackExchange"
}
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Peterborough solar farm: Archaeologists unearth Roman finds Published duration 6 November 2013
image caption Part of a pot believed to be from a Roman settlement at Newborough
Roman pottery, evidence of a Roman settlement and "possibly Saxon" artefacts have been found at a proposed solar farm site near Peterborough.
The land at Newborough is being excavated ahead of a city council decision about the solar farm plan.
Richard O'Neill, from Wessex Archaeology, described the finds as "locally and regionally significant".
Work is expected to continue for three weeks, after which the council will consider the archaeologists' report.
Plans for the solar energy farm at three council-owned sites at Newborough, Morris Fen and America Farm were put on hold after English Heritage stepped in suggesting the area could be "nationally important".
'Not a Flag Fen'
Mr O'Neill described the finds at Newborough as "the most interesting".
"We've got a number of fragments of pottery dating from between the 1st and 3rd Centuries AD, and one potential Romano-British settlement.
"It's quite a small farmstead with perhaps a number of roundhouses," he said.
"We've also identified a couple of sites that may be late prehistoric, possibly settlements or funerary sites which we still need to look at."
Mr O'Neill confirmed experts were examining artefacts believed to date from the Saxon era.
Archaeologist Dr Francis Pryor discovered the nearby Bronze Age settlement of Flag Fen in 1982 which comprises thousands of timbers connecting Whittlesey Island with Peterborough and was used for ritual and worship for 1,000 years.
He believes the three sites could be historically significant.
"The edges of the Fen are where people have stayed and settled in prehistory, and there's absolutely no reason why there shouldn't be another Flag Fen out there, or a site that we can't imagine," he said.
Mr O'Neill said the discoveries made so far were "not a Flag Fen, but of local and regional significance".
Archaeologists are expected to continue excavating for three weeks, although Mr O'Neill said work would continue beyond that if evidence of older settlements was found.
Nick Harding, from the City Council's planning services department, said: "We will discuss the results of the survey with English Heritage and that will help us decide what to do next.
"The relative quality and the rarity of the finds... will determine how best to deal with them, whether that involves keeping developments clear of those sensitive areas or whether once those sites are recorded for posterity they can be covered over and development allowed to continue.
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|
How To Measure The Tough Stuff
It's no surprise that some people resist performance measurement. This kind of reaction is normal when people are presented with unfamiliar things. People are often reluctant to embrace change in their work environment, because change can mean more work, or more responsibilities. or more challenges, without any guarantee of a payback (for them).
Resistance is often displayed by statements like 'you can't measure what we do'. Resistance can show up in other objections as well, like 'that’s been tried here and it didn’t work', or 'I don’t know what to measure', or 'I have too many other priorities', but lets deal with the first one first. Here's how to measure the tough stuff that your objectors believe can't be measured.
1. Begin with the objective in mind. Measuring the tough stuff does not begin with crafting measures! Always start with understanding objectives; don't consider the measures until you are clear what you are trying to achieve i.e. the desired impacts, benefits and consequences of your work.
2. Define the characteristics of this objective. For example, let's say we're trying to measure 'policy advice'. Presumably, the objective of policy advice is to allow the recipient of the advice to make a 'sound decision'. What, then, are the desirable characteristics of that objective? This is something that should be determined in conversation or consultation, but here are some possibilities to describe a 'sound decision':
Multiple options have been considered;
Consultation with key stakeholders has been conducted;
Conclusions and recommendations are linked to and driven by the above research and consultations;
The advice given is relevant to the decision to be made.
3. Use facts and apply judgement to evaluate results. Using the example above, the question of whether 'multiple options were considered' is easily answered by reviewing the process by which policy advice was developed. So is the fact of 'consultation with stakeholders'. You can also examine how options were evaluated e.g. what pros and cons were considered, which values were employed in making the recommendation, and the relative weight given to each value.
So you can 'measure the tough stuff', but how best to make use of this information? Since the real purpose of performance measurement is to influence behaviors that drive organizational learning and improvement, you can use this information to best advantage by taking advantage of the judgement and experience of your people. Discuss results with them, and encourage them to assess and compare their own judgements and experience and to learn from each other.
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{
"pile_set_name": "Pile-CC"
}
|
Q:
Dependency errors when loading custom dll in python, built with Visual Studio 2017 and boost
I am trying to build the BGSLibrary python module from C++ and boost source. The library compiles without a problem on linux. For windows I am using Visual Studio 2017 and Cmake 3.9. Here were my steps.
Visual Studio Install options
Download Boost, Install Script from within Visual Studio Command Line Terminal
bootstrap.bat
b2 -j%cores% toolset=msvc-14.1 address-model=32 architecture=x86 link=static threading=multi runtime-link=static --build-type=complete stage --with-python
Rename boost_python-vc141-mt-s-1_64.lib to python_boost.lib to satisfy cmake requirements.
CMake Config options
Visual Studio External Include Directories
Visual Studio External Lib Directories
Move a copy of the originally named boost_python-vc141-mt-s-1_64.lib to the bgs build folder.
Execute Visual Studio Build. It successful creates libbgs python dll
According to this question I rename libbgs.dll to .pyd and have the boost lib in the folder. I added bgslibrary/build to path. Unfortunately not quite there yet.
Some dependency issue. A quick look at DependencyWalker is very intimidating, a huge number of problems.
Before I go and try to individual add all those .dll manually to the bgslibrary/build folder, is there a higher level error that I've done. Should I have selected "static library" in the general properties of visual studio, would that make a difference?
A:
Solved. Dependency walker is old enough where it just shows alot of errors. Really it was jut the 4 opencv dlls. Adding opencv/build/release/bin to my path did it.
|
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"pile_set_name": "StackExchange"
}
|
Großer Zschirnstein
The Großer Zschirnstein () is the highest hill in the Saxon and German part of the Elbe Sandstone Mountains.
Origin of the name
The name appears to be derived from the Slavic root word for "black".
Location and area
There are two climbing peaks on the Großer Zschirnstein - the Großer and Kleiner Zschirnsteinturm ("Great" and "Little Zschirnstein Tower"). There is also the Südwand (IV) climbing route that ends directly at the highest point on the hill. This climbing route is one of the three exceptions to Saxon climbing regulations which state that climbing of massifs is generally forbidden.
On the south summit, near the viewing point, a Nagel Column (Nagelsche Säule) has stood since 1865. It recalls August Nagel, the head of survey in Saxony in the 19th century. The survey was carried out using triangulation. Other trig points in the area are located inter alia on the Raumberg, the Lilienstein, the Cottaer Spitzberg and the Hoher Schneeberg. The column on the Großer Zschirnstein was lost around 1900. In May 2011 a replica was erected in its place.
Geology
This typical table hill is made of sandstone. On the summit plateau is a Tertiary basaltic extrusion which was quarried in a small quarry in order to win gravel.
View
The following hills, rock formations and settlements can be seen from the Großer Zschirnstein (from northeast through south to northwest): Falkenstein, Schrammsteine, Tanečnice (Tanzplan), Großer Winterberg, Zirkelstein, Kottmar, Prebischtor, Mezní Louka (Rainwiese), Vlčí hora (Wolfsberg), Jedlová (Tannenberg), Pěnkavčí vrch (Finkenkoppe), Studenec (Kaltenberg), Zlatý vrch (Goldberg), Růžovský vrch (Rosenberg), Ještěd (Jeschken), Klíč (Kleis), Bezděz (Bösig), Buková hora (Zinkenstein) (with its prominent TV tower), Lovoš (Lobosch), Kletečna (Kletschen), Milešovka (Milleschauer), Děčínský Sněžník (Hoher Schneeberg), Dresden.
Air crash
On 14 February 2010 around 8.20 pm a Cessna Citation 550 light aircraft crashed into the southern flank of the hill in a craggy area. The aircraft belonged to the Czech airline, Time Air, and was under way from Prague to Karlstad in Sweden. The two pilots were killed. According to an evaluation of the voice recorder the cause of the crash was an aerobatic manoeuvre (aileron roll) for which the aircraft is not authorised.
See also
List of mountains in the Elbe Sandstone Mountains
References
External links
Photos of the Großer Zschirnstein
Category:Hills of Saxony
Category:Mountains of Saxon Switzerland
Category:Reinhardtsdorf-Schöna
Category:Rock formations of Saxon Switzerland
eo:Großer Zschirnstein
|
{
"pile_set_name": "Wikipedia (en)"
}
|
A cognitive behavioural approach to working with parents and families.
This article examines the difference between cognitive behavioural therapy (CBT) and the cognitive behaviour approach (CBA) in relation to its use in health visiting practice and school nursing. Two areas of practice are illustrated: support in postnatal depression; and support with positive parenting. The 'Five Areas' approach to assessment and intervention is discussed alongside behavioural activation, cognitive restructuring and problem solving to reduce avoidance strategies.
|
{
"pile_set_name": "PubMed Abstracts"
}
|
Suzanne Somers: ‘If I Had a Hot Date, I’d Manipulate Taking the Pill’
Not only that, but she has in recent years become something of a wellness guru, thanks to her 2006 book Ageless: The Naked Truth About Bioidentical Hormones.
And now she’s got a follow-up titled Breakthrough: Eight Steps to Wellness.
“What an awful thing to do to nature,” Suzanne (above) tells us of her recreational pill schedule.
But on Gab with the Gurus this week, the Three’s Company star discusses how she came to realize that her old lifestyle was doing her in.
“When I got cancer, it was like being cold-cocked. That was nine years ago, and I thought, What have I been doing in my diet and lifestyle habits that has created this in me?” she tells host Connie Bennett.
“I took full respons- ibility for my cancer. So I sat back and I thought, Well, Suzanne, all those years on television series, every time you passed a crafts table you always stopped. And a bite of this, a bite of that.
“It was all crap . . . There was no real food [but] I never connected the dots. And then I thought, What else have I done?
“Well, I took birth-control pills for 22 years. All of us baby boomers who took those, we were told they were safe. We manipulated our periods.
“If I had a hot date – with who I’m now married to – I’d manipulate taking the pill so I wouldn’t have to get my period ‘til Monday or Tuesday.”
|
{
"pile_set_name": "Pile-CC"
}
|
import unittest
from speeqeweb.speeqe.models import Theme
from django.contrib.auth.models import User
class TestThemeModel(unittest.TestCase):
""" Test that the theme model works."""
def testTheme(self):
user,created = User.objects.get_or_create(username='test@speeqe.com')
theme,created = Theme.objects.get_or_create(name="test",
owner=user,
content="<html></html>")
self.assert_(theme.name == "test")
|
{
"pile_set_name": "Github"
}
|
Gas to olive oil partition coefficients: a linear free energy analysis.
Literature values of gas to olive oil partition coefficients at 37 degrees C have been assembled for 218 compounds. Application of an Abraham linear free energy equation correlates 215 compounds with R2=0.981 and a standard deviation, SD, of 0.196 log units. One hundred and eight compounds were then used as a training set, and the resulting equation was used to predict the remaining 107 compounds with an average error of 0.025, an absolute average error of 0.150, and a standard deviation of 0.224 log units. The linear free energy equation shows that as a solvent olive oil is not very polar but is reasonably basic, although with a weaker hydrogen bond base than ethyl acetate or acetone, and has no hydrogen bond acidity. The coefficients for partition from the gas phase to biological phases such as blood and brain lie between those for water and olive oil, which explains why gas to biological phase partition can be described in an empirical way by a combination of gas to olive oil and gas to saline coefficients.
|
{
"pile_set_name": "PubMed Abstracts"
}
|
Q:
HTML5 canvas, resize a background image
I have a canvas thas is created dynamically, so width and height are always differents.
I have a background image i want to put on this canvas, so i just add in CSS :
canvas { background:url(/URL/background-canvas.jpg) }
But, how can i auto resize the image to the size of my canvas ? Thanks !
A:
I believe you can do something like this:
canvas {
background:url(/URL/background-canvas.jpg);
background-size: 100% 100%;
}
See this for more info on it.
|
{
"pile_set_name": "StackExchange"
}
|
package config
import (
"fmt"
"log"
"os"
"strings"
"text/tabwriter"
"time"
"github.com/inbucket/inbucket/pkg/stringutil"
"github.com/kelseyhightower/envconfig"
)
const (
prefix = "inbucket"
tableFormat = `Inbucket is configured via the environment. The following environment variables
can be used:
KEY DEFAULT DESCRIPTION
{{range .}}{{usage_key .}} {{usage_default .}} {{usage_description .}}
{{end}}`
)
var (
// Version of this build, set by main
Version = ""
// BuildDate for this build, set by main
BuildDate = ""
)
// mbNaming represents a mailbox naming strategy.
type mbNaming int
// Mailbox naming strategies.
const (
UnknownNaming mbNaming = iota
LocalNaming
FullNaming
DomainNaming
)
// Decode a naming strategy from string.
func (n *mbNaming) Decode(v string) error {
switch strings.ToLower(v) {
case "local":
*n = LocalNaming
case "full":
*n = FullNaming
case "domain":
*n = DomainNaming
default:
return fmt.Errorf("Unknown MailboxNaming strategy: %q", v)
}
return nil
}
// Root contains global configuration, and structs with for specific sub-systems.
type Root struct {
LogLevel string `required:"true" default:"info" desc:"debug, info, warn, or error"`
MailboxNaming mbNaming `required:"true" default:"local" desc:"Use local, full or domain addressing"`
SMTP SMTP
POP3 POP3
Web Web
Storage Storage
}
// SMTP contains the SMTP server configuration.
type SMTP struct {
Addr string `required:"true" default:"0.0.0.0:2500" desc:"SMTP server IP4 host:port"`
Domain string `required:"true" default:"inbucket" desc:"HELO domain"`
MaxRecipients int `required:"true" default:"200" desc:"Maximum RCPT TO per message"`
MaxMessageBytes int `required:"true" default:"10240000" desc:"Maximum message size"`
DefaultAccept bool `required:"true" default:"true" desc:"Accept all mail by default?"`
AcceptDomains []string `desc:"Domains to accept mail for"`
RejectDomains []string `desc:"Domains to reject mail for"`
DefaultStore bool `required:"true" default:"true" desc:"Store all mail by default?"`
StoreDomains []string `desc:"Domains to store mail for"`
DiscardDomains []string `desc:"Domains to discard mail for"`
Timeout time.Duration `required:"true" default:"300s" desc:"Idle network timeout"`
TLSEnabled bool `default:"false" desc:"Enable STARTTLS option"`
TLSPrivKey string `default:"cert.key" desc:"X509 Private Key file for TLS Support"`
TLSCert string `default:"cert.crt" desc:"X509 Public Certificate file for TLS Support"`
Debug bool `ignored:"true"`
}
// POP3 contains the POP3 server configuration.
type POP3 struct {
Addr string `required:"true" default:"0.0.0.0:1100" desc:"POP3 server IP4 host:port"`
Domain string `required:"true" default:"inbucket" desc:"HELLO domain"`
Timeout time.Duration `required:"true" default:"600s" desc:"Idle network timeout"`
Debug bool `ignored:"true"`
}
// Web contains the HTTP server configuration.
type Web struct {
Addr string `required:"true" default:"0.0.0.0:9000" desc:"Web server IP4 host:port"`
BasePath string `default:"" desc:"Base path prefix for UI and API URLs"`
UIDir string `required:"true" default:"ui/dist" desc:"User interface dir"`
GreetingFile string `required:"true" default:"ui/greeting.html" desc:"Home page greeting HTML"`
MonitorVisible bool `required:"true" default:"true" desc:"Show monitor tab in UI?"`
MonitorHistory int `required:"true" default:"30" desc:"Monitor remembered messages"`
PProf bool `required:"true" default:"false" desc:"Expose profiling tools on /debug/pprof"`
}
// Storage contains the mail store configuration.
type Storage struct {
Type string `required:"true" default:"memory" desc:"Storage impl: file or memory"`
Params map[string]string `desc:"Storage impl parameters, see docs."`
RetentionPeriod time.Duration `required:"true" default:"24h" desc:"Duration to retain messages"`
RetentionSleep time.Duration `required:"true" default:"50ms" desc:"Duration to sleep between mailboxes"`
MailboxMsgCap int `required:"true" default:"500" desc:"Maximum messages per mailbox"`
}
// Process loads and parses configuration from the environment.
func Process() (*Root, error) {
c := &Root{}
err := envconfig.Process(prefix, c)
c.LogLevel = strings.ToLower(c.LogLevel)
stringutil.SliceToLower(c.SMTP.AcceptDomains)
stringutil.SliceToLower(c.SMTP.RejectDomains)
stringutil.SliceToLower(c.SMTP.StoreDomains)
stringutil.SliceToLower(c.SMTP.DiscardDomains)
return c, err
}
// Usage prints out the envconfig usage to Stderr.
func Usage() {
tabs := tabwriter.NewWriter(os.Stderr, 1, 0, 4, ' ', 0)
if err := envconfig.Usagef(prefix, &Root{}, tabs, tableFormat); err != nil {
log.Fatalf("Unable to parse env config: %v", err)
}
tabs.Flush()
}
|
{
"pile_set_name": "Github"
}
|
Great Storm 1987: The day 18 people were killed
Ask people about the Great Storm which ravaged the south of England in 1987 and most will remember “that” forecast by weatherman Michael Fish, or Sevenoaks losing six of the trees that gave the town its name. What is mentioned far less is the loss of 18 lives. “When we eventually got him out, he had suffocated under the rubble. They couldn’t find a broken bone in his body.”Alec Homewood was about five miles away from his childhood home when its roof fell in and killed his brother.Cyril Homewood, known as Bob, was upstairs asleep in his bedroom when the chimney collapsed – the force of which pushed the legs of his bed through the ceiling into the kitchen.”It just devastated the house,” his brother said. “Virtually all the roof came down. Mother said he’d been killed, but we didn’t know.”
Mr Homewood set out for the house at Biddenden in Kent, but countless trees felled by ferocious winds had made roads around the village impassable. Using a chainsaw, he hacked at them as he went. When he arrived at Beacon Hill Farm, he found his mother had been rescued from the drawing room by people living nearby.But when they tried to reach his 59-year-old brother, they found the bedroom was full of bricks and debris.”It took me ages to get there,” Mr Homewood, now 72, remembered. “They [the emergency services] got him out in the end, but he was dead.”
Media playback is unsupported on your device
Severe weather had been predicted before the Great Storm – as it later became known – hit the south coast of England in the early hours of 16 October.The previous afternoon, the Met Office had forecast winds for the Channel and very heavy rain overland.The BBC’s weather presenter Michael Fish had quashed rumours a hurricane was on the way: “Don’t worry, there isn’t”, he infamously told the nation.But just a few hours later, the storm changed direction.Severe weather warnings were issued to emergency responders, including the Ministry of Defence and London Fire Brigade.But what became the worst storm since 1703 was by that point unstoppable.
A maximum gust of 115mph was recorded at Shoreham in West Sussex, while London was battered by gales of up to 94mph.On the south coast the Royal Sovereign lightship witnessed an average wind speed of 86mph. A ship capsized at Dover and a Channel ferry was driven ashore near Folkestone.Thousands of homes were left without power for several days, and the damage caused by the storm was put at more than £1bn.The number of trees lost was estimated at 15 million.Eighteen people in the UK – and four in France – were killed.
Kent police constable Douglas Stitt was five miles away in Tenterden when he got the call for help.He said the five-mile drive to Biddenden – normally a 10-minute journey – took them more than two hours.Trees were strewn across the road every quarter of a mile and a fireman with a chainsaw had to cut through the debris as they went.Great Storm: The healing power of natureMichael Fish talks about ‘that’ forecastWhen they got there, they found a scene of devastation. The 999 crews knew they were dealing not with a rescue, but a recovery.”It was beyond that stage,” Mr Stitt said.”We managed to climb through the back door. The whole landing was smashed in.”It was a case of gradually picking our way over the rubble. It looked like a bomb had hit it.”
In the months and years that followed, debate raged about whether the storm had been a hurricane. Experts agreed it was not by definition, because it had not originated in the tropics.After an internal inquiry, the Met Office improved its forecasting technology amid allegations it had failed to alert the nation.For Mr Homewood, the shock of his brother’s death did not hit him until days after the storm had passed. He remains adamant it was a hurricane – even having words to that effect inscribed on his brother’s gravestone.”I’ll never ever forget him. I think of him nearly every day,” he said.”When I think back, it was terrible. But you can’t defeat nature.”The Great Storm of 1987 was as bad as having a bomb dropped on the place.”
Media playback is unsupported on your device
Mr Homewood was not the only fatality of the Great Storm, but media coverage of those killed was limited.John Dowling, who was deputy editor of the Bexhill Observer, remembers how Ronald Davies died at the Queens Hotel in Hastings when a chimney crashed through the roof.But the newspaper did not report his death, because it happened outside its patch.Instead it focused on the community’s response, including how a group of people in their 70s went out to clear roads with chainsaws.”Memories are very selective,” said Mr Dowling. “Think of memories of ’87 and you have certain images and perhaps people tend to wipe out the nasty bits and remember the silly bits.”
The journalist said it was “darned difficult” finding people after the storm. Many had left their houses, and neighbours did not know where they had gone.He remembered a roof being torn off one property leaving a bedroom open to the sea and sky, an entire penthouse that was swept into a car park, and a rowing boat that ended up in a road, 400 yards from the sea.”It was all hands to the pump, by everyone who could help. Builders, people, emergency services, it was the Dunkirk spirit.”The Great Storm was later categorised as a one-in-200-year event.On top of the environmental cost, there was structural damage as trees, ripped from the ground by their roots, crushed houses and vehicles and blocked roads and railways.Even now, residents and historians agree the loss of an estimated 15 million trees was devastating.”When we looked and saw the trees, hundreds of years old… that was just heartbreaking,” said Biddenden parish councillor, Eileen Cansdale.”There was structural damage that could be addressed, but the trees couldn’t be replaced. It completely changed everything.”Those killed in the Great Storm
Mrs Beryl Agha, Hove
John Barton, Petersfield
Patricia Bellwood, Wrotham
David Birch, lost at sea
Sylvia Brown, Canvey Island
Anthony Burton, Salisbury
Ronald Davies, Hastings
Robert Doke, Croydon
Robert Homewood, Biddenden
Ronald Horlock, lost at sea
David Gregory, Christchurch
Terence Marrin, Lincoln’s Inn Fields
James Read, Hastings
Sidney Riches, Kings Lynn
Sosammi Shilling, Chatham
Georgina Wells, Haywards Heath
Graham White, Christchurch
Source: Windblown, by Tamsin Treverton JonesHistorian Bob Ogley said news of the loss of life emerged only in the days after the storm because people in the area were still without power.”There was no radio communication, because most people used electric radios, and there was no TV at all.”It was only later we learned people had died.”
He said people remember the damaged landscape more than anything else. “Here in Sevenoaks, we lost our name. Sevenoaks was reduced to one oak.”Most people went to bed and woke up and found a tree in their garden.”So, people think about the countryside. People don’t think about those who died, because they were spread over a large area. “Having said that, every death is a tragedy.”See more about the Great Storm on Inside Out, on BBC One South East, South West and South on Monday 16 October at 19:30 BST, and later on the BBC iPlayer.
Source: BBC Hamp
|
{
"pile_set_name": "Pile-CC"
}
|
As the filing deadline looms large, you may be gathering those final details, including receipts for your deductions. Did you purchase hearing aids last year? If so, you’re in luck! Hearing aids are tax deductible if you itemize your medical deductions on your federal income taxes. In fact, the savings includes hearing-related costs for you, your spouse and your dependents. As with most things related to taxes, there are some caveats. We’ve gathered some of the most relevant information for you. And if you’ve already filed, keep this in mind as you plan medical spending for 2018, so you’re ready next year.
To deduct or not to deduct – that is the first question
Not sure if you can deduct your hearing aids? To start, you must decide if you will itemize your medical expenses or not. If you don’t itemize your deductions, then you can’t take advantage of this savings. However, if you have significant medical expenses, it might be worth it for you or your family to do so this year. For the next two years, if you spend more than 7.5% of your income on medical expenses1, you can deduct medical costs from your insurance. (Previously, the threshold had been 10%.) Some years, itemizing may make more sense than others. If you have invested in hearing aids and had other significant medical expenses, such as a hospital stay or surgery where you paid a portion of the cost, this may be the right year to deduct these expenses.
What can you deduct?
According to TurboTax2, the following hearing-related expenses can be deducted:
Of course, we are not tax experts, and highly advise you to bring specific financial questions to your tax advisor or an accountant.
Need more information on medical expenses and taxes?
You may wonder what counts as a medical expense. Another great source for information is the IRS’s information page on medical and dental expenses.3 If you have a person in your household, such as a parent or child, who purchased hearing aids last year, you can only deduct these costs if you claim this person as a dependent on your taxes – even if you paid for the hearing aids.
Already filed your taxes? No worries – there’s always next year
If you are a first-time hearing aid wearer or you are looking to upgrade, remember to save your receipts, because before you know it, you’ll need them for next year’s filing. If you know you will have significant medical expenses coming soon, this might be a good year to spring for the latest technological advances. That way, Uncle Sam can pay you back next year. For more information on the latest in high-tech hearing aids, give us a call at (888) 430-1821.
“Hear the future and prepare for it” is the World Health Organization’s (WHO’s) message for World Hearing Day 2018. To that end, Hearing Healthcare of Virginia advises everyone to take care of their hearing health.
Take action for hearing health on World Hearing Day
On World Hearing Day, March 3rd, 2018, Hearing Healthcare of Virginia hopes to encourage more people to be mindful of their hearing health.1 Based on statistical projections, the World Health Organization (WHO) has revealed that the prevalence of hearing loss is set to increase globally, and this World Hearing Day discusses how preventative measures could help curb the rise. With more than 5% of the global population already affected by disabling hearing loss2, now is the time to raise awareness and address why people do not recognize the signs when they are affected.
Causes of hearing loss
Many things can cause hearing loss – both in and out of our control. The most common include:
Exposure to excessive noise
Genetic causes
Complications at birth
Certain infectious diseases
Chronic ear infections
Certain medications
Aging2
Approximately 60% of childhood hearing loss is due to preventable causes.2 Although not all hearing loss can be prevented, we can take action to take better care of our ears, such as wearing ear protection when working with loud machinery. More importantly, we can pay more attention to our hearing and seek advice from an expert if we have any concerns.
Hearing loss can be a slow process, so it can be difficult to read the signs of deterioration, and in many cases, is easily ignored. In comparison to loss of sight, hearing loss is not always noticeable. Many people have a vision test annually to maintain eye health. Unfortunately, many people don’t take the same precautions for their ears, because hearing is as important as sight.
Knowing the signs of hearing loss
One key element to maintaining hearing health is paying attention to the early signs of hearing loss, such as:
Having the television or radio consistently at a loud volume
Struggling to follow conversations (especially in noisy environments such as restaurants)
Asking people to repeat themselves often
Withdrawal and isolation to avoid tough listening situations
Repositioning to point your ears toward sound
Not hearing the phone ring, the doorbell or sirens
Untreated hearing loss can be detrimental
Our professionals urge you to address the symptoms of hearing loss. We advise you begin with a professional hearing assessment* to eliminate guesswork. Untreated hearing loss can cause serious long-term conditions, especially later in life, so we implore everyone to maintain their hearing care now.
Hearing loss has a number of side effects. Untreated, hearing loss can cause people to withdraw from socializing and lead to feelings of isolation and depression. Several studies have concluded that hearing loss contributes to the early onset of dementia, including the recent study authored by the Lancet Commissions on Dementia Prevention, Intervention, and Care.3 Addressing hearing loss is key to remaining cognitive and socially active.
Hearing loss is widespread – and growing
According to the WHO, approximately one third of people over 65 years of age are affected by disabling hearing loss2 and are potentially at risk of affecting their overall health if untreated. With the number of people aged 65 and above predicted to have doubled in 2050 compared to today4, age-related hearing loss is almost certainly a contributing factor to the increasing prevalence of hearing loss. That’s partially why the WHO’s slogan for 2018 is “Hear the future and prepare for it.” Now is the best time to act.
How can you take action on World Hearing Day?
Just by reading this to educate yourself, you are taking an important step. If you have concerns about your hearing, or have someone in your life who shows signs of hearing loss, make an appointment for a free, no-obligation hearing assessment* so you can learn more about your individual needs. Call (888) 430-1821 for more information.
Do you have hearing loss? Maybe. Imagine if you could hear and remember better with less effort and stress on your brain. Wouldn’t life be easier if you had solutions to help you recall what people say? Good news! The latest hearing aids do just that.
How prevalent is hearing loss?
The answer is that many people have hearing loss and could benefit from using hearing aids. It could be you or a loved one.
Did you know?
One in three adults age 65 and above experience some form of hearing loss.1
Older adults who use hearing aids show reduced depression symptoms and improved quality of life.1
60% of our military personnel return home from overseas with hearing impairment2, often as a result of noise exposure.
One in five teenagers has some level of hearing loss.2
Only 3 in 10 adults who had a physical exam in the last year say it included a hearing screening.3
Are you one of the nearly 50 million Americans4 with some degree of hearing loss? (If you aren’t sure, then it might be time for a hearing assessment.*)
Innovative solutions and advanced devices
Today’s hearing aids include very advanced hearing devices with innovative options. Their minuscule size, coupled with hair-toned color options, provides true discreetness. There are exciting new features that will change the way you think about and use hearing aids, including features that:
Automatically adjust to different soundscapes
Enable you to listen to multiple speakers, even in noisy environments
Connect directly to the internet, your smartphone or television via Bluetooth® and wireless capabilities
Most noteworthy, some models offer a convenient, new rechargeable+ unit that saves hundreds of dollars on disposable batteries annually.
Do I have hearing loss?
The first step is to identify your needs.* This involves:
Hearing assessment*, complete with baseline and familiar voice tests
Otoscopy exam of your ear canal (hearing loss may be from earwax)
Live demonstration* of the latest hearing aid technology
In addition, you can learn about the products through a demonstration.
Could your solution lie with high-tech hearing aids?
Our professional team is happy to discuss your needs and solutions that make sense for your lifestyle, habits and budget. Most of all, we want you to feel comfortable with solutions for your hearing loss. Rather than guess, we welcome you to call (888) 430-1821 to make an appointment today.
*The purpose of this hearing assessment and/or demonstration is for hearing wellness to determine if the patient(s) may benefit from using hearing aids. Products demonstrated may differ from products sold. Test conclusion may not be a medical diagnosis. The use of any hearing aid may not fully restore normal hearing and does not prevent future hearing loss. Testing is to evaluate your hearing wellness, which may include selling and fitting hearing aids. Hearing instruments may not meet the needs of all hearing-impaired individuals. One offer per customer. Insurance benefit, including Managed Care or federal reimbursements, cannot be combined with any of our promotional offers, coupons or discounts. Other terms may apply. See office for details. +Rechargeable unit is sold as a kit only. ZPower®
Rechargeable Kit includes charging dock with power supply, 2 x silver-zinc rechargeable batteries and 2 x battery drawers. Hearing aids are not included.
Hearing loss can occur at birth – three out of every 1,000 children born in the U.S. are born with a detectable hearing loss in one or both ears, and 15 percent of U.S. school children have some degree of hearing loss.
But more common is hearing loss that comes on gradually.
What is called presbycusis – the loss of hearing that occurs gradually as we age – is most common for those 55 and older.
By age 65, one of three people has a hearing loss.
The most common cause is exposure to loud noises – loud music, workplace noises, etc.
There is good news and bad news when it comes to hearing loss. The bad news first: you can’t reverse most types of hearing loss.
Now, the good news: you can take steps to improve your hearing.
The key there is to see a hearing specialist as soon as you notice a degradation in your hearing. The longer you wait, the harder it will be to see improvement.
The reason is, over time, reduced stimulation to your ears and brain can actually impair the brain’s ability to process sound and recognize speech.
If you feel you or a loved one has an issue hearing, the sooner you take action to contact a hearing specialist, the sooner you put a stop to many negative effects of hearing loss.
How Hearing Healthcare of Virginia can help
According to the Hearing Loss Association of America, hearing loss is the third most common health condition among adults. Our experts can help you stay connected and thrive in daily life. Understand where your strengths and areas of weakness lie so you can take steps toward improvement. Learn what to expect on your first visit with our experienced and reliable experts.
Contact us for more information on hearing healthcare
Hearing healthcare is vital to your well-being. Find out if you are a candidate for hearing aids with our free hearing assessment*. Call Hearing Healthcare of Virginia at (888) 430-1821 to learn more.
Sign up for our free newsletter
Newsletter Signup
*The purpose of this hearing assessment and/or demonstration is for hearing wellness to determine if the client(s) may benefit from using hearing aids. Products demonstrated may differ from products sold. Test conclusion may not be a medical diagnosis. The use of any hearing aid may not fully restore normal hearing and does not prevent future hearing loss. Testing is to evaluate your hearing wellness, which may include selling and fitting hearing aids. Hearing instruments may not meet the needs of all hearing-impaired individuals. One offer per customer. Insurance benefit, including Managed Care or federal reimbursements, cannot be combined with any of our promotional offers, coupons or discounts. Other terms may apply. See office for details.
|
{
"pile_set_name": "Pile-CC"
}
|
FINAL SCORE FRIDAY: Greenbriar Christian at BSH
POWHATAN, VA (WTVR) – New coach, same result for the Knights of Blessed Sacrament-Huguenot. Under first year head coach Brice Fritts, they won their opening round VISAA, Division 4 playoff game knocking off Greenbriar Christian 28-21 at home.
Ethan Johnson capped a pair of long drives for the Knights (7-4) with two touchdown runs as part of his 135 yard rushing night. Chandler Emberlin added 60 rushing yards and a touchdown.
The win avenges one of the Knights regular season losses and moves them into the VISAA D-4 championship game for the fourth straight season. Greenbriar Christian finishes their season at 6-5.
|
{
"pile_set_name": "Pile-CC"
}
|
Synthesis and antiinflammatory activity of 2H-tetrazol-2-acetic acids, esters and amides.
A series of 5-(pyridyl)-2H-tetrazol-2-acetic acids (16-21), esters (10-15), and amides (22-27) was synthesized in order to investigate the effect of 5-substituents (R1 = 2-, 3- or 4-pyridyl) and alpha-substituents (R2 = H, Me) on anti-inflammatory activity. The point of attachment of the R1-pyridyl substituent influenced potency. The relative potencies in the acetic acid ester, acetic acid and acetamide classes of compounds were 2- and 4- greater than 3-pyr, 2- and 3- greater than 4-pyr, and 4- greater than 2- and 3-pyr, respectively. In the acetic acid ester and acetamide classes, compounds having a R2 hydrogen substituent were generally more potent than corresponding methyl substituted compounds, whereas, in the acetic acid class the reverse applied. The relative order of anti-inflammatory potency was generally amide greater than ester greater than acid. 2-[5-(4-Pyridyl)-2H-tetrazol-2-yl]acetamide (26) was the most effective antiinflammatory agent in the series, reducing inflammation by 53% at 3 and 5 hr after a 25 mg/kg po dose.
|
{
"pile_set_name": "PubMed Abstracts"
}
|
Q:
Wrapping HTML in an app for Android
I have an existing site (social in nature) and it already has a mobile web version too, so what I basically want to do is wrap that view in an Android app and maybe add a nice splash screen to it. So essentially a "branded" browser window.
Any advice would be appreciated.
A:
You would need two activites
Splash Screen (use a timer and after x seconds move to the next activity)
Main
In the main activity you would need to set a layout with a webView in your layout so something like:
<?xml version="1.0" encoding="utf-8"?>
<WebView xmlns:android="http://schemas.android.com/apk/res/android"
android:id="@+id/webview"
android:layout_width="fill_parent"
android:layout_height="fill_parent"
/>
and the code:
public void onCreate(Bundle savedInstanceState) {
super.onCreate(savedInstanceState);
setContentView(R.layout.main);
mWebView = (WebView) findViewById(R.id.webview);
mWebView.getSettings().setJavaScriptEnabled(true);
mWebView.loadUrl("http://www.google.com");
}
and the permissions:
<uses-permission android:name="android.permission.INTERNET" />
in the manifest file.
If you want to turn the title bar off you will also need to add:
<activity android:name=".Main" android:label="@string/app_name"
android:theme="@android:style/Theme.NoTitleBar">
Read the docs for more help! An example for Google for this exactly and I referenced is http://developer.android.com/resources/tutorials/views/hello-webview.html
A:
There also exist several frameworks that wrap HTML5 inside a native app and gives you access to APIs.
Phonegap is the most well-known
http://phonegap.com/
|
{
"pile_set_name": "StackExchange"
}
|
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DflAW5/7y 7S2AI
|
{
"pile_set_name": "FreeLaw"
}
|
Q:
How to customize angular ui-grid row background color?
I am trying to change background color of angular ui-grid row based on condition so if riskValue is 1 trying to make it red and if value is 2 row background color should be Yellow. Any easy way to achieve this task ?
config.js
"columnDefs": [{
"name": "Ticket Number",
"field": "ticketNum",
"width": 120
},
{
"name": "Asset Id ",
"field": "assetID",
"width": 100
},
{
"name": "Severity",
"field": "severity",
"width": 100
},
{
"name": "Risk Index",
"field": "riskIndex",
"width": 100
},
{
"name": "Risk Val",
"field": "riskValue",
"cellTemplate": "<div ng-if=\"row.entity.Comments_Col1 != 'none'\" title={{row.entity.riskValue}} \" ><div style='white-space:nowrap;border-bottom: 1px solid red !important; height:100%;width:100%;'>{{row.entity.riskValue}}</div></div>",
"sort": {
"direction": "aesc",
"priority": 0
},
"width": 100,
"visible": false
}
],
A:
You can use gridOptions.cellClass
cellClass: function(grid, row, col, rowRenderIndex, colRenderIndex) {
if (row.entity.riskValue === 1)
return 'red';
if (row.entity.riskValue === 2)
return 'yellow';
}
where red and yellow are css classes.
This method requires adding the function to all of your columnDefs but allows to choose only some columns, which should have changed background color.
Sample: http://plnkr.co/edit/Xie68a3sT9CXTdCuI3tq?p=preview
|
{
"pile_set_name": "StackExchange"
}
|
Q:
Why do you need to redefine serialVersionUID if you extends a class which implements Serializable "down the line"?
For one of my projects, I need to define a new exception which extends ProviderMismatchException.
From the javadoc link, you can see that this exception:
extends IllegalArgumentException, which
extends RuntimeException, which
extends Exception, which
extends Throwable.
All of them define their own static final serialVersionUID except for Throwable which adds the private modifier.
Now, if you implement an interface Foo, then all inherited classse also implement that interface, and this stands for Serializable as well; however, why do subclasses in the JDK redefine it for each subclass? What is the danger of not defining it again for inherited classes?
A:
The serialVersioUID is a static long value, thus it won't be inherited through the class hierarchy.
You need this to indicate if a prior serialized instance of a class has the same version as the current implementation or not.
If a serializable class does not explicitly declare a serialVersionUID, then the serialization runtime will calculate a default serialVersionUID value for that class based on various aspects of the class, as described in the Java(TM) Object Serialization Specification. However, it is strongly recommended that all serializable classes explicitly declare serialVersionUID values, since the default serialVersionUID computation is highly sensitive to class details that may vary depending on compiler implementations, and can thus result in unexpected InvalidClassExceptions during deserialization.
For Details see here:
What is a serialVersionUID and why should I use it?
|
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"pile_set_name": "StackExchange"
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|
The Blues Turnaround
Most blues songs contain a musical device called the turnaround. This is a two bar melodic chord phrase starting on the second to last bar of a blues chord progression. This signifies the end of the chord progression and sets up the progression’s repeat. The typical blues chord progression is twelve bars long, but there are many eight and sixteen bar chord progressions too as well as an occasional odd numbered set of chords.
In this article you will be taught some of the more well known classic blues turnaround phrases in the key of A, as well as the techniques to create some unique turnarounds of your very own. The following examples assume the reader has a basic working knowledge of music theory. If not, no worry! Often this stuff is on a need to know basis, so feel free to jump ahead and learn the licks.
|
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We are pleased to announce that Tears For Fears will be performing at @BBCRadio2 #BiggestWeekend on May 27th. Tickets go on-sale at 8:30 AM. More info: http://bbc.co.uk/biggestweekend pic.twitter.com/W2UwRxikz7 […]
|
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Friday, April 19, 2013
Narrated by the talented sports narrator, Dan Czerwonka, this hockey novel centers on Graham Wilson, a recreational league hockey player. Graham decides to try goaltending, and the result is like life -- there is comedy, drama, tragedy, and perseverance. It is a journey that shows Graham what truly is "all that counts" in life.
You can get your copy of the All That Counts audio book at Amazon, Audible.com or iTunes. You can hear an audio sample here.In celebration of the audio book release, I am making the Kindle version of All That CountsFREE for 5 days!You can get the Kindle version of this book for free from Saturday, April 20th until Wednesday, April 24th. Just go here and download!Just in time for the NHL playoffs!
|
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Passive Q switching of a solar-pumped Nd:YAG laser.
Passive Q switching is a preferable choice for switching the Q factor of a solar-pumped laser because it requires neither a driver nor an electrical power supply. The superior thermal characteristics and durability of Cr(4+):YAG single crystals as passive Q switches for lamp and diode-pumped high-power lasers has been demonstrated. Here we report on an average power of 37 W and a switching efficiency of 80% obtained by use of a solar-pumped Nd:YAG laser Q switched by a Cr(4+):YAG saturable absorber. Concentration of the pumping solar energy on the laser crystal was obtained with a three-stage concentrator, composed of 12 heliostats, a three-dimensional compound parabolic concentrator (CPC) and a two-dimensional CPC. The water-cooled passive Q switch also served as the laser rear mirror. Repetition rates of as much as 50 kHz, at pulse durations between 190 and 310 ns (FWHM) were achieved. From the experimental results, the saturated single-pass power absorption of the Cr(4+):YAG device was estimated as 3 ? 1%.
|
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{
"_args": [
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"raw": "abbrev@1",
"scope": null,
"escapedName": "abbrev",
"name": "abbrev",
"rawSpec": "1",
"spec": ">=1.0.0 <2.0.0",
"type": "range"
},
"/var/www/html/star/node_modules/nopt"
]
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"_from": "abbrev@>=1.0.0 <2.0.0",
"_id": "abbrev@1.1.1",
"_inCache": true,
"_location": "/abbrev",
"_nodeVersion": "8.5.0",
"_npmOperationalInternal": {
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"tmp": "tmp/abbrev-1.1.1.tgz_1506566833068_0.05750026390887797"
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"_npmUser": {
"name": "isaacs",
"email": "i@izs.me"
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"/nopt"
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"_shasum": "f8f2c887ad10bf67f634f005b6987fed3179aac8",
"_shrinkwrap": null,
"_spec": "abbrev@1",
"_where": "/var/www/html/star/node_modules/nopt",
"author": {
"name": "Isaac Z. Schlueter",
"email": "i@izs.me"
},
"bugs": {
"url": "https://github.com/isaacs/abbrev-js/issues"
},
"dependencies": {},
"description": "Like ruby's abbrev module, but in js",
"devDependencies": {
"tap": "^10.1"
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"directories": {},
"dist": {
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"tarball": "https://registry.npmjs.org/abbrev/-/abbrev-1.1.1.tgz"
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"files": [
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"gitHead": "a9ee72ebc8fe3975f1b0c7aeb3a8f2a806a432eb",
"homepage": "https://github.com/isaacs/abbrev-js#readme",
"license": "ISC",
"main": "abbrev.js",
"maintainers": [
{
"name": "gabra",
"email": "jerry+1@npmjs.com"
},
{
"name": "isaacs",
"email": "i@izs.me"
}
],
"name": "abbrev",
"optionalDependencies": {},
"readme": "ERROR: No README data found!",
"repository": {
"type": "git",
"url": "git+ssh://git@github.com/isaacs/abbrev-js.git"
},
"scripts": {
"postpublish": "git push origin --all; git push origin --tags",
"postversion": "npm publish",
"preversion": "npm test",
"test": "tap test.js --100"
},
"version": "1.1.1"
}
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|
Rating Agency Downgrades 'Anglo-American Interests' and the Currency War Myth
The Germans love a good conspiracy theory. The latest is about the evil American rating agencies that want to destroy the wonderful euro. It is a viewpoint shared even in the highest political circles. But that doesn't make it any less absurd.
|
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Pimax Vr All In One
User Experience
In terms of software application, the setup experience was sort of a discomfort in the butt. You can own a company that produces the best hardware on the planet, however it will still require world-class software application and here’s where the absence of software application engineers comes to mind. Shenzhen is hardware-savvy city, however software engineers aren’t exactly easily found. In order to get PIMAX 4K to work, we had to download PiPlay first. At the end of an uneventful set up, an user has to plug in the headset. While this sounds excellent in theory, real world experience revealed that on a fresh set up of Windows 10 Anniversary Edition we had to download these chauffeurs numerous times until PiPlay lastly recognized the headset. To keep the matters weird, Windows install keep pressing the motorist install for Oculus DK2 once PiPlay cannot spot the motorists for PIMAX 4K VR. This is a possibly limiting factor for the users, as DK2 motorists vary from Rift. As the name goes, Oculus Development Kit 2 is meant for advancement, while the Rift is a commercial product. And no, you can not play Oculus Studio exclusives such as The Climb … a pity, truly.Immerse Virtual Reality Headset UkPc Gaming Virtual Reality
Drivers are not the only thing you need to beware about. If you own a graphics card with a single HDMI adapter, such as my trusty XFX R9 390X 8GB– including just one HDMI port, one need to end up being an Apple user and begin buying dongles. In the end, I linked my display using DVI. If you own newest generation, VR Ready hardware– there must disappear show stoppers.
Once PiPlay/ PIMAX combination sorted itself out, we needed to do some adjustment to get rid of “crossed eyes feeling” while utilizing it. The driver includes “Compatible Mode”, bringing assistance for majority of SteamVR and Oculus VR video games. While it sounds great, the PiPlay itself often does not recognize the headset itself. I personally didn’t have actually seen the troublesome position tracking other reviewers and clients speak about.
After the unpleasant installation, I crossed another issue in VRMark, our “go to” standard after SteamVR. The benchmark could not introduce in Full Screen, solvable by inspecting the compatibility items around DirectX 11. Despite the fact that both SteamVR and Oculus test mark our recommendation system as “VR Ready”, the truths are that there aren’t many systems that can tackle this monstrous resolution. PC Requirements from PIMAX states that you satisfy the following elements:Pimax Vr All In One
This PC exceeds the minimum configuration by a mile, yet it still did not manage to break 90 fps in any of the tests. 78 FPS in Orange Room, and 41 in Blue Room. The genuine question now is might a GeForce GTX 1080 and or a Pascal-based Titan X run Blue Room at 90+ FPS. Given the current advancements in Multi-GPU assistance inside DirectX 12, and AMD’s typically high outcomes as their hardware age one must wonder must NVIDIA be terrified of this kind of tasks. After all, a single GeForce GTX 1080 need to offer you the performance needed to run VR. Then again, the concern beckons– need to VR players just buy two RX 480 rather.
For games, having a powerful system might assist with Assetto Corsa or Elite Dangerous. In addition, if you’re not into VR, but want to video game on an actually large screen, setting up Virtual Desktop.
In general we could not see the complete ability of this VR headset. For the half the rate requested Rift as well as more for HTC Vive you can get headset that is much better in some aspects. With some small tweaks this headset would be a beast. If they included sensing units for the room and controllers, and handled to develop a working software obviously. You can feel the 110 degree seeing angle, as well as lack of any pixels on the screen– which annoys me with the otherwise exceptional Vive. All things considered I wouldn’t blink an eye and take Pimax for all VR stuff I need (virtual desktop, and maybe viewing a motion picture). If you want to purchase it yourself you can do it here. Pimax will also be on discount on Gearbest 11.11 occasion, so you can save a lot more. The Singles Day in China, i.e. 11.11 or November 11th is a new significantly worldwide day, bringing the tradition of Black Friday a number of weeks prior to the real occasion. From Singles Day onwards, the price of the headset is down to $286.99 if you use the “PIMAX11” code.
Conclusion
4K resolution video gaming is an unusual type, but will begin to end up being more common. Ultra HD video gaming in VR is a dream in the meantime, as the amount of hardware horse power you need to run 750 million pixels each second is staggering. Both HTC and Oculus do not need more than 233 million pixels each second. this is not so bad VR headset considering it costs around $300. From the comfort point of view, and supported titles– it is way better then OSVR HDK 2.0 that’s in the very same rate variety. This headset you will get a great device hardware-wise however with average software application and limited functionalities. By consisting of a couple of small tweaks, controllers and space positioning, PIMAX could quickly become next big thing in world of VR. This is also the main reason that we can not provide a greater award than Bronze. We could conclude that PIMAX 4K is a product a bit ahead of its time, however if you want to trouble your surroundings by owning the very first 4K VR headset, by all methods, consider PIMAX.Pimax Vr All In OneImmerse Virtual Reality Headset UkPc Gaming Virtual Reality
|
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Risky business: emotion, decision-making, and addiction.
Although metabolic abnormalities in the orbitofrontal cortex have been observed in substance dependent individuals (SDI) for several years, very little attention was paid to the role of this brain region in addiction. However, patients with damage to the ventromedial (VM) sector of the prefrontal cortex and SDI show similar behaviors. (1) They often deny, or they are not aware, that they have a problem. (2) When faced with a choice to pursue a course of action that brings an immediate reward at the risk of incurring future negative consequences, they choose the immediate reward and ignore the future consequences. Studies of patients with bilateral lesions of the VM prefrontal cortex support the view that the process of decision-making depends in many important ways on neural substrates that regulate homeostasis, emotion, and feeling. Parallel lines of study have revealed that VM cortex dysfunction is also evident in subgroups of individuals who are addicted to substances. Thus, understanding the neural mechanisms of decision-making has direct implications for understanding disorders of addiction and pathological gambling, and the switch from a controlled to uncontrolled and compulsive behavior. On the clinical front, the approach to treat addictive disorders has been dominated by a diagnostic system that focuses on behaviors, physical symptoms, or choice of drugs. The article emphasizes the concept of using neurocognitive criteria for subtyping addictive disorders. This is a significant paradigm shift with significant implications for guiding diagnosis and treatment. Using neurocognitive criteria could lead to more accurate subtyping of addictive disorders, and perhaps serve as a guide for more specific, and potentially more successful, behavioral and pharmacological interventions.
|
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|
2016 İstanbul Cup – Doubles
Daria Gavrilova and Elina Svitolina were the defending champions, but chose not to participate this year.
Andreea Mitu and İpek Soylu won the title by walkover when Xenia Knoll and Danka Kovinić withdrew from the final. Mitu and Soylu won the title by playing only two matches, since their semifinal opponents also withdrew.
Seeds
Draw
References
Main Draw
Category:2016 in Istanbul
Category:2016 in Turkish sport
Istanbul Cup - Doubles
Category:İstanbul Cup
İstanbul Cup
|
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|
2008–09 Regionalliga
The 2008–09 Regionalliga season was the first season of the Regionalliga at tier four of the German football league system and the 15th overall since re-establishment of the league in 1994. It was contested in three regional divisions of eighteen teams in each. The champions, Holstein Kiel, Borussia Dortmund II and 1. FC Heidenheim 1846 were promoted to the 3. Liga.
Team Movements
Teams Promoted from Regionalliga
To 2. Bundesliga
From Nord
Rot-Weiß Ahlen (Nord Champions)
Rot-Weiß Oberhausen (Nord Runners-Up)
From Süd
FSV Frankfurt (Süd Champions)
FC Ingolstadt 04 (Süd Runners-Up)
To 3. Liga
From Nord
Fortuna Düsseldorf
1. FC Union Berlin
SV Werder Bremen II
Wuppertaler SV
Rot-Weiß Erfurt
Dynamo Dresden
Kickers Emden
Eintracht Braunschweig
From Süd
VfB Stuttgart II
VfR Aalen
SV Sandhausen
SpVgg Unterhaching
SV Wacker Burghausen
FC Bayern München II
SSV Jahn Regensburg
Stuttgarter Kickers
Teams promoted from the Oberliga
To Nord
From NOFV-Oberliga Nord
Hertha BSC II
Hansa Rostock II
Türkiyemspor Berlin
From NOFV-Oberliga Süd
Hallescher FC
Chemnitzer FC
VFC Plauen
FC Sachsen Leipzig
From Oberliga Nord
Holstein Kiel
Altona 93
SV Wilhelmshaven
Hannover 96 II
BV Cloppenburg
To West
From Oberliga Westfalen
Preußen Münster
FC Schalke 04 II
VfL Bochum II
Sportfreunde Lotte
From Oberliga Nordrhein
Borussia Mönchengladbach II
Bayer Leverkusen II
1. FC Köln II
1. FC Kleve
From Oberliga Südwest
1. FSV Mainz 05 II
1. FC Kaiserslautern II
Wormatia Worms
Eintracht Trier
To Süd
From Oberliga Baden-Württemberg
SC Freiburg II
SSV Ulm 1846
Waldhof Mannheim
1. FC Heidenheim
From Bayernliga
SpVgg Greuther Fürth II
1. FC Nürnberg II
TSV Großbardorf
1. FC Eintracht Bamberg
From Hessenliga
SV Darmstadt 98
SV Wehen Wiesbaden II
Viktoria Aschaffenburg
Eintracht Frankfurt II
Regionalligas
Regionalliga Nord
Top Scorers
Source: Weltfussball.de
Regionalliga West
Top Scorers
Source: Weltfussball.de
Regionalliga Süd (South)
Top scorers
Source:Weltfussball.de
References
External links
Regionalliga at the German Football Association
Regionalliga Nord 2008–09 at kicker.de
Regionalliga Süd 2008–09 at kicker.de
Regionalliga West 2008–09 at kicker.de
Category:Regionalliga seasons
4
German
|
{
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|
Q:
Create rounded button with inset edge, gradient and inset text with Gimp
This is my first attempt at seriously using Gimp. I am more of a front end developer slash developer myself and I have only used Gimp or Photoshop for very basic stuff such as removing backgrounds, cropping. So this the first time I want to do more and as I am planning on ditching PS I am trying to work with Gimp.
Please see attached image
.
It shows simple rounded buttons with nice inner shades and a beveled background as well as inlaid text. How in Gimp do I:
Create this shade gradient effect on the button?
Do the inlaid/embossed inset text effect?
Make the button background with the inset lines?
Thanks in advance for your help!
Update
Checking http://www.youtube.com/watch?v=p1K3L7RdbKw for engraved text (engraved = embossed)
A:
You will have to use gradient to get that kind of background.
Go through this nice tutorial to understand how gradient works :
http://mygimptutorial.com/round-web-20-button-with-a-metal-ring
And then play around according to your needs. Let me know if you need help with anything specific.
|
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War Diaries of a Little Englander.
Being the toy soldier, wargaming and kit bashing ramblings of a middle-aged Englishman.
Total Pageviews
Greetings!
'A gaping silken dragon,/Puffed by the wind, suffices us for God./We, not the City, are the Empire's soul:/A rotten tree lives only in its rind.'
Sunday, 26 April 2015
One-Hour Wargame...
...on St. George's Day.
Many readers will be familiar with Neil Thomas' book, One-Hour Wargames; Practical Tabletop Battles for Those With Limited Time and Space. Mr Thomas has addressed the issue of time and space, and come up with a solution based on a 3 foot by 3 foot playing area and fast play rules for 18 historical periods. His book also provides 30 different scenarios, applicable to all periods. All-in-all a useful book addressing a clear need. So, on this year's St. George's Day (23rd April), Dr. Alf R. Ont and his long-term adversary, Master Ont, sought to play test the rules and, as they say, see how they stacked up.
We chose scenario 'Pitched Battle 2', and our force-creation dice roles gave us matching forces of 4 line infantry regiments, 1 cavalry regiment, and 1 battery of guns each. Our chosen period was Horse and Musket, for which period elements of my sort-of-Seven Years War stood duty.
The set-up:
Above, three of Army Red's line regiments poised for battle, along with:
the horse, and in the far distance, on the hilltop, another of foot and the guns. While, below,
the bearded Master Ont sets out his Army Blue. The whole affair looking like this:
The game was for 15 turns, the victory conditions were to be in control of both the hill and the crossroads at the end of the game.
Below, first blood to Army Blue's horse, as they manage a flank attack on the left of Red's line, which was in the process of attempting to enfilade a Blue regiment of foot:
Brigadier A.R.Ont had hoped that the presence of his own horse would have prevented such an event (and the large number of hits sustained - each unit can take only 15 hits before it is removed from the field). Fortunately, Brig. Ont was able to fortify himself:
Then unleashed his own horse on those of Blue, catching them as they withdrew from contact with Brig. Ont's foot.
Two rounds of horse melee and Blue's horse left the field. This allowed Red's three regiments of foot, plus Red's hilltop guns and fourth regiment, to pound the three regiments that Blue had pushed towards the hill. The overpowering weight of fire quickly saw first one, then another Blue regiment removed. Below:
the situation shortly before the surviving Blue regiment was defeated. Which, in turn, left Blue's crossroads forces - guns, and a regiment of foot - outnumbered. However, they managed to see off Red's horse. So, by the end of turn 7:
The crossroads were held by the brave fellows above. At this point we called the game a draw, as further fighting would undoubtedly have left only one, perhaps two, regiments in the field, which just seemed too unlikely.
Verdict? Well, it was quick - the game last 35minutes from set-up to draw. Had we taken it to the bitter end, it might have lasted another 5-10 minutes. It was bloody (in a tin and enamel sort of way), as concentrating fire on single units quickly led to 15 hits being sustained. With 12 units (each with a 5 inch frontage) on the 3 foot by 3 foot table, there was little room to manoeuvre, but, then, it was the 'Pitched Battle' scenario. Overall, worth trying again a good few times, using different periods, and getting a much better feel for the approach. And, a pleasant way to spend a St. George's Day evening at home.
Postscript on the PR Spitfire. In my last post, I was prevaricating about how much wear and tear I should add to the excellent Airfix PR Spitfire in Swedish service. It was suggested that I should go for the light touch, which I did:
The refreshments being the most splendid! I'm going to try and run through a number of different periods and scenarios from One Hour Wargames just to see how they work in practice. I'm far, far from being anything like a 'scientific' wargamer, so it will be a case of are they enjoyable, reasonably convincing quick games. More soon-ish, I hope.
A splendid little war indeed.Great fun it looks too. It goes to show that great fun can be had with a small number of troops and a wee space. I do hope we see some more games posted here soon. Spitfire looks splendid too by the way!
I am very interested in this book and its rulesets. I also hope see some more OHW games posted here soon.
I also played this scenario with these rules and I found it a little bit dull but when I played C.S.Grant "Sawmill Village" and D.Featherstone "Battles With Model Soldiers" scenarios I really enjoyed the games.
Quotation of the moment
'In a sense, nothing in life is planned - or everything is - because in the dance every step is ultimately the corollary of the step before; the consequence of being the kind of person one chances to be.'
Anthony Powell, The Acceptance World (A Dance to the Music of Time), 1955.
Cpt. Front
About Me
New Men-At-Arms
Not out until February 2018, but order your copy early - you know it makes sense!
NOW IN PAPERBACK!!!
The Home Guard - 'This is likely to be the standard reference book on the subject for many years to come'; Bernard Lowry, Fortress Study Group.
A Vanished Ideology Essays on the Jewish Communist Movement in the English-Speaking World
Yiddish-speaking, English-speaking, Jews in the Communist movement. With a chapter on British Jews, ethnicity and class, by Al Front.
When Jews had a place on the Left.
The Labour Party is sunk in a mess of anti-Semitism, but it was not always thus:
Alf R. Ont on the wireless
Click on the image and scroll to 01:05:23 for the dulcet tones of Mr Ont, talking about women in the Home Guard.
Women in the Home Guard
From The Conversation, 5th February, 2016. Active, patriotic British women to the fore...
NEW BIOGRAPHY of 'FLYING' FAY TAYLOUR
277 pages of thrills and spills. 'Fanatical Fay Taylour', the greatest woman motor sports champion yet. A speed fiend on race tracks across the world, and a political activist who was banned from the USA, and interned in the UK. Member of the ultra-right underground in 1940s London and Dublin, later an Irish republican and supporter of Castro. Click image for a FREE ,yes, FREE, Pdf version provided by the University of Warwick.
Evolution and change in politics
A review of a new history of what was once a notable element of political allegiance among the Jewish diaspora. (Clink on the image for free link).
Germany calling...
The woman who recruited 'Lord Haw Haw' to the Berlin wireless. Socialist, Bolshevik, National Socialist, enemy broadcaster. (From The Historian 119; click on image for Pdf)
BBC Radio 4: Red Clydeside, Decoy Defences and Invasion panic
More Radio 4 'Making History' rambling - from 20th November 2012 (click on the image for link)
'The Land of My Dreams'
British Great War literary combatants and their writing about the war and home. A Pdf of an article from Cultural & Social History, vol. 8, no: 2, June 2011. (Click on image for link).
British Jews & the Communist Party of Great Britain
More reading for the VBCW enthusiast, not to mention the discerning reader (click on image for link). From Socialist History, vol.12, no: 41, September 2012
BBC Radio 4: Speed, women, and fascism
Listen to my dulcet tones, talking about 'Flying' Fay Taylour on BBC Radio 4's Making History (click on the image for link)
'Fay Taylour: a dangerous woman in sport and politics'
A must for the VBCW gamer - the most successful woman motor sport ace ever and a fascist. Click on image for journal link, an open access Pdf will eventually be available.
The Armourer magazine, March/April 2012
The true daughters of Britannia who joined the Home Guard
Political internment without trial, 1940 style
Fascists, nazis, and the IRA interned. Click on image for back issue of Britain At War, issue 46, Feb 2011
George Blake, literary Scot in the Great War
The Great War fiction of the veteran, George Blake - from Cencrastus no:67. Out of print, but I can send a photocopy, if you wish.
For the VBCW war gamer
In History Scotland, March/April 2011; click on image for free Pdf.
Fifth Column panic!
Buy a back issue - all that is left
The incomparable generation of 1914
from The Historian no:110, Summer 2011, magazine of The Historical Association; click on image for Pdf.
BBC Radio 4: Stand By the King!
Listen to my words of historical wisdom about the BUF in Norfolk on Radio 4's 'Making History'. Click on image for link.
One I did earlier...
Musso and the RSI
Fascism in Scotland
From the Scottish Historical Review, volume 87 (2) 2008 (click on the image for Pdf link)
Another Home Guard one...
A 50 page booklet, now out of print, but available as a pdf from Warwick University - click on the image for the link.
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{
"pile_set_name": "Pile-CC"
}
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Q:
Angular 2 RC1: Get parameters from the initial URL used
Some users enter my web app via invitations. so they would have a link that looks something like this: https://example.com/invitaion/12345 where 12345 is their unique invitation number.
When users click the link, and my AppComponent is initialized on the client side by the framework, how do I get the fact that the URL used was "invitation/*" and how do I get the invitation number?
A:
You'll want to use RouteParams to access that variable, and use it within your Component.
// let's assume you labeled it as `path : '/invitation/:id'` in your @Route setup.
@Route([
{ path : '/invitation/:id', component : MyComponent }
])
Now within the Component itself:
import { RouteParams } from '@angular/router';
// Now simply get the ID when injecting RouteParams within your constructor
class MyComponent {
id: string;
constructor(_params: RouteParams) {
this.id = _params.get('id');
}
}
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{
"pile_set_name": "StackExchange"
}
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Christopher Alpiar
Atlanta, GA
I am a composer, orchestrater, arranger, music technology consultant, studio owner, audio engineer, and most importantly I have spent the last 25 years playing saxophones, woodwinds, keyboards and African hand drums. I went to Berklee College of Music (90-94) and won the Quincy Jones Award for Jazz composition there. As a performer I have played in many styles of music ranging from the most insane avant garde free jazz to the simplest pop music.
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{
"pile_set_name": "Pile-CC"
}
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Rajiv Gauba, IAS (Jharkhand cadre-1982 batch) on 31st August 2017 took over as Secretary to the Government of India in the Ministry of Home Affairs. Shri Gauba joined the Ministry of Home Affairs as Officer on Special Duty on June 27, 2017 and took charge as the Union Home Secretary upon the superannuation of Shri Rajiv Mehrishi. Prior to this, Shri Gauba was Secretary in the Ministry of Urban Development. He has wide-ranging experience in senior positions in the Central and State Governments and in international organisations. Hailing from Punjab, the 1959 born Shri Gauba is a Physics graduate.
He has worked as Chief Secretary, Jharkhand. Earlier, Shri Gauba served in the Central Government in the Ministries of Home, Defence, Environment and Forests and Department of Electronics and Information Technology. Shri Gauba also served in the International Monetary Fund representing the country for four years on the Board of IMF.
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"pile_set_name": "Pile-CC"
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{
"pile_set_name": "Github"
}
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---
abstract: 'The Klein group contains only four elements. Nevertheless this little group contains a number of remarkable entry points to current highways of modern representation theory of groups. In this paper, we shall describe all possible ways in which the Klein group can act on vector spaces over a field of two elements. These are called representations of the Klein group. This description involves some powerful visual methods of representation theory which builds on the work of generations of mathematicians starting roughly with the work of K. Weiestrass. We also discuss some applications to properties of duality and Heller shifts of the representations of the Klein group.'
address:
- |
Department of Mathematics\
Illinois State University\
Normal, IL 61761 USA
- |
Department of Mathematics\
University of Western Ontario\
London, ON, N6A 5B7, Canada
author:
- Sunil Chebolu
- Ján Minác
bibliography:
- 'lit.bib'
title: Representations of The miraculous Klein group
---
Introduction
============
Consider the familiar complex plane $\mathbb{C} = \{ x+ iy \, | \, x, y \text{ are real numbers} \}$ with two reflections $\sigma$ and $\tau$ in the standard axes $X$ and $Y$ respectively. Precisely, we have $$\begin{aligned}
\sigma(x+iy) & = & x - iy, \text{ and } \\
\tau(x+iy) & = & -x+iy.
\end{aligned}$$ Thus, $\sigma$ is the complex conjugation and $\tau$ is like a real brother of $\sigma$. Note that if we apply $\sigma$ or $\tau$ twice, we get the identity map: $\sigma^{2} = 1 = \tau^{2}$. Also, we see that $\sigma \tau = \tau \sigma = - 1$. Geometrically, the maps $\sigma \tau$ and $\tau \sigma$ are rotations by $180$ degrees in the complex plane. The set of maps $$\{1, \sigma, \tau, \sigma \tau\}$$ forms a group under composition and is called the Klein four group or just Klein group, often denoted by $V_{4}$. One would guess that the letter $V$ here is a sign of victory but the reason is that “*Vier*” in German means “four.” “Klein” in German also means “small” and indeed Klein group $V_{4}$ having only four elements is quite small. It is an absolutely amazing fact that this small and ostensibly innocent group contains remarkable richness and that important mathematics can be developed by just studying this one group. The world’s smallest field is ${\mathbb{F}_2}= \{ 0, 1\}$, and one can think of this as a toy model of complex numbers. The problem to be investigated in this paper is the following: What are all the finite dimensional representations of $V_{4}$ over ${\mathbb{F}_2}$? That is, can one describe all possible actions of the group $V_{4}$ on finite dimensional vector spaces $W$ over ${\mathbb{F}_2}$. Although, we work over an arbitrary field of characteristic two, not much is lost if the reader assumes through out that the ground field $k$ is ${\mathbb{F}_2}$. The reason for restricting to fields of characteristic $2$ is due to the fact that when the characteristic of the ground field $k$ is either zero or odd, the finite dimensional representations $W$ of $V_{4}$ have a very simple nature. Namely, $W$ is a sum of one dimensional representations. One each of these one-dimensional subspaces, the generators $\sigma$ and $\tau$ act as multiplication by $1$ or $-1$. We therefore stick with fields of characteristic $2$. This bring us to the world of modular representations. (That is, the characteristic of the field is a positive divisor of the order of the group.)
Note that $V_4$ is a product of two cyclic groups of order two. In terms of generators and relations, $V_4$ has the following presentation. $$V_4 = \langle \sigma, \tau \; | \; \sigma^2 = \tau^2 = 1, \sigma \tau = \tau \sigma \rangle .$$ The group algebra $kV_4$ is then isomorphic to $$k[a , b]/(a^2, b^2),$$ where $a$ corresponds to $1+ \sigma$ and $b$ to $1+\tau$. We define an ideal $U$ of the $kV_4$ as the ideal generated by $a$ and $b$. This is an extremely important ideal called the augmentation ideal of our group ring. Sometime it will be convenient to divide $kV_4$ by ideal generated by $ab$. This simply amounts adding further relation $ab = 0$. The reason for this is that often $ab$ acts on our vector spaces as $0$ and therefore why not simplify our ring even further and add the relation $ab= 0$? We still call the image of $U$ in this new ring $U$ as we do not want to make our notation too complicated. In this paper we present a rather accessible proof of the well-known classification of all the finite dimensional representations of $V_{4}$, or equivalently, of the finitely generated indecomposable $kV_{4}$-modules. These are also known as the modular representations of $V_{4}$. Note that a $V_{4}$ representation where $ab$ acts as zero can be viewed as a finite dimensional $k$-linear space equipped with a pair commuting linear maps $a$ and $b$ both of which square to zero.
Having explained what a representation of $V_{4}$ is, the following two questions have to be answered.
1. Why do we care about the representations of $V_{4}$?
2. What is unique about our approach?
In answer to the first question, first note that groups act naturally on various algebraic objects including vector spaces, rings, algebraic varieties and topological spaces. These actions tend to be quite complex in general. Therefore it is important to find simple pieces of this action and find ways to glue these pieces together to reconstruct the original action. Often this is related to other invariants of the group or our given representation like cohomology groups and support varieties. Amazingly, this goal in modular representation theory turns out to be exceedingly difficult. It turns out that besides the cyclic groups whose representations are very easily understood, Klein four group is one of the very few (other groups are the dihedral groups) interesting yet non-trivial examples for which representation theorists are able to completely classify all the finite dimensional modular representations. There is a lot to be learned by studying the representation theory of this one group and it goes to tell how complex the study of modular representations can be for an arbitrary group.
Now we turn to the second question. Although the classification of the finite dimensional representations of $V_{4}$ is well-known and many proofs can be found in the literature, we could not find a proof to our heart’s content. This is what motivated us to write up one – one that is transparent and which takes a minimal background. Furthermore, our approach is diagrammatic, so the reader can see what is happening through pictures. These methods, besides making the statements of theorems and proofs elegant and conceptual, give a better insight into the subject. We mostly follow Benson’s approach [@ben-1] but we approach some parts of his proof from a different point of view and simplify them and in particular we make our proof accessible for a general reader. One ingredient that is new in our approach is Auslander-Reiten sequences which will be introduced later in the paper.
The subject of classifying the indecomposable representations of the Klein group has a long and rich history that can be traced all the way back to V. A. Bašev [@basev], a student of I.R. Šafarevič, who observed that an old result of L. Kronecker on pairs of matrices can be used effectively in the classification, but over algebraically closed fields. This result of L. Kronecker on pairs of matrices was actually a completion of the work of K. Weierstrass. Then later on I. M. Gelfand and V. Ponomarev [@Gel-Pon] observed in their analysis of the representations of the Lorentz group that quiver techniques were quite useful and they both knew that G.Szekeres had a result in this direction. However, they did not know enough details about Szekeres’s techniques and therefore they invented their new innovative and influencial quiver method which is influenced by Maclane’s notion of relations – a generalization of a linear map. In [@hell-rei] A. Heller and I. Reiner provided another nice approach to the classification where they also worked over fields that are not necessarily algebraically closed. Finally D. Benson [@ben-1] wrote a modern treatment of the classification of the indecomposable representations of the Klein group in which he combined some of the crucial ideas in the works of the aforementioned people. The diagrammatic methods in our paper are inspired by S. B. Conlon who introduced these in [@conlon]. It is quite remarkable that a complete understanding of an innocent looking group on four elements would take the works of some of the great minds of the 19th, 20th, and 21st centuries.
Before going further, we remind the reader some basis facts and terminology. We refer the reader to Carlson lecture notes for basic representation theory [@carlson-modulesandgroupalgebras]. In the category of modules over a the Klein group (or more generally, over a $p$-group), the three terms “injective", “projective" and “free" are synonymous. Given a $V_{4}$-module $M$, its Heller shift $\Omega( M)$ is defined to be the kernel of a minimal projective cover of $M$. It can be shown that minimal projective covers are unique up to isomorphism and from that it follows that $\Omega(M)$ is well-defined. Inductively one defines $\Omega^n (M)$ to be $\Omega( \Omega^{n-1} M)$. Similarly, $\Omega^{-1} M$ is defined to be the cokernel of an injective envelope of $M$, and $\Omega^{-n}
(M)$ to be $\Omega^{-1}( \Omega^{-n+1} M)$. Again one can shown that these are well-defined modules. The modules $\Omega^i M$ are also known as the syzygies of $M$. By the classical Krull-Remak-Schmidt theorem, one knows that every representation of a finite group decomposes as a direct sum of indecomposable ones. Thus it suffices to classify the indecomposable representations.
Advice for the novice: some arguments in our paper are only sketched and some notions maybe still unfamiliar for a novice. If that is the case, we advice readers to skip these parts on the first reading as they may became more clear later on and they most likely will not influence the basic understanding of the key ideas. The main point of this article is to provide overview of the remarkable proof of classification of representations of Klein group $V_4$ with appreciation of the works of number of people and to show that this proof open doors to study modern group representation where Auslander-Reiten sequences play increasingly important role. We hope that after reading our article a reader will read more texts in the references and possibly go on to further exciting heights in group representation theory.
Indecomposable Representations of Klein’s four group
====================================================
We list all the indecomposable representations of $V_4$ below. Note that these are just the finitely generated modules over the group algebra $$kV_{4} \cong k[a, b]/(a^{2}, b^{2})$$ which cannot be written as a sum of strictly smaller modules (much the same way prime numbers cannot be written as product of smaller numbers). Since we take a diagrammatic approach, we first explain the diagrams that follow. Each bullet represents a one dimensional $k$ vector space, a southwest arrow “$\swarrow$” connecting two bullets corresponds to the action of $a$ and maps one bullet to the other in the indicated direction, and similarly the south east arrows “$\searrow$” correspond to the action of $b$. If no arrow emanates from a bullet in given direction, then the corresponding linear action is understood to be zero.
*(Kronecker, Weierstrass, Basev, Gelfand, Ponomarev, Conlon, Heller, Reiner, Benson)* [@Gel-Pon; @conlon; @hell-rei; @basev; @ben-1] Let $k$ be a field of characteristic $2$. Every isomorphism class of an indecomposable $V_4$ representation over $k$ is precisely one of the following.
1. The projective indecomposable module $kV_4$ of dimension 4. $$\xymatrix@=2em{
& \bullet \ar[dl]_a \ar[dr]^b & \\
\bullet \ar[dr]& & \bullet \ar[dl]\\
& \bullet &
}$$
2. The (non-projective) indecomposable even dimensional modules:
1. For each even dimension $2n$ and an indecomposable rational canonical from corresponding to the power of an irreducible monic polynomial $f(x)^l = \sum_{i=0}^n \theta_i x^i$, $(\theta_n = 1)$ there is an indecomposable representation given by $$\xymatrix@=1.5em{
& & \overset{g_{n-1}}{\bullet} \ar@{..>}[d] \ar[dr]& & \overset{g_{n-2}}{\bullet}\ar[dl]^a \ar[dr] & & \overset{g_{n-3}}{\bullet} \ar[dl] & \bullet \hspace{1 mm}
\bullet \hspace{1 mm} \bullet
& & \overset{g_0}{\bullet} \ar[dl] \ar[dr] \\
& & & \underset{f_{n-1}}{\bullet} & & \underset{f_{n-2}}{\bullet} & & & \underset{f_1}{\bullet} & &
\underset{f_0}{\bullet}
}$$ where $a(g_{n-1}) = \sum_{i = 0}^{n-1} \theta_i f_i$, as represented by the vertical dotted arrow emanating from $g_{n-1}$ above.
2. For each even dimension $2n$ there is an indecomposable representation given by $$\xymatrix@=2em{
& & \bullet \ar[dr]^b \ar[dl]_a & & \bullet \ar[dl] \ar[dr] & & &
\bullet \ar[dr] & & \bullet \ar[dl] \\
& \bullet & & \bullet & & \bullet & \bullet \hspace{1 mm}
\bullet \hspace{1 mm} \bullet & & \bullet &
}$$
3. The (non-projective) indecomposable odd dimensional modules:
1. The trivial representation $k$. $$\bullet$$
2. For each odd dimension $2n+1$ greater than one, there is an indecomposable representation given by $$\xymatrix@=2em{
& \bullet \ar[dr]_b & & \bullet\ar[dl]^a \ar[dr] & & \bullet \ar[dl] & \bullet \hspace{1 mm}
\bullet \hspace{1 mm} \bullet & \bullet \ar[dr]
& & \bullet \ar[dl] \\
& & \bullet & & \bullet & & & & \bullet &
}$$
3. For each odd dimension $2n+1$ greater than one, there is an indecomposable representation given by $$\xymatrix@=2em{
& & \bullet \ar[dr]^b \ar[dl]_a & & \bullet \ar[dl] \ar[dr] & &
& & \bullet \ar[dl] \ar[dr] & \\
& \bullet & & \bullet & & \bullet & \bullet \hspace{1 mm}
\bullet \hspace{1 mm} \bullet & \bullet & & \bullet
}$$
The reader may decide to make a pleasant check that the above diagrams are indeed representations of $V_{4}$. For each $V_{4}$-module $M$, one can define the dual $V_{4}$-module $M^{*}$, where $M^{*}$ is the dual $k$-vector space of $M$, and a group element $\sigma$ of $V_{4}$ acts on $f$ in $M$ via the rule $\sigma f(m) = f(\sigma^{-1} m)$. Then, as a fun exercise we ask the reader to verify that the diagrams in 3(a) and 3(b) are dual to each other. This will help the reader to get acquainted with some of the diagrammatic methods that will appear later on. We now begin by proving the easy part of the theorem.
\[lemma0\] All representations of $V_4$ that appear in the above theorem are indecomposable and pair-wise non-isomorphic.
Item (1) is not isomorphic to the rest because it is the only module that contains a non-zero element $x$ such that $(ab)x \ne 0$. Modules in item (2) are even dimensional and those in (3) are odd dimensional and hence there is no overlap between the two. To see that all the $2n$ dimensional representations of item $2(a)$ are distinct, it is enough to observe that the rational canonical forms of the linear transformations on the co-invariant submodules, $$b^{-1}a : M/UM {\ensuremath{\rightarrow}}M/UM$$ are distinct, where $U$ is the ideal generated by $a$ and $b$. To see that the $2n$ dimensional representation of item $2(b)$ does not occur in item $2(a)$ observe that kernel of the $b$-action in both cases have different dimensions: $n$ for the module in $2(a)$ and $n+1$ for that in 2$(b)$. The two $2n+1$ dimensional modules in items $3(b)$ and $3(c)$ are non-isomorphic because it is clear from the diagrams that the dimensions of the invariant submodules in both cases are different: $n$ for those in item $3(b)$, and $n+1$ for those in item $3(c)$.
Of course the hard thing is to show that every indecomposable representation of $V_4$ is isomorphic to one in the above list. Since projective modules over $p$-groups are free, there is only one indecomposable projective $V_4$-module, namely $kV_4$ which occurs as item (1) in the list. Therefore we only consider indecomposable projective-free (modules which do not have projective summands) $V_4$-modules.
One can get a better handle on the projective-free representations of $V_4$ by studying the representations of the so called Kronecker Quiver, which is a directed graph $Q$ on two vertices as shown below. $$\xymatrix{
u_1 \bullet \ar@/^10pt/[rr]^f \ar@/_10pt/[rr]_g & & \bullet u_2
}$$ A representations of the above quiver is just a pair of finite dimensional $k$-vector spaces $V$ and $W$ and a pair of $k$-linear maps $\psi_1$ and $\psi_2$ from $V$ to $W$. Such a representation will be denoted by the four tuple $[V, W ; \psi_1, \psi_2]$, and given two such representations, the notion of direct sum, and morphisms between them are defined in the obvious way. Thus it makes sense to talk about the isomorphism class of an indecomposable representation of $Q$. Let us call a representation of $Q$ special if the following conditions hold: $$\begin{aligned}
\operatorname{Ker}(\psi_1) \; \bigcap \; \operatorname{Ker}(\psi_2) & = & 0 \\
{\text{Image}}(\psi_1) + {\text{Image}}(\psi_2) & = & V_2.\end{aligned}$$
\[prop1\] [@hell-rei] There is a one-one correspondence between the isomorphism classes of (indecomposable) projective-free representations of $V_4$ and those of the special (indecomposable) representations of the Kronecker quiver. Under this correspondence, an (indecomposable) projective-free representation $M$ of $G$ corresponds to the (indecomposable) representation of $Q$ that is given by $[M/UM, UM; a, b]$. Conversely, given an (indecomposable) special representation $[V, W ; \psi_1, \psi_2]$ of $Q$, the corresponding (indecomposable) $G$-module $M$ is given by $M = V
\oplus W$ where $a(\alpha, \beta) := (0, \psi_1(\alpha))$ and $b(\alpha, \beta) := (0, \psi_2(\alpha)).$
We will use this translation between the representations of the Klein group and the Kronecker Quiver freely through out the paper.
If $M = [V_1, V_2; a, b]$ is an indecomposable projective-free representation, then we have $$\begin{aligned}
V_1 &= 0 \; \Leftrightarrow \; M = 0 \\
V_2 &= 0\; \Leftrightarrow \; M = k.\end{aligned}$$ So henceforth it will be assumed that the spaces $V_1$ and $V_2$ are non-zero, i.e., $M$ is an indecomposable projective-free and a non-trivial representation of $V_4$.
We begin with some lemmas that will help streamline the proof of the classification theorem. The proofs of these lemmas will be deferred to the last section. It should be noted that these lemmas are also of independent interest.
[@ben-1]\[lemma1\] Let $M$ be a projective-free $V_4$-module given by $[V_1, V_2; a, b]$. Then we have the following.
1. $M$ contains a copy of $\Omega^l(k)$ for some positive integer $l$ if and only if the transformation $$a + \lambda b : V_1 \otimes_k k[\lambda] {\ensuremath{\rightarrow}}V_2 \otimes_k k[\lambda]$$ is singular, i.e, $det( a + \lambda b) = 0$.
2. Dually, $\Omega^{-l} (k)$ is a quotient of $M$ for some positive integer $l$ if and only if the transformation $$a^* + \lambda b^* : V_2^* \otimes_k k[\lambda] {\ensuremath{\rightarrow}}V_1^* \otimes_k k[\lambda]$$ is singular.
The next lemma is very crucial to the classification. To the best of our knowledge, nowhere in the literature is this lemma stated explicitly, although it is secretly hidden in Benson’s proof of the classification [@ben-1]. We use Auslander-Reiten sequences to give a transparent proof of this lemma in the last section.
\[lemma2\] Let $M$ be a projective-free $V_4$-module. Then we have the following.
1. If $l$ is the smallest positive integer such that $\Omega^l(k)$ is isomorphic to a submodule of $M$, then $\Omega^l(k)$ is a summand of $M$.
2. Dually, if $l$ is the smallest positive integer such that $\Omega^{-l}(k)$ is isomorphic to a quotient module of $M$, then $\Omega^{-l}(k)$ is a $G$-summand of $M$.
[@johnson-1]\[lemma3\] For all integers $n$, $\Omega^n (k)$ is isomorphic to the dual representation $\Omega^{-n} (k) ^*$. Furthermore,
1. If $n$ is positive, then $\Omega^n (k)$ is a $2n+1$ dimensional indecomposable representation given by $$\xymatrix@=2em{
& \bullet \ar[dr]_b & & \bullet\ar[dl]^a \ar[dr] & & \bullet \ar[dl] & \bullet \hspace{4 mm}
\bullet \hspace{4 mm} \bullet & \bullet \ar[dr]
& & \bullet \ar[dl] \\
& & \bullet & & \bullet & & & & \bullet &
}$$
2. If $n$ is a negative integer, then $\Omega^n (k)$ is a $2n+1$ dimensional indecomposable representation given by $$\xymatrix@=2em{
& & \bullet \ar[dr]^b \ar[dl]_a & & \bullet \ar[dl] \ar[dr] & &
& & \bullet \ar[dl] \ar[dr] & \\
& \bullet & & \bullet & & \bullet & \bullet \hspace{4 mm}
\bullet \hspace{4 mm} \bullet & \bullet & & \bullet
}$$
We now give the proof of the classification theorem assuming these lemmas. The lemmas will be proved in the last section. Let $M = (V_1,
V_2; a, b)$ be an indecomposable projective-free representation of $V_4$. We will show that $M$ is isomorphic to one of the representation that appear in items (2) it is even dimensional, and to those in item (3) if it odd dimensional.
Even dimensional representations
--------------------------------
Let $M$ be an even dimensional ($2n$ say) indecomposable representation. We break the argument into cases for clarity.\
*Case 1:* $\det (a + \lambda b)$ is non-zero. We have two subcases. First assume that $\det b \ne 0$. Then consider the map $$b^{-1}a : V_1 \longrightarrow V_1.$$ We claim that this map is indecomposable. Suppose we have a decomposition $f \oplus g$ of $b^{-1}a$ as follows $$\xymatrix{ V_1 \ar[r]^{b^{-1}a} \ar[d]_{\cong} & V_1 \ar[d]^{\cong}\\
A \oplus B \ar[r]_{f \oplus g} & A \oplus B
}$$ Set $C:= b(A)$ and $D:= b(B)$. Then it is straightforward to verify that $M = (V_1, V_2; a, b)$ decomposes as $$(A, C; a|_{A}, b|_{A}) \; \bigoplus \; (B, D; a|_{B}, b|_{B}).$$ Since $M$ is indecomposable it follows that the map $b^{-1}a$ is indecomposable. Now since $b^{-1}a$ is indecomposable we can choose a basis $\{g_0, g_1, \cdots, g_{n-1}\} $ of $V_1$ such that the rational canonical form of $b^{-1}a$ has only one block which corresponds to some power of an irreducible polynomial $f(x)^r =
\sum_{i = 0}^{n-1} \theta_i x^i$. This means we have $$\begin{aligned}
b^{-1}a \; (g_i) &= & g_{i+1} \hspace{3 mm} \text{for} \;\; 0 \le i \le n-2, \\
b^{-1}a \; (g_{n-1}) &=& \sum_{i=0}^{n-1} \theta_i g_i. \hspace{3
mm} (*)\end{aligned}$$
Now the vectors $f_i := b(g_i)$ for $0 \le i \le n-1$ define a basis for $V_2$ because $b$ is non-singular. With respect to the bases $(g_i)$ of $V_1$ and $(f_i)$ of $V_2$, it is now clear that $M$ has the description $$\xymatrix@=1.9em{
\overset{g_{n-1}}{\bullet} \ar[dr]_b & & \overset{g_{n-2}}{\bullet}\ar[dl]^a \ar[dr] & &
\overset{g_{n-2}}{\bullet} \ar[dl] & \bullet \hspace{4 mm}
\bullet \hspace{4 mm} \bullet
& & \overset{g_0}{\bullet} \ar[dl] \ar[dr] \\
& \underset{f_{n-1}}{\bullet} & & \underset{f_{n-2}}{\bullet} & & & \underset{f_1}{\bullet} & &
\underset{f_0}{\bullet}
}$$ The action of $a$ on $g_{n-1}$ can be seen by applying $b$ on both sides of the equation (\*) above: $a(g_{n-1}) = \sum_{i=0}^{n-2}
b(g_i) = \sum_{i=0}^{n-1} f_i$. These representations are the exactly ones in item 3(a).
Now if $\det(b) = 0$, we do a change of coordinate trick. We assume that $k$ is an infinite field. If $k$ is finite, we can pass to an extension field and do a descent argument; see [@ben-1] for details. Then there exists some $\lambda_0$ in $k$ such that $\det(a + \lambda_0 b) \ne 0$. Now consider the tuple $(V_1, V_2; b, a+\lambda_0 b)$. By case (i), we know that there exist bases for $V_1$ and $V_2$ such that $a +
\lambda_0 b = I$ and $b = J_0$ (the rational canonical form [@LinearAlgebra] [^1] corresponding to any indecomposable singular transformation). This gives the representation in item 2(b).\
*Case 2:* $\det (a + \lambda b) = 0$. We will show that this case cannot arise. First suppose that there is a copy of $\Omega^{l} (k)$ in $M$ for some positive integer $l$. Now pick $l$ to be the smallest such integer, then by lemma \[lemma2\] we know that $\Omega^l (k)$ is a direct summand of $M$. Since $M$ is indecomposable, this means $M$ has to be isomorphic to $\Omega^l(k)$, which is impossible since the latter is odd dimensional while $M$ was assumed to be even dimensional. So the upshot is that $M$ does not contain $\Omega^l(k)$ for any positive $l$. By lemma \[lemma1\] this is equivalent to the fact $\det (a +
\lambda b) \ne 0$ in the ring $k[\lambda]$ which contradicts our hypothesis.
Odd dimensional representations
-------------------------------
If $M$ is odd dimensional, then clearly $\dim V_1 \ne \dim V_2$. We consider the two cases.\
*Case 1:* $\dim V_1 > \dim V_2$. Then there is a non-zero vector $\omega( \lambda)$ in $ V_1 \otimes_k K[\lambda]$ such that $(a + \lambda b) (\omega (\lambda)) = 0$ which then implies, by lemma \[lemma1\], the existence of a copy of $\Omega^l(k)$ inside $M$ for some $l > 0$. Picking $l$ to be minimal, we can conclude from lemma \[lemma2\] that $\Omega^l(k)$ is a direct summand of $M$. Since $M$ is indecomposable, we have $M \cong \Omega^l(k)$. This gives the modules in item 3(b).\
*Case 2 :* $\dim V_1 < \dim V_2$. Dualising $M = (V_1, V_2;
a , b)$, we get the dual representation $M^* = (V_2^*, V_1^*; a^*,
b^*)$ which is also indecomposable. Now $\dim V_2^* > \dim V_1^*$, so by Case(1) we know that $M^* \cong \Omega^l(k)$ for some $l$ positive. Taking duals on both sides and invoking lemma $\ref{lemma3}$, we get $M \cong \Omega^{-l}(k)$. This recovers the modules in item 3(c).
This completes the proof of the classification of the indecomposable representations of $V_4$.
Some applications
=================
Having a good classification of the indecomposable representations of a finite group helps a great deal in answering general module theoretic questions. In this section, we illustrate this by proving some facts about module over the Klein group. Note that we don’t know of any direct proofs of the statements below that do not depend on the classification of the indecomposable representations.
Heller Shifts of the $V_4$-representations.
-------------------------------------------
We will show how our knowledge of the representations of $V_4$ can be used to give a homological characterisation of the parity of the dimensions of the representations. Proofs of the propositions are given in the last section.
\[prop:heller\] [@ring] If $M$ is an even dimensional indecomposable projective-free representation of $V_4$, then $\Omega(M) \cong M$.
A finite dimensional projective-free representation $M$ of $V_4$ is even dimensional if and only if $\Omega(M) \cong M$.
We only have to show that if $M$ is an odd dimensional indecomposable then $\Omega(M) \ncong M$. By the classification theorem, we know that $M$ is isomorphic to $\Omega^l(k)$ for some integer $l$. Then $\Omega(M) \cong \Omega(\Omega^l(k)) \cong
\Omega^{l+1}(k)$, which is clearly not isomorphic to $M$ just for dimensional reasons: just note that dimension of $\Omega^{n} (k)$ is $2n+1$.
Dual representations of $V_4$
-----------------------------
We will use our knowledge of the representations of $V_4$ to characterise the parity of the dimension of a representation using the concept of self-duality.
Recall that if $M$ is a finite dimensional representation of a group $G$, then one can talk about the dual representation $M^* := \operatorname{Hom}(M,
k)$, where a group element $g$ acts on a linear functional $\phi$ by $(g \cdot \phi)(x) := \phi(x g^{-1})$. A representation of $G$ is self-dual if it is isomorphic to its dual.
When $G = V_4$, it is not hard to see that if $M = (V_1, V_2; a,
b)$ is a projective-free representation of $V_4$, then $M^* =
(V_2^*, V_1^*; a^*, b^*)$.
\[prop:dual\] Even dimensional indecomposable representations of $V_4$ are self-dual.
A non-trivial indecomposable representation of $V_4$ is even dimensional if and only if it is self-dual.
If $M$ is a non-trivial odd dimensional representation of $V_4$, then we know that $M \cong \Omega^l(k)$ for some $l \ne
0$. Then $M^* \cong (\Omega^l(k))^* \cong \Omega^{-l}(k)$. In particular, $M^* \ncong M$.
Proofs
======
In this section we give the proofs of the lemmas and propositions that were used in the classification theorem and applications.
Proof of proposition \[prop1\]
------------------------------
Let $M$ be a projective-free $V_4$ module. Then we have we have $ab(M) = 0$, it follows that $UM$ is included in $U^V_4$. Remarkably one can show that if $M$ is additionally not trivial representation and $M$ is indecomposable then $UM$ is actually equal $M^V_4$, the $V_4$ invariant submodule of $M$. Consider short exact sequence of $V_4$ modules $$0 {\ensuremath{\rightarrow}}UM {\ensuremath{\rightarrow}}M {\ensuremath{\rightarrow}}M/UM {\ensuremath{\rightarrow}}0.$$ Let $\pi: M {\ensuremath{\rightarrow}}UM$ be a vector space retraction of the inclusion $UM \hookrightarrow M$. Define a $V_4$ action on the vector space $M/UM \oplus M$ as follows: $$\begin{aligned}
a(x, y) := (0, ax) \\
b(x, y) := (0, by).\end{aligned}$$ Then it is easy to verify that the map $x \mapsto (x, \pi(x))$ establishes an isomorphism of $V_4$ modules between $M$ and $M/UM
\oplus UM$. Thus $M$ is determined by the vector spaces $M/UM$ and $UM$ and the linear maps $a, b: M/UM {\ensuremath{\rightarrow}}M$. This data amounts to giving a special representation of $Q$.
In the other direction, suppose $[V_1, V_2; \psi_1, \psi_2]$ is a special representation of $Q$. Define a $V_4$ action on the vector space $V_1 \oplus V_2$ by setting $a(x, y):=(0, \psi_1(x))$ and $b(x, y):= (0, \psi_2(x))$. This is easily shown to be a projective free $V_4$ module.
We leave it as an exercise to the reader to verify that the recipes are inverses to each other.
It is also clear that these recipes respect direct sum of representations. Thus the indecomposables are also in 1-1 correspondence.
Proof of lemma \[lemma1\]
-------------------------
Suppose $M$ contains a copy of $\Omega^{l}(k)$, for some $l \ge 1$. $$\xymatrix@=2em{
& \overset{g_0}{\bullet} \ar[dr]_b & & \overset{g_1}{\bullet} \ar[dl]^a \ar[dr] & & \overset{g_2}{\bullet} \ar[dl] & \bullet \hspace{1 mm}
\bullet \hspace{1 mm} \bullet & \overset{g_{l-1}}{\bullet} \ar[dr]
& & \overset{g_l}{\bullet} \ar[dl] \\
& & \underset{f_0}{\bullet} & & \underset{f_1}{\bullet} & & & & \underset{f_{l-1}}{\bullet} &
}$$ Define a vector $V(\lambda): = g_0 + g_1 \lambda + g_2 \lambda^2 +
\cdots + g_l \lambda^l$. A trivial verification shows that $(a +
\lambda b) (V(\lambda)) = 0$ and therefore $a + \lambda b$ is a singular transformation as desired.
Conversely, suppose $a + \lambda b$ is singular. Then there is a non-zero vector $V(\lambda) = g_0 + g_1 \lambda + g_2 \lambda^2
\cdots g_l \lambda^l$ of smallest degree $l$ in $V_1 \otimes
k[\lambda]$ (so $g_l \ne 0$) such that $(a + b \lambda) (V(\lambda))
= 0$. This means: $a(g_0) = 0$, $b(g_i) = a(g_{i+1})$ for $0 \le i
\le l-1$, and $b(g_l) = 0$. We now argue that these equations give a copy of $\Omega^l(k)$ inside $M$. To this end, it suffices to show that the vectors $\{g_0, g_1, g_2, \cdots, g_l \}$ are linearly independent. As a further reduction, we claim that it suffices to show that $\{ a(g_1), a(g_2), \cdots, a(g_l) \}$ are linearly independent. For, then it will be clear that $\{ g_1, g_2, \cdots,
g_l \}$is linearly independent, and moreover if $g_0 = \sum_{i=1}^l
c_i \, g_i$, applying $a$ on both sides we get $a(g_0) = 0 = \sum_{i
= 1}^l c_i \, a(g_i)$. Linear independence of $a(g_i)$ forces all the $c_i = 0$. Thus we will have shown that $\{g_0, g_1, g_2,
\cdots, g_l \}$ is linearly independent. So it remains to establish our claim that $\{ a(g_1), a (g_2), \cdots, a (g_l) \}$ is a linearly independent set. Suppose to the contrary that there is a non-trivial linear combination of $a(g_i)$’s which is zero: say $\sum_{i=1}^l \gamma_i \, a (g_i) = 0$ (\*). We will get a contradiction by showing that there is a vector of smaller degree ($
< l$) in $\operatorname{Ker}(a + \lambda b)$. It suffices to produce elements $(\tilde{g}_i)_{0 \le i \le l-1}$ such that $a(\tilde{g}_0) = 0 $, $b(\tilde{g_{l-1}}) = 0$, and for $0 \le i \le l-2$, $b(\tilde{g}_i)
= a (\tilde{g_{i+1}})$ ($\diamond$). For then the vector $\sum_{i=0}^{l-1} \tilde{g}_i \lambda^i$ will be of degree less than $l$ belonging to the kernel of $a + \lambda b$. To start, we set $\tilde{g}_0 = \sum_{i=0}^l \gamma_i\, g_i$. The condition $a
(\tilde{g}_0) = 0$ is satisfied by assumption (\*). Now define $\tilde{f_0} := b( \tilde{g}_0) = \sum_{i=1}^l \gamma_i \, b(g_i) =
\sum_{i = 1}^{l-1} \gamma_i \, b(g_i)$ (since $b(g_l) = 0$). Then we define $\tilde{g}_1 = \sum_{i=0}^{l-1} \gamma_i \, g_{i+1}$ so that we have the required condition $a(\tilde{g}_1) = b(\tilde{g}_0)$. Now we simply repeat this process: Inductively we define, for $ 0
\le t \le l-1 $, $$\begin{aligned}
\tilde{g}_t &= &\sum_{i=1}^{l-t} \gamma_i \;g_{i+t}, \\
\tilde{f}_t &= & \sum_{i=1}^{l-t} \gamma_i\; b(g_{i+t}).\end{aligned}$$ When $t = l-1$, we have $\tilde{g}_{l-1} = \gamma_1 g_l$ and $\tilde{f}_{l-1} = 0$. So this inductive process terminates at $t=
l-1 (< l) $ and the requirements $(\diamond)$ are satisfied by construction. Thus we have shown that the vector $\sum_{i=0}^{l-1}
\tilde{g}_{i}\, \lambda^i$ is of smaller degree in the kernel of $a
+ \lambda b$ contradicting the minimality of $l$. Therefore the vectors $\{a(g_1), a(g_2), \cdots, a(g_l) \}$ should be linearly independent. This completes the proof of the first statement in the lemma. The second statement follows by a straightforward duality argument.
Proof of lemma \[lemma2\]
-------------------------
First note that the second part of this lemma follows by dualising the first part; here we also use the fact that $(\Omega^l\,k)^*\cong \Omega^{-l}\,k$ which will be proved in the next lemma. So it is enough to prove the first part. Although this lemma is secretly hidden in Benson’s treatment [@ben-1 Theorem 4.3.2], it is hard very to extract it. So we give a clean proof of this lemma using almost split sequences, a.k.a Auslander-Reiten sequences. Recall that a short exact sequence $$0 {\ensuremath{\rightarrow}}A {\stackrel{f}{\longrightarrow}} B {\ensuremath{\rightarrow}}C {\ensuremath{\rightarrow}}0$$ of finitely generated modules over a group $G$ is an almost split sequence if it is a non-split sequence with the property that every map out of $A$ which is not split injective factors through $f$. It has been shown in [@aus-rei-sma] that given an finitely generated indecomposable non-projective $kG$-module $C$, there exists a unique (up to isomorphism of short exact sequences) almost split sequence terminating in $C$. In particular, if $G = V_4$ and $C = \Omega^l\,k$, these sequences are of the form; see [@ben-trends Appendix, p 180]. $$0 {\ensuremath{\rightarrow}}\Omega^{l+2}\,k {\ensuremath{\rightarrow}}\Omega^{l+1}\, k \oplus \Omega^{l+1}\, k {\ensuremath{\rightarrow}}\Omega^l\,k {\ensuremath{\rightarrow}}0 \hspace{9 mm} l \ne -1$$ $$0 {\ensuremath{\rightarrow}}\Omega^1\,k {\ensuremath{\rightarrow}}kV_4 \oplus k \oplus k {\ensuremath{\rightarrow}}\Omega^{-1}\,k {\ensuremath{\rightarrow}}0 \hspace{20 mm}$$ To start the proof, let $l$ be the smallest positive integer such that $\Omega^l\,k$ embeds in a projective-free $V_4$-module $M$. If this embedding does not split, then by the property of an almost split sequence, it should factor through $\Omega^{l-1}\,k \oplus \Omega^{l-1}\,k$ as shown in the diagram below. $$\xymatrix{ 0 \ar[r] & \Omega^{l}\,k \ar[r] \ar@{^{(}->}[d] & \Omega^{l-1}\,k
\oplus \Omega^{l-1}\,k
\ar[r] \ar@{..>}[dl]^{f \oplus g} \ar[r]& \Omega^{l-2}\,k \ar[r] & 0 \\
& M & & & & }$$ Now if either $f$ or $g$ is injective, that would contradict the minimality of $l$, so they cannot be injective. So both $f$ and $g$ should factor through $\Omega^{l-2}\,k
\oplus \Omega^{l-2}\,k$ as shown in the diagrams below. $$\xymatrix{ 0 \ar[r] & \Omega^{l-1}\,k \ar[r] \ar[d]_f & \Omega^{l-2}\,k \oplus
\Omega^{l-2}\,k
\ar[r] \ar@{..>}[dl]^{(f_1 \oplus f_2)} \ar[r] & \Omega^{l-3}\,k \ar[r] & 0 \\
& M & & & & }$$ $$\xymatrix{ 0 \ar[r] & \Omega^{l-1}\,k \ar[r] \ar[d]_g & \Omega^{l-2}\,k \oplus
\Omega^{l-2}\,k
\ar[r] \ar@{..>}[dl]^{(g_1 \oplus g_2)} \ar[r] & \Omega^{l-3}\,k \ar[r] & 0 \\
& M & & & & }$$
Proceeding in this way we can assemble all the lifts obtained using the almost split sequences into one diagram as shown below. $$\xymatrix{
\Omega^l\, k \ar@{^{(}->}[rrrrrr] \ar@{^{(}->}[d] & &&&&& M \\
\Omega^{l-1}\,k \oplus \Omega^{l-1}\,k \ar@{..>}[urrrrrr] \ar@{^{(}->}[d]& &&&&& \\
(\Omega^{l-2}\,k \oplus \Omega^{l-2}\,k)\oplus(\Omega^{l-2}\,k \oplus
\Omega^{l-2}\,k) \ar@{..>}[uurrrrrr] \ar@{^{(}->}[d] \\
\vdots \ar@{^{(}->}[d] \\
(\Omega^1\, k \oplus \Omega^l\,k)\oplus \cdots \oplus(\Omega^1\, k \oplus
\Omega^l\,k) \ar@{..>}[uuuurrrrrr] \ar@{^{(}->}[dd]\\
\\
(kV_4 \oplus k \oplus k) \oplus \cdots \oplus (kV_4 \oplus k \oplus k)
\ar@{..>}[uuuuuurrrrrr]}$$ So it suffices to show that for a projective-free $M$ there cannot exist a factorisation of the form $$\xymatrix{
\Omega^l\, k \ar@{^{(}->}[r] \ar@{^{(}->}[d] & M \\
(kV_4)^s \oplus k^t \ar@{.>}[ur]_{\phi} & }$$ where $l$ is a positive integer. It is not hard to see that the invariance $(\Omega^l\,k)^G$ of $\Omega^l\,k$ maps into $((kV_4)^s)^G$. We will arrive at a contradiction by showing $((kV_4)^s)^G$ maps to zero under the map $\phi$. Since $((kV_4)^s)^G \cong
((kV_4)^G)^s$ it is enough to show that $\phi$ maps each $(kV_4)^G$ to zero. $(kV_4)^G$ is a one-dimensional subspace, generated by say $v$. It $v$ maps to a non-zero element, then it is easy to see that the restriction of $\phi$ on the corresponding copy of $kV_4$ is injective, but $M$ is projective-free, so this is impossible. In other words $\phi(v) = 0$ and that completes the proof of the lemma.
Proof of lemma \[lemma3\]
-------------------------
Recall that $\Omega^1(k)$ is defined to be the kernel of the augmentation map $kV_4 {\ensuremath{\rightarrow}}k$. Dualising the short exact sequence $$0 {\ensuremath{\rightarrow}}\Omega^1(k) {\ensuremath{\rightarrow}}kV_4 {\ensuremath{\rightarrow}}k {\ensuremath{\rightarrow}}0,$$ we get $$0 \leftarrow \Omega^1(k)^* \leftarrow kV_4 \leftarrow k \leftarrow 0$$ because $kV_4$ and $k$ are self-dual. This shows that $\Omega^{-1}(k
) \cong \Omega^1(k)^*$. Now a straightforward induction gives $\Omega^{-l}(k ) \cong \Omega^l(k)^*$ for all $l \ge 1$.
So it is enough to prove the part (1) of the lemma because it is not hard to see that the representations in part (2) are precisely the duals of those in part (1). We leave this as an easy exercise to the reader.
As for (1) we will prove the cases $n =1$ and $n=2$. The general case will then be abundantly clear. For $n=1$, we have to identify the kernel of the augmentation map $kV_4 {\ensuremath{\rightarrow}}k$ which is defined by mapping the generator $e_0$ of $kV_4$ to the basis element $g_0$ of $k$, so the kernel $\Omega^1(k)$ is a three dimensional representation as shown in the diagram below $$\xymatrix{ \\ 0 \\ } \xymatrix{\\ \longrightarrow \\}
\xymatrix@=2em{ \\
\overset{a_0}{\bullet} \ar[dr] & & \overset{b_0}{\bullet} \ar[dl] \\
& \underset{c_0}{\bullet} &
} \xymatrix{\\ \longrightarrow \\} \xymatrix@=2em{
& \overset{e_0}{\bullet} \ar[dl] \ar[dr] & \\
\overset{a_0}{\bullet} \ar[dr]& & \overset{b_0}{\bullet} \ar[dl]\\
& \underset{c_0}{\bullet} &
}
\xymatrix{\\ \longrightarrow \\} \xymatrix{\overset{g_0}{\bullet} \\ \\ } \xymatrix{\\
\longrightarrow
\\}
\xymatrix{\\ 0
\\}$$ Now consider the case $n=2$. Note the $\Omega^1(k)$ is generated by two elements $g_0$ and $g_1$. So a minimal projective cover will be $kV_4 \oplus kV_4$ generated by $e_0$ and $e_1$. The projective covering maps $e_i$ to $g_i$, $i = 0, 1$. The kernel $\Omega^2(k)$ of this projective covering will be $5$-dimensional and can be easily seen in the diagram below. $$\xymatrix@=0.5em{ \\ \\ 0 \\ \\ } \xymatrix@=0.5em{ \\ \\ {\ensuremath{\rightarrow}}\\
\\ }\xymatrix@=0.5em{ & & & & \\ \\
\overset{a_1}{\bullet} \ar[ddr] & & \overset{b_1 + a_0}{\bullet} \ar[ddl] \ar[ddr] & & \overset{b_0}{\bullet} \ar[ddl]
\\ \\
&\underset{c_1}{\bullet} & & \underset{c_0}{\bullet} &
} \xymatrix@=0.5em{\\ \\ {\ensuremath{\rightarrow}}\\ \\}
\xymatrix@=0.5em{
& \overset{e_1}{\bullet} \ar[ddl] \ar[ddr] & \\ \\
\overset{a_1}{\bullet} \ar[ddr]& & \overset{b_1}{\bullet}
\ar[ddl]\\ \\
& \underset{c_1}{\bullet} &
}
\xymatrix@=0.5em{\\ \\ \bigoplus \\ \\} \xymatrix@=0.5em{
& \overset{e_0}{\bullet} \ar[ddl] \ar[ddr] & \\ \\
\overset{a_0}{\bullet} \ar[ddr]& & \overset{b_0}{\bullet}
\ar[ddl]\\ \\
& \underset{c_0}{\bullet} & }
\xymatrix@=0.5em{\\ \\ {\ensuremath{\rightarrow}}\\ \\} \xymatrix@=0.5em{
\overset{g_1}{\bullet} \ar[ddr] & & \overset{g_0}{\bullet} \ar[ddl]
\\ \\
& \underset{f_0}{\bullet} & \\ \\
} \xymatrix@=0.5em{\\ \\ {\ensuremath{\rightarrow}}\\ \\}
\xymatrix@=0.5em{\\ \\ 0
\\ \\}$$ Now it is clear that in general $\Omega^l(k)$ for $l \ge 1$ will be a $2l+1$ dimensional representation and has the shape of the zig-zag diagram as shown in the statement of the lemma.
Proof of proposition \[prop:heller\].
-------------------------------------
We begin by showing the modules in item 2(b) are fixed by the Heller shift operator. Recall that these have the form $$\xymatrix@=2em{
& & \overset{g_{n-1}}{\bullet} \ar[dr]^b \ar[dl]_a & &
\overset{g_{n-2}}{\bullet} \ar[dl] \ar[dr] & & &
\overset{g_1}{\bullet} \ar[dr] & & \overset{g_0}{\bullet} \ar[dl] \\
& \bullet & & \bullet & & \bullet & \bullet \hspace{1 mm}
\bullet \hspace{1 mm} \bullet & & \bullet &
}$$ It is clear that the $\{g_0, g_1, g_2, \cdots g_{n-1} \}$ is a minimal generating set for the above module, $M$ say. So a minimal projective cover of this module will be a free $V_4$-module of rank $n$ generated by basis elements $\{e_0, e_1, e_2, \cdots ,e_{n-1}
\}$, and the covering map sends $e_i$ to $g_i$, for all $i$. Counting dimensions, it is then clear that the dimension of the kernel ($\Omega(M)$) of this projective cover is of dimension $2n$. We only have to show that the $V_4$-module structure on the kernel is isomorphic to the one on $M$. This will be clear from the following diagrams. We consider the cases $n=2$ and $3$, the general case will then be clear. $$\xymatrix{ \\ 0 \\ } \xymatrix{\\ \longrightarrow \\}
\xymatrix@=2em{ \\
& \overset{b_0}{\bullet} \ar[dl] \\
\underset{c_0}{\bullet} &
} \xymatrix{\\ \longrightarrow \\} \xymatrix@=2em{
& \overset{e_0}{\bullet} \ar[dl] \ar[dr] & \\
\overset{a_0}{\bullet} \ar[dr]& & \overset{b_0}{\bullet} \ar[dl]\\
& \underset{c_0}{\bullet} &
}
\xymatrix{\\ \longrightarrow \\} \xymatrix{& \overset{g_0}{\bullet} \ar[dl] \\ \underset{f_0}\bullet & \\ } \xymatrix{\\
\longrightarrow
\\}
\xymatrix{\\ 0
\\}$$ $$\xymatrix@=0.5em{ \\ \\ 0 \\ \\ } \xymatrix@=0.5em{ \\ \\ {\ensuremath{\rightarrow}}\\
\\ }\xymatrix@=0.5em{ & & & \\ \\
& \overset{b_1 + a_0}{\bullet} \ar[ddl] \ar[ddr] & & \overset{b_0}{\bullet} \ar[ddl]
\\ \\
\underset{c_1}{\bullet} & & \underset{c_0}{\bullet} &
} \xymatrix@=0.5em{\\ \\ {\ensuremath{\rightarrow}}\\ \\}
\xymatrix@=0.5em{
& \overset{e_1}{\bullet} \ar[ddl] \ar[ddr] & \\ \\
\overset{a_1}{\bullet} \ar[ddr]& & \overset{b_1}{\bullet}
\ar[ddl]\\ \\
& \underset{c_1}{\bullet} &
}
\xymatrix@=0.5em{\\ \\ \bigoplus \\ \\} \xymatrix@=0.5em{
& \overset{e_0}{\bullet} \ar[ddl] \ar[ddr] & \\ \\
\overset{a_0}{\bullet} \ar[ddr]& & \overset{b_0}{\bullet}
\ar[ddl]\\ \\
& \underset{c_0}{\bullet} & }
\xymatrix@=0.5em{\\ \\ {\ensuremath{\rightarrow}}\\ \\} \xymatrix@=0.5em{ &
\overset{g_1}{\bullet} \ar[ddl] \ar[ddr] & & \overset{g_0}{\bullet}
\ar[ddl]
\\ \\
\underset{f_1}{\bullet} & & \underset{f_0}{\bullet} & \\ \\
} \xymatrix@=0.5em{\\ \\ {\ensuremath{\rightarrow}}\\ \\}
\xymatrix@=0.5em{\\ \\ 0
\\ \\}$$ We now show that the modules in item 2(a) are fixed under the Heller. Recall that in each even dimension $2n$, these modules correspond to indecomposable rational canonical forms given by powers of an irreducible polynomials $f(x)^l = \sum_{i=0}^n \theta_i
x^i$, schematically: $$\xymatrix@=1.9em{
\overset{g_{n-1}}{\bullet} \ar[dr]_b & & \overset{g_{n-2}}{\bullet}\ar[dl]^a \ar[dr] & & \overset{g_{n-3}}{\bullet} \ar[dl] & \bullet \hspace{1 mm}
\bullet \hspace{1 mm} \bullet
& & \overset{g_0}{\bullet} \ar[dl] \ar[dr] \\
& \underset{f_{n-1}}{\bullet} & & \underset{f_{n-2}}{\bullet} & & & \underset{f_1}{\bullet} & &
\underset{f_0}{\bullet}
}$$ where $a(g_{n-1}) = \sum_{i = 0}^{n-1} \theta_i f_i$. It is again clear that $\{g_0, g_1, g_2, \cdots g_{n-1} \}$ is a minimal generating set, and hence a projective cover can be taken to be a free $V_4$-module of rank $n$ with basis elements $\{e_0, e_1, e_2,
\cdots e_{n-1} \}$, and the mapping sends the elements $e_i$ to the generators $g_i$. We will again convince the reader that these modules are fixed under the Heller by examining the cases $n=1$ and $n=2$. We begin with the case $n=1$. Here the rational canonical form is determined by constant $\theta_0$, and $a(g_0) = \theta_0
f_0$. The following diagram shows that the Heller fixes these two dimensional modules.
$$\xymatrix{ \\ 0 \\ } \xymatrix{\\ \longrightarrow \\}
\xymatrix@=2em{ \\
\overset{a_0 + \theta_0 b_0}{\bullet} \ar[dr] & \\
& \underset{c_0}{\bullet}
} \xymatrix{\\ \longrightarrow \\} \xymatrix@=2em{
& \overset{e_0}{\bullet} \ar[dl] \ar[dr] & \\
\overset{a_0}{\bullet} \ar[dr]& & \overset{b_0}{\bullet} \ar[dl]\\
& \underset{c_0}{\bullet} &
}
\xymatrix{\\ \longrightarrow \\} \xymatrix{ \overset{g_0}{\bullet} \ar[dr] & \\ & \underset{f_0}\bullet \\ } \xymatrix{\\
\longrightarrow
\\}
\xymatrix{\\ 0
\\}$$ Now consider the four dimensional modules: $n=2$ and the rational conical form corresponds to a polynomial $x^2 + \theta_1 x +
\theta_0$. In the diagram below $a(g_1) = \theta_0 f_0 + \theta_1
f_1.$ $$\xymatrix@=0.5em{ \\ \\ 0 \\ \\ } \xymatrix@=0.5em{ \\ \\ {\ensuremath{\rightarrow}}\\
\\ }
\xymatrix@=0.5em{ & & & \\ \\
\overset{\gamma}{\bullet} \ar[ddr] & & \overset{b_1 + a_0}{\bullet}
\ar[ddl] \ar[ddr] &
\\ \\
& \underset{c_1}{\bullet} & & \underset{c_0}{\bullet}
} \xymatrix@=0.5em{\\ \\ {\ensuremath{\rightarrow}}\\ \\}
\xymatrix@=0.5em{
& \overset{e_1}{\bullet} \ar[ddl] \ar[ddr] & \\ \\
\overset{a_1}{\bullet} \ar[ddr]& & \overset{b_1}{\bullet}
\ar[ddl]\\ \\
& \underset{c_1}{\bullet} &
}
\xymatrix@=0.5em{\\ \\ \bigoplus \\ \\} \xymatrix@=0.5em{
& \overset{e_0}{\bullet} \ar[ddl] \ar[ddr] & \\ \\
\overset{a_0}{\bullet} \ar[ddr]& & \overset{b_0}{\bullet}
\ar[ddl]\\ \\
& \underset{c_0}{\bullet} & }
\xymatrix@=0.5em{\\ \\ {\ensuremath{\rightarrow}}\\ \\} \xymatrix@=0.5em{
\overset{g_1}{\bullet} \ar[ddr] & & \overset{g_0}{\bullet} \ar[ddr]
\ar[ddl] &
\\ \\
& \underset{f_1}{\bullet} & & \underset{f_0}{\bullet} \\ \\
} \xymatrix@=0.5em{\\ \\ {\ensuremath{\rightarrow}}\\ \\}
\xymatrix@=0.5em{\\ \\ 0
\\ \\}$$ where $\gamma = a_1 + \theta_0 b_0 + \theta_1 b_1$. Note that $a(\gamma) = \theta_0 c_0 + \theta_1 c_1$, as desired.
Proof of proposition \[prop:dual\].
-----------------------------------
Note that it suffices to show that the indecomposable representations in item 2(a) are self-dual; for that forces the representations in item 2(b) to be self-dual, and it is well known that $kV_4$ is self-dual.
A $2n$ dimensional representation $M$ of item 2(a) can be chosen to be of the form (after a suitable choice of bases) $$M = (V, V; I, J)$$ where $V$ is an $n$-dimensional vector space, $I$ denotes the identity transformation, and $J$ an indecomposable rational canonical form. It is then clear that the dual of $M$ is given by $$M^* = (V^*, V^*; I , J^T )$$ It is a interesting exercise [^2] to show that a square matrix is similar to its transpose, so there exists an invertible matrix $D$ such that $J^T = D J D^{-1}$. The following commutative diagram then tells us that $M$ is isomorphic to $M^*$. $$\xymatrix{
V \ar[r]^J \ar[d]_D^{\cong} & V \ar[d]^D_{\cong} \\
V^* \ar[r]_{J^T} & V^* }$$
The quest continues
===================
In our paper we concentrated on Klein group but what about $C_{3} \oplus C_{3}$? What are all the representation of this group? Interestingly enough this is an extremely difficult question. Yet, some progress has be made very recently which involves more sophisticated machinery of representation theory. For the curious reader we refer to a recent paper [@CFP].
[^1]: Most readers are familiar with the Jordan canonical form of an operator acting on a vector space over $\mathbb{C}$ or other algebraically closed fields. These forms use critically the fact that non-constant polynomials have roots. However, a parallel and beautiful theory also exists when the field is not algebraically closed, and this is not so well-known. One often thinks about the base field as the field of rational numbers and the name “The rational canonical form” stick also to completely different fields including ${\mathbb{F}_2}$.
[^2]: Hint: Use Jordan decomposition
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{
"pile_set_name": "ArXiv"
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In U.S. Pat. No. 4,232,184 which was issued to me on Nov. 04, 1980, I show a cable adapter, commonly referred to in the trade as a boot, for use with a cable closure at each of its ends in aerial telephone plant. The cable closure protects a cable splice. Likewise, some aerial cable terminals may use a boot at each end. The terminal provides a location for terminating a loop.
The boot which I have described in the aforesaid patent has a plurality of tapered nozzles for adapting to the size of the cable. Initially, the boot was made of soft material. But rodents could eat through the soft material, exposing the cable to elements and resulting in potential maintenance problems. An improved boot was made from a hard substance. This, however, made it difficult for a craftperson to work with the apparatus.
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{
"pile_set_name": "USPTO Backgrounds"
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Semyon Pomogayev
Semyon Vyacheslavovich Pomogayev (; born 1 November 1993) is a Russian football midfielder. He plays as a central midfielder.
Club career
He made his debut in the Russian Second Division for FC Tyumen on 16 September 2012 in a game against FC Lada-Togliatti Togliatti.
He made his Russian Football National League debut for FC Ural Yekaterinburg on 1 April 2013 in a game against FC Tom Tomsk.
Career statistics
Club
References
External links
Career summary by sportbox.ru
Category:1993 births
Category:Living people
Category:Russian footballers
Category:Association football midfielders
Category:FC Tyumen players
Category:FC Ural Yekaterinburg players
Category:FC Dynamo Saint Petersburg players
Category:FC Baltika Kaliningrad players
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{
"pile_set_name": "Wikipedia (en)"
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