Input: We demonstrate that electrolyte flow is most likely driven by electrochemical potential gradients of reaction products formed during the inhomogeneous copper dissolution.

copper


Input: New prospects for vinblastine analogues as anticancer agents.

vinblastine


Input: Boger et al. synthesized a series of C20' urea derivatives of vinblastine that matched or exceeded the potency of vinblastine in cell growth inhibition assays.

urea

vinblastine

vinblastine


Input: The studies demonstrated the importance of the H-bond donor on the C20' position and revealed the presence of a space surrounding the C20' substituent that tolerates a wide variety of substituents, remarkably enhancing potency of vinblastine analogues.

H

vinblastine


Input: Rheological study of mutarotation of fructose in anhydrous state.

fructose


Input: Rheological measurement was employed to study the mutarotation of D-fructose in anhydrous state.

D-fructose


Input: By monitoring the evolution of shear viscosity with time, rate constants for mutarotation were estimated, and two different stages of this reaction were identified.


Input: One of the mutarotation stages is rapid and has a low activation energy, whereas the other is much slower and has a much higher activation energy.


Input: Possible conversions corresponding to these two phases are discussed.


Input: This work demonstrates that, in addition to the routine techniques such polarimetry and gas-liquid chromatography, rheological measurement can be used as an alternative method to continuously monitor the mutarotation of sugars.

sugars


Input: One-pot synthesis of tin-embedded carbon/silica nanocomposites for anode materials in lithium-ion batteries.

tin

carbon

silica

lithium


Input: We report a facile " one-pot " method for the synthesis of Sn-embedded carbon-silica (CS) mesostructured (nanostructured) composites through the selective interaction of resol (carbon precursor), tetraethylorthosilicate (TEOS), and tributylphenyltin (Sn precursor) with an amphiphilic diblock copolymer, poly (ethylene oxide-b-styrene), PEO-b-PS.

Sn

carbon

silica

carbon

tetraethylorthosilicate

TEOS

tributylphenyltin

Sn

poly (ethylene oxide-b-styrene)

PEO-b-PS


Input: A unique morphology transition from Sn nanowires to spherical Sn nanoparticles embedded in CS framework has been obtained.

Sn

Sn


Input: Metallic Sn species are homogeneously embedded in a rigid CS framework and are effectively confined within the nanostructures.

Sn


Input: The resulting composites are used as anode materials for lithium-ion batteries and exhibit high specific capacities (600 mA h g-(1) at a current density of 45 mA g-(1), and 440 mA h g-(1) at a current density of 300 mA g-(1)) and an excellent cyclability of over 100 cycles with high Coulombic efficiency.

lithium


Input: Most of all, the novel method developed in this work for synthesizing functional hybrid materials can be extended to the preparation of various functional nanocomposites owing to its versatility and facileness.


Input: Enhancement of angiogenesis by a 27 kDa lectin from perivitelline fluid of horseshoe crab embryos through upregulation of VEGF and its receptor.


Input: Angiogenesis, the expansion of a capillary network, is implicated in several pathological conditions.


Input: Drug-based inhibition of angiogenesis is being explored as therapy.


Input: Conversely, therapeutic angiogenesis contributes to control conditions such as ischemia.


Input: Here we report pro-angiogenic activity of perivitelline fluid (PVF) from Indian horseshoe crab embryos and one of its purified fractions, a 27 kDa lectin, using the chick embryonic chorioallantoic membrane assay.


Input: Enhancement in number and diameter of blood vessels after treatment with PVF and lectin suggested their pro-angiogenic effect.


Input: Quantitative RT-PCR showed that this effect is mediated through modulation of expression of VEGF and VEGFR-2/kinase domain receptor genes.


Input: Novel insights into the pervasive role of M (3) muscarinic receptor in cardiac diseases.


Input: Cardiac diseases remain the leading cause of morbidity and mortality worldwide.


Input: Heart functions are regulated by autonomic nervous systems through their transmitters and modulators, binding to cell surface receptors.


Input: Among them, the cardiac M (3) muscarinic acetylcholine receptor (M (3)-mAChR) has been studied for more than 2 decades since its first discovery in mammalian heart in 1990s.

acetylcholine


Input: The location and pathophysiological role of M (3)-mAChR in the cardiovascular system have been extensively studied and many pathways involved have been uncovered.


Input: Gain-and loss-of-function studies have revealed the ubiquitous roles of M (3)-mAChR in physiological and pathological conditions.


Input: Recently, many new findings have been uncovered about the relationship between M (3)-mAChR and cardiac diseases, including cardiac ischemia, pathological cardiac hypertrophy, cardiac arrhythmias, cardiac conduction and heart failure.


Input: Furthermore, the novel potential cardioprotective role of M (3)-mAChR against heart injury by regulation of microRNAs (miRNAs) has been revealed in the most updated research.


Input: In this review, the current new findings on the role of M (3)-mAChR in heart diseases are updated, the downstream signaling pathways are summarized, perspectives and challenges of M (3)-mAChR as therapeutic targets are discussed.


Input: Growth of Pt nanowires by atomic layer deposition on highly ordered pyrolytic graphite.

Pt

graphite


Input: The formation of Pt nanowires (NWs) by atomic layer deposition on highly ordered pyrolytic graphite (HOPG) is investigated.

Pt

graphite


Input: Pt is deposited only at the step edges of HOPG and not on the basal planes, leading to the formation of laterally aligned Pt NWs.

Pt

Pt


Input: A growth model involving a morphological transition from 0-D to 1-D structures via coalescence is presented.


Input: The width of the NWs grows at a rate greater than twice the vertical growth rate.


Input: This asymmetry is ascribed to the wetting properties of Pt on HOPG as influenced by the formation of graphene oxide.

Pt

graphene oxide


Input: A difference in Pt growth kinetics based on crystallographic orientation may also contribute.

Pt


Input: The impact of oxidative stress on islet transplantation and monitoring the graft survival by non-invasive imaging.


Input: Islet transplantation is an attractive strategy to treat severe diabetic conditions in patients suffering from autoimmune derived diabetes, and it has currently been considered a forefront research arena in diabetes.


Input: Major aim of islet transplantation is to achieve successful insulin independent disease free survival.


Input: The key challenges in transplanted islets are the generation of reactive oxygen species (ROS) and associated oxidative stress, pro-inflammatory cytokine-(TNF alpha) mediated apoptotic induction, attack by immune cells, and achieving revascularization with minimal hypoxic microenvironment.

oxygen


Input: Free radicals and their derivatives are constantly produced in living systems, but at relatively low level, and in a balanced state.


Input: Oxidative stress, which occurs as a result of an imbalance between the intracellular free radicals production and the cellular antioxidant defense mechanisms in the transplanted islets, can lead to cell death.


Input: The balance between oxidants and antioxidants in a cell can be easily disturbed by increase in ROS production or reduction in the level of cellular antioxidant defensive substances, which can cause many metabolic complications, including pancreatic beta-cell damage.


Input: Antioxidants function as blockers of radical processes by eliminating harmful ROS produced during normal cellular metabolism.


Input: A complex antioxidant defense mechanism has been developed by nature in cells to protect the cellular homeostasis.


Input: This system mainly includes antioxidant enzymes, vitamins and minerals.


Input: As transplanted islet survival is crucial for achieving successful therapy, most of these antioxidants can be used as a supplement to scavenge the local ROS thereby improving the survival of transplanted islets.


Input: Currently, very few techniques have been routinely used to qualitatively and quantitatively assess the survival and function of islet grafts, especially to confirm the success of treatment, which includes metabolic parameters such as blood glucose, insulin and C-peptide levels.

glucose


Input: These biochemical measurements provide markers at only the late stages of islet rejection.


Input: Use of molecular imaging techniques has the potential for real-time non-invasive monitoring of the functional status and viability of transplanted islet grafts in living animals.


Input: This review mainly focuses on the current status of islet transplantations, potential preventive strategies used to reduce oxidative stress-mediated toxicity in islet grafts, and use of molecular imaging as a tool to quantitatively evaluate the functional status of the transplanted islets in living animals.


Input: Computational peptidology: a new and promising approach to therapeutic Peptide design.


Input: The recent focus on protein-protein interaction networks has increasingly been shifted towards the disruption of protein complexes, which either are mediated by the binding of a globular domain in one protein to a short peptide stretch in another, or involve flat, large, and hydrophobic interfaces that classical small-molecule agents are not always ideally suited.


Input: Rational design of therapeutic peptides with high affinity targeting such interactions has emerged as a new and promising tool in discovery of potential drug candidates against associated diseases.


Input: The design is commonly based on bioinformatics methods or molecular modeling techniques, indirectly exploiting structure-activity relationship at the level of peptide sequence or directly deriving lead entities from protein complex architecture.


Input: Here, a newly rising subfield called computational peptidology that focuses on the use of computational and theoretical approaches to treat peptiderelated problems is comprehensively reviewed on the design and discovery of peptide agents targeting protein-protein interactions.


Input: We address a systematic discussion on several representative cases in which the computational peptidology is successfully employed to develop peptide therapeutics.


Input: Besides, some problems and pitfalls accompanied with the current use of computational methods in peptide modeling and design are also present.


Input: Thermal sintering: a novel technique used in the design, optimization and biopharmaceutical evaluation of propranolol HCl gastric floating tablets.

propranolol HCl


Input: Abstract The objective of the present investigation was to study the applicability of thermal sintering technique for the development of gastric floating tablets of propranolol HCl.

propranolol HCl


Input: Formulations were prepared using four independent variables, namely (i) polymer quantity, (ii) sodium bicarbonate concentration, (iii) sintering temperature and (iv) sintering time.

sodium bicarbonate


Input: Floating lag time and t (95) were taken as dependent variables.


Input: Tablets were prepared by the direct compression method and were evaluated for physicochemical properties, in vitro buoyancy and dissolution studies.


Input: From the drug release studies, it was observed that drug retarding property mainly depends upon the sintering temperature and time of exposure.


Input: The statistically optimized formulation (PTSso) was characterized by Fourier transform infrared spectroscopy and differential scanning calorimetry studies, and no significant chemical interaction between drug and polymer was observed.


Input: Optimized formulation was stable at accelerated conditions for a period of six months.


Input: PTSso was evaluated for in vivo buoyancy studies in humans for both fed and fasted states and found that gastric residence time of the floating tablets were enhanced by fed stage but not in fasted state.


Input: Optimized formulation PTSso and commercial formulation Ciplar LA 80 were subjected to bioavailability studies in healthy human volunteers by estimating pharmacokinetic parameters such as C (max), T (max), area under curve (AUC) (,) elimination rate constant (K (el)), biological half-life (t (1/2)) and mean residence time (MRT).

Ciplar LA 80


Input: There was a significant increase in the bioavailability of the propranolol HCl from PTSso formulation, which was evident from increased AUC levels and larger MRT values than Ciplar LA 80.

propranolol HCl

Ciplar LA 80


Input: Study of the scale formation mechanism on gold modified with an alkanethiol monolayer.

alkanethiol


Input: Scaling is a problem in many industrial processes.


Input: To control and minimize it, it is important to understand the dynamics of the scale formation.


Input: In this paper, the scale formation was examined on two kinds of gold surfaces.


Input: One was a pure metallic gold surface, and the other was a gold surface modified with an alkanethiol self-assembled monolayer.

alkanethiol


Input: A series of surface characterization experiments were performed to ensure a good understanding of the gold-thiol bond stability in a caustic solution.

gold-thiol


Input: A multivalent approach towards linked dual-pharmacology prostaglandin F receptor agonist/carbonic anhydrase-II inhibitors for the treatment of glaucoma.

prostaglandin F


Input: Lowering of intra-ocular pressure is the primary pharmacologic approach for the treatment of glaucoma and a number of distinct mechanisms of action have been clinically validated.


Input: Targeting of multiple mechanisms in combination therapies has proven effective both clinically and commercially although potential improvements with regards to efficacy, tolerability and dosing frequency remain.


Input: Application of Theravance' s multivalent approach to drug discovery towards linked dual-pharmacology prostaglandin F receptor (FP) agonist/carbonic anhydrase (CA)-II inhibitor compounds is described.

prostaglandin F


Input: Compound 29 exhibits weak potency (pEC (50) = 5. 7, IA > 1. 0) as an FP agonist with high binding affinity (pK (i) = 8. 1) to the CA-II enzyme, and has comparable corneal permeability to the CA-II inhibitor dorzolamide.

dorzolamide


Input: The cancer biology of whole-chromosome instability.


Input: One form of chromosome instability (CIN), the recurrent missegregation of whole chromosomes during cell division (W-CIN), leads to aneuploidy.


Input: Although W-CIN is a hallmark of most cancers, mutations in genes involved in chromosome segregation are exceedingly rare.


Input: We discuss an oncogene-induced mitotic stress model that provides a mechanistic framework to explain this paradox.


Input: We also review the tumor-promoting and tumor-suppressing consequences of W-CIN.


Input: Importantly, we do this in the context of cancer as a complex systemic disease, rather than as a simple linearly progressing disorder that arises from a single abnormal cell population.


Input: Accordingly, we highlight the often neglected effects of W-CIN on key non-cell-autonomous entities, such as the immune system and the tumor microenvironment.


Input: Distinct tissue-specific susceptibilities to W-CIN-induced tumorigenesis and the clinical implications of W-CIN are also discussed. Oncogene advance online publication, 14 January 2013; doi: 10. 1038/onc. 2012. 616.


Input: Neuroprotective efficacy and pharmacokinetic behavior of novel anti-inflammatory para-phenyl substituted diindolylmethanes in a mouse model of Parkinson' s disease.

para-phenyl substituted diindolylmethanes


Input: There are currently no registered drugs that slow the progression of neurodegenerative diseases, in part because translation from animal models to the clinic has been hampered by poor distribution to the brain.


Input: The present studies examined a selected series of para-phenyl-substituted diindolylmethane (C-DIM) compounds that display anti-inflammatory and neuroprotective efficacy in vitro.

para-phenyl-substituted diindolylmethane


Input: We postulated that the pharmacokinetic behavior of C-DIM compounds after oral administration would correlate with neuroprotective efficacy in vivo in a mouse model of Parkinson' s disease.


Input: Pharmacokinetics and metabolism of 1, 1-bis (3'-indolyl)-1-(p-methoxyphenyl) methane (C-DIM5), 1, 1-bis (3'-indolyl)-1-(phenyl) methane, 1, 1-bis (3'-indolyl)-1-(p-hydroxyphenyl) methane (C-DIM8), and 1, 1-bis (3'-indolyl)-1-(p-chlorophenyl) methane (C-DIM12) were determined in plasma and brain of C57Bl/6 mice after oral and intravenous administration at 10 and 1 mg/Kg, respectively.

1, 1-bis (3'-indolyl)-1-(p-methoxyphenyl) methane

1, 1-bis (3'-indolyl)-1-(phenyl) methane

1, 1-bis (3'-indolyl)-1-(p-hydroxyphenyl) methane

1, 1-bis (3'-indolyl)-1-(p-chlorophenyl) methane


Input: Putative metabolites were measured in plasma, liver, and urine.


Input: C-DIM compounds given orally displayed the highest area under the curve, Cmax, and Tmax levels, and C-DIM12 exhibited the most favorable pharmacokinetics of the compounds tested.


Input: Oral bioavailability of each compound ranged from 6% (C-DIM8) to 42% (C-DIM12).


Input: After pharmacokinetic studies, the neuroprotective efficacy of C-DIM5, C-DIM8, and C-DIM12 (50 mg/Kg per oral) was examined in mice exposed to 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and probenecid for 14 days, a model of progressive neurodegeneration with a strong neuroinflammatory component.

1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine

MPTP

probenecid


Input: C-DIM5 and C-DIM12 given orally once daily after one week of exposure to MPTP and probenecid prevented further loss of dopaminergic neurons in the substantia nigra pars compacta and striatal dopamine terminals, indicating that these compounds could be effective therapeutic agents to prevent neurodegeneration.

MPTP

probenecid

dopaminergic


Input: Peroxynitrite mediates testosterone-induced vasodilation of microvascular resistance vessels.

Peroxynitrite

testosterone


Input: Our knowledge of how androgens influence the cardiovascular system is far from complete, and this lack of understanding is especially true of how androgens affect resistance vessels.

androgens

androgens


Input: Our aim was to identify the signaling mechanisms stimulated by testosterone (TES) in microvascular arteries and to understand how these mechanisms mediate TES-induced vasodilation.

testosterone

TES

TES


Input: Mesenteric microvessels were isolated from male Sprague-Dawley rats.


Input: Tension studies demonstrated a rapid, concentration-dependent, vasodilatory response to TES that did not involve protein synthesis or aromatization to 17 beta-estradiol.

TES

17 beta-estradiol


Input: Dichlorofluorescein fluorescence and nitrotyrosine immunoblot experiments indicated that TES stimulated peroxynitrite formation in microvessels, and functional studies demonstrated that TES-induced vasodilation was inhibited by scavenging peroxynitrite.

Dichlorofluorescein

nitrotyrosine

TES

peroxynitrite

TES

peroxynitrite


Input: As predicted, TES enhanced the production of both peroxynitrite precursors (i. e., superoxide and nitic oxide), and xanthine oxidase was identified as the likely source of TES-stimulated superoxide production.

TES

peroxynitrite

superoxide

nitic oxide

xanthine

TES

superoxide


Input: Functional and biochemical studies indicated that TES signaling involved activity of the phosphoinositide 3 (PI3) kinase-protein kinase B (Akt) cascade initiated by activation of the androgen receptor and culminated in enhanced production of cGMP and microvascular vasodilation.

TES

phosphoinositide

androgen

cGMP


Input: These findings, derived from a variety of analytical and functional approaches, provide evidence for a novel nongenomic signaling mechanism for androgen action in the microvasculature: TES-stimulated vasodilation mediated primarily by peroxynitrite formed from xanthine oxidase-generated superoxide and NO.

androgen

TES

peroxynitrite

xanthine

superoxide

NO


Input: This response was associated with activation of the PI3 kinase-Akt signaling cascade initiated by activation of the androgen receptor.

androgen


Input: We propose this mechanism could account for TES-stimulated cGMP production in microvessels and, ultimately, vasodilation.

TES

cGMP


Input: Ordered mesoporous boron-doped carbons as metal-free electrocatalysts for the oxygen reduction reaction in alkaline solution.

boron-doped carbons

oxygen


Input: Ordered mesoporous boron-doped carbons (BOMCs) were prepared by co-impregnation and carbonization of sucrose and 4-hydroxyphenylboronic acid into SBA-15 silica template.

boron-doped carbons

sucrose

4-hydroxyphenylboronic acid

SBA-15 silica


Input: Nitrogen sorption, small angle X-ray diffraction (XRD), and transmission electron microscopy (TEM) reveals that BOMCs possess highly ordered mesoporous structure, uniform pore size distribution, and high surface area.

Nitrogen


Input: X-ray photoelectron spectroscopy (XPS) analysis demonstrates that B atoms can be successfully doped into the framework of OMCs.

B


Input: Due to the desirable characteristics of BOMCs, BOMCs are highly active, cheap, and selective metal-free electrocatalysts for the oxygen reduction reaction (ORR) in alkaline solution.

oxygen


Input: Although B content is a key factor in determining ORR activity, the ORR activity of BOMCs is also dependent on the surface area.

B


Input: The high surface area of BOMCs facilitates the exposure of the active sites for ORR.


Input: BOMCs may be further exploited as potentially efficient and inexpensive metal-free ORR catalysts with good long-term stability in alkaline solution.


Input: Elevated vaspin and leptin levels are associated with obesity in prepubertal Korean children.


Input: Adipokines are associated with obesity.


Input: However, the relationships between adipokines, specifically vaspin, obesity, and obesity-related variables remain controversial, and only a few studies have been conducted which examines them in children.


Input: We investigated the relationships between obesity in prepubertal Korean children and three types of adipokines: vaspin, leptin, and visfatin.


Input: In this cross-sectional study, 168 nine-year-old boys and 176 nine-year-old girls participated in a school-based health examination program.


Input: Children were classified as overweight using the Korean Pediatric Society 2007 guidelines.


Input: Overweight boys and girls had higher leptin and vaspin levels than both boys and girls of normal weight, whereas only overweight boys had higher visfatin levels than normal weight boys.


Input: Leptin, visfatin and vaspin concentrations were correlated with obesity-related variables.


Input: A multiple logistic regression analysis showed that systolic blood pressure (SBP), total cholesterol (TC), alanine aminotransferase (ALT), homeostasis model assessment of insulin resistance (HOMA-IR), leptin, and vaspin were associated with an increased risk of being overweight, whereas high-density lipoprotein (HDL) cholesterol was associated with a decreased risk of being overweight.

cholesterol

alanine

cholesterol


Input: Elevated vaspin and leptin levels are associated with obesity in prepubertal Korean children.


Input: Peginesatide clearance, distribution, metabolism, and excretion in monkeys following intravenous administration.

Peginesatide


Input: Peginesatide, a polyethylene glycol (PEG) ylated peptide-based erythropoiesis-stimulating agent, stimulates the erythropoietin receptor dimer that governs erythropoiesis.

Peginesatide

polyethylene glycol

PEG


Input: Studies were designed to determine the erythropoietic response, pharmacokinetics (PK), tissue distribution, metabolism, and excretion of peginesatide in nonhuman primates following a single i. v. dose.

peginesatide


Input: The PK profile of peginesatide (0. 1-5 mg/kg) is characterized by low, dose-dependent plasma clearance; small volume of distribution; and long half-life.

peginesatide


Input: The peginesatide PK profile following a single i. v. dose is consistent with the sustained erythropoiesis.

peginesatide


Input: Biodistribution quantitative whole-body autoradiography demonstrated high peginesatide levels in bone marrow (i. e., primary hematopoietic site) as well as other known hematopoietic sites persisting through at least 3 weeks at 2. 1 mg/kg.

peginesatide


Input: Microautoradiography analysis at 48 hours postdose revealed uniform and high distribution of radioactivity in the bone marrow and splenic red pulp with less extensive distribution in the renal cortex (glomeruli, associated ducts, interstitial cells).


Input: Radioactivity in the kidney was most prominent in the outer medullary and papillary interstitium.


Input: At 2 weeks after dosing, cumulative radioactivity recovery in the urine and feces was 60 and 7% of the administered dose, respectively, with most of the radioactivity associated with the parent molecule.


Input: In conclusion, the PK characteristics are consistent with a PEGylated peptide of a 45-kDa molecular mass, specifically low volume of distribution and long half-life.


Input: Drug was localized principally to hematopoietic sites, and nonspecific tissue retention was not observed.


Input: The nonhuman primate data indicate that peginesatide is metabolically stable and primarily excreted in the urine.

peginesatide


Input: Effects of nicotine, its metabolites and tobacco extracts on human platelet function in vitro.

nicotine


Input: Cigarette smoking is a leading cause of cardiovascular disease.


Input: The cardiovascular effects of smoking are probably multifactorial, including effects on platelets.


Input: Previous reports investigating the effects of nicotine and tobacco on platelet function are inconsistent.

nicotine


Input: The present study investigated in vitro effects of nicotine, its major metabolites, tobacco extracts and extract of tobacco-free snuff on human platelets.

nicotine


Input: None of the metabolites cotinine, cotinine-N-oxide, nicotine-1'-N-oxide or trans-3'-hydroxycotinine (0. 1-10 mu M) affected platelet aggregation or P-selectin expression.

cotinine

cotinine-N-oxide


Input: Nicotine (10 mu M) weakly increased platelet aggregation, whereas trans-3'-hydroxycotinine (0. 1 mu M) and nicotine-1'-N-oxide (1-10 mu M) weakly inhibited adhesion to fibrinogen.

Nicotine


Input: To elucidate the influence of other tobacco compounds, we investigated the impact of moist tobacco and smoke extracts on platelet function.


Input: Filtered extracts of oral snuff, cigarette smoke and tobacco free snuff inhibited platelet adhesion concentration-dependently.


Input: The inhibitory effects of tobacco extracts on platelet adhesion were independent of nicotine content and the nitric-oxide-pathway and not mediated through a platelet-nicotine-receptor.

nicotine

nitric-oxide

nicotine


Input: Taken together, tobacco extracts inhibit platelet activation during short-term in vitro challenge.


Input: As only limited effects of nicotine and nicotine metabolites were seen, the tobacco-induced platelet inhibition are likely induced by other compounds present in tobacco and tobacco free snuff.

nicotine

nicotine


Input: Re-print of " Intestinal luminal nitrogen metabolism: role of the gut microbiota and consequences for the host ".

nitrogen


Input: Alimentary and endogenous proteins are mixed in the small intestinal lumen with the microbiota.


Input: Although experimental evidences suggest that the intestinal microbiota is able to incorporate and degrade some of the available amino acids, it appears that the microbiota is also able to synthesize amino acids raising the view that amino acid exchange between the microbiota and host can proceed in both directions.

amino acids

amino acids

amino acid


Input: Although the net result of such exchanges remains to be determined, it is likely that a significant part of the amino acids recovered from the alimentary proteins are used by the microbiota.

amino acids


Input: In the large intestine, where the density of bacteria is much higher than in the small intestine and the transit time much longer, the residual undigested luminal proteins and peptides can be degraded in amino acids by the microbiota.

amino acids


Input: These amino acids cannot be absorbed to a significant extent by the colonic epithelium, but are precursors for the synthesis of numerous metabolic end products in reactions made by the microbiota.

amino acids


Input: Among these products, some like short-chain fatty acids and organic acids are energy substrates for the colonic mucosa and several peripheral tissues while others like sulfide and ammonia can affect the energy metabolism of colonic epithelial cells.

fatty acids

sulfide

ammonia


Input: More work is needed to clarify the overall effects of the intestinal microbiota on nitrogenous compound metabolism and consequences on gut and more generally host health.


Input: Impaired in vitro erythropoiesis following deletion of the Scl (Tal1) + 40 enhancer is largely compensated for in vivo despite a significant reduction in expression.


Input: The Scl (Tal1) gene encodes a helix-loop-helix transcription factor essential for hematopoietic stem cell and erythroid development.


Input: The Scl + 40 enhancer is situated downstream of Map17, the 3' flanking gene of Scl, and is active in transgenic mice during primitive and definitive erythropoiesis.


Input: To analyze the in vivo function of the Scl + 40 enhancer within the Scl/Map17 transcriptional domain, we deleted this element in the germ line.


Input: Scl (Delta 40/Delta 40) mice were viable with reduced numbers of erythroid CFU in both bone marrow and spleen yet displayed a normal response to stress hematopoiesis.


Input: Analysis of Scl (Delta 40/Delta 40) embryonic stem (ES) cells revealed impaired erythroid differentiation, which was accompanied by a failure to upregulate Scl when erythropoiesis was initiated.


Input: Map17 expression was also reduced in hematopoietic tissues and differentiating ES cells, and the Scl + 40 element was able to enhance activity of the Map17 promoter.


Input: However, only Scl but not Map17 could rescue the Scl (Delta 40/Delta 40) ES phenotype.


Input: Together, these data demonstrate that the Scl + 40 enhancer is an erythroid cell-specific enhancer that regulates the expression of both Scl and Map17.


Input: Moreover, deletion of the + 40 enhancer causes a novel erythroid phenotype, which can be rescued by ectopic expression of Scl but not Map17.


Input: Long-term physicochemical and immunological stability of a liquid formulated intact ovine immunoglobulin-based antivenom.


Input: An antivenom should be stable under the conditions that it will be both transferred and stored.


Input: Thus instability may lead to a loss of efficacy and an increased incidence and severity of adverse effects.


Input: Stability is a particular problem in countries where the temperatures and humidity are high.


Input: Here we investigate the stability of a liquid-formulated, intact ovine immunoglobulin-based antivenom, EchiTAbG (TM), which is used extensively in Nigeria to treat envenoming by the West African saw-scaled viper, Echis ocellatus.


Input: Ampoules of antivenom were assessed as to their specific antibody content by small scale affinity chromatography and their purity by size exclusion gel filtration and turbidity.


Input: Three different batches of the antivenom revealed no significant changes, using these assessment techniques, during 42 months storage at 4 degrees C or at ambient temperature, followed by one month at 37 degrees C.


Input: These real-time studies indicate that the antivenom remains stable for a minimum of 3. 5 years and that it can be exposed to tropical temperatures without any loss in immunoglobulin binding activity.


Input: This further highlights the clinical utility of liquid formulated ovine IgG antivenoms by demonstrating their retention of potency in the event of a short term failing in the cold chain.


Input: Spontaneous and experimental intoxication of cattle by Simarouba versicolor A.


Input: St.-Hill (Simaroubaceae).


Input: This study describes an outbreak of Simarouba versicolor intoxication in cattle from Mato Grosso do Sul, Brazil, and reproduces it experimentally.


Input: Clinical signs of the affected animals were weakness, tremors, hind limbs incoordination, reluctance to move, sternal and lateral recumbency and death.


Input: The main necropsy findings, observed in the abomasum and in segments of the small and large intestines, were diffuse redness and mucosal and serosal swelling.


Input: Histological examination revealed necrosis of lymphoid tissues and necrotizing enterocolitis.


Input: One experiment was carried out using 3 male calves to test the toxicity of a single dose of S. versicolor leaves at 15 g/kg, 5 g/kg and 2. 5 g/kg.


Input: Clinical signs, necropsy findings and histological examination of calves receiving 15 g/kg and 5 g/kg leaves were similar to those of cattle from the intoxication outbreak.


Input: The calf fed 2. 5 g/kg leaves developed clinical symptoms of poisoning and recovered naturally.


Input: In a second experiment, two male calves received daily administration of S. versicolor leaves at 1. 5 g/kg and 2. 5 g/kg for 10 days.


Input: They developed clinical signs of intoxication within 24 h and recovered eight to nine days after the leaves were administered.


Input: These findings suggest that S. versicolor was responsible for the outbreak studied, although this plant does not have cumulative intoxication effects on cattle.


Input: Effective fragment potential method in Q-CHEM: A guide for users and developers.


Input: A detailed description of the implementation of the effective fragment potential (EFP) method in the Q-CHEM electronic structure package is presented.


Input: The Q-CHEM implementation interfaces EFP with standard quantum mechanical (QM) methods such as Hartree-Fock, density functional theory, perturbation theory, and coupled-cluster methods, as well as with methods for electronically excited and open-shell species, for example, configuration interaction, time-dependent density functional theory, and equation-of-motion coupled-cluster models.


Input: In addition to the QM/EFP functionality, a " fragment-only " feature is also available (when the system is described by effective fragments only).


Input: To aid further developments of the EFP methodology, a detailed description of the C + + classes and EFP module' s workflow is presented.


Input: The EFP input structure and EFP job options are described.


Input: To assist setting up and performing EFP calculations, a collection of Perl service scripts is provided.


Input: The precomputed EFP parameters for standard fragments such as common solvents are stored in Q-CHEM' s auxiliary library; they can be easily invoked, similar to specifying standard basis sets.


Input: The instructions for generating user-defined EFP parameters are given.


Input: Fragments positions can be specified by their center of mass coordinates and Euler angles.


Input: The interface with the IQMOL and WEBMO software is also described.


Input: (c) 2013 Wiley Periodicals, Inc.


Input: Strategic applications of gene expression: from drug discovery/development to bedside.


Input: Gene expression is useful for identifying the molecular signature of a disease and for correlating a pharmacodynamic marker with the dose-dependent cellular responses to exposure of a drug.


Input: Gene expression offers utility to guide drug discovery by illustrating engagement of the desired cellular pathways/networks, as well as avoidance of acting on the toxicological pathways.


Input: Successful employment of gene-expression signatures in the later stages of drug development depends on their linkage to clinically meaningful phenotypic characteristics and requires a biologically meaningful mechanism combined with a stringent statistical rigor.


Input: Much of the success in clinical drug development is hinged on predefining the signature genes for their fitness for purposes of application.


Input: Specific examples are highlighted to illustrate the breadth and depth of the potential utility of gene-expression signatures in drug discovery and clinical development to targeted therapeutics at the bedside.


Input: ICA-105574 interacts with a common binding site to elicit opposite effects on inactivation gating of EAG and ERG potassium channels.

potassium


Input: Rapid and voltage-dependent inactivation greatly attenuates outward currents in ether-a-go-go-related gene (ERG) K (+) channels.

ether

K (+)


Input: In contrast, inactivation of related ether-a-go-go (EAG) K (+) channels is very slow and minimally reduces outward currents.

ether

K (+)


Input: ICA-105574 (ICA, or 3-nitro-N-[4-phenoxyphenyl]-benzamide) has opposite effects on inactivation of these two channel types.

ICA


Input: Although ICA greatly attenuates ERG inactivation by shifting its voltage dependence to more positive potentials, it enhances the rate and extent of EAG inactivation without altering its voltage dependence.

ICA


Input: Here, we investigate whether the inverse functional response to ICA in EAG and ERG channels is related to differences in ICA binding site or to intrinsic mechanisms of inactivation.

ICA

ICA


Input: Molecular modeling coupled with site-directed mutagenesis suggests that ICA binds in a channel-specific orientation to a hydrophobic pocket bounded by the S5/pore helix/S6 of one subunit and S6 of an adjacent subunit.

ICA


Input: ICA is a mixed agonist of mutant EAG and EAG/ERG chimera channels that inactivate by a combination of slow and fast mechanisms.

ICA


Input: With the exception of three residues, the specific amino acids that form the putative binding pocket for ICA in ERG are conserved in EAG.

amino acids

ICA


Input: Mutations introduced into EAG to replicate the ICA binding site in ERG did not alter the functional response to ICA.

ICA

ICA


Input: Together these findings suggest that ICA binds to the same site in EAG and ERG channels to elicit opposite functional effects.

ICA


Input: The resultant agonist or antagonist activity is determined solely by channel-specific differences in the mechanisms of inactivation gating.


Input: The pharmacology of L-DOPA-induced dyskinesia in Parkinson' s disease.

L-DOPA


Input: L-3, 4-Dihydroxyphenylalanine (L-DOPA) remains the most effective symptomatic treatment of Parkinson' s disease (PD).

L-3, 4-Dihydroxyphenylalanine

L-DOPA


Input: However, long-term administration of L-DOPA is marred by the emergence of abnormal involuntary movements, i. e., L-DOPA-induced dyskinesia (LID).

L-DOPA

L-DOPA


Input: Years of intensive research have yielded significant progress in the quest to elucidate the mechanisms leading to the development and expression of dyskinesia and maintenance of the dyskinetic state, but the search for a complete understanding is still ongoing.


Input: Herein, we summarize the current knowledge of the pharmacology of LID in PD.


Input: Specifically, we review evidence gathered from postmortem and pharmacological studies, both preclinical and clinical, and discuss the involvement of dopaminergic and nondopaminergic systems, including glutamatergic, opioid, serotonergic, gamma-aminobutyric acid (GABA)-ergic, adenosine, cannabinoid, adrenergic, histaminergic, and cholinergic systems.

gamma-aminobutyric acid

GABA

adenosine


Input: Moreover, we discuss changes occurring in transcription factors, intracellular signaling, and gene expression in the dyskinetic phenotype.


Input: Inasmuch as a multitude of neurotransmitters and receptors play a role in the etiology of dyskinesia, we propose that to optimally alleviate this motor complication, it may be necessary to develop combined treatment approaches that will target simultaneously more than one neurotransmitter system.


Input: This could be achieved via three ways as follows: 1) by developing compounds that will interact simultaneously to a multitude of receptors with the required agonist/antagonist effect at each target, 2) by targeting intracellular signaling cascades where the signals mediated by multiple receptors converge, and/or 3) to regulate gene expression in a manner that has effects on signaling by multiple pathways.


Input: It is the outside that counts: chemical and physical control of dynamic surfaces.


Input: Materials capable of dynamically controlling surface chemistry and topography are highly desirable.


Input: We have designed a system that is uniquely able to remotely control the presented functionality and geometry at a given time by using a functionalizable shape memory material.


Input: This was accomplished by incorporating controlled amounts of an azide-containing monomer into a shape memory polymeric material.

azide


Input: These materials are capable of physically changing surface geometry over a broad range of length scales from > 1 mm to 100 nm.


Input: Using copper-assisted click chemistry, they can be functionalized with a variety of molecules to yield different surfaces.

copper


Input: Combining these features gave materials that can change both the presented geometry and functionality at tunable transition temperatures.


Input: Development of a novel bioerodible dexamethasone implant for uveitis and postoperative cataract inflammation.

dexamethasone


Input: Delivery of anti-inflammatory steroids concurrently to both anterior and posterior segments of the eye is a challenge.

steroids


Input: The anterior ocular structures limit topical delivery.


Input: Injection can be disproportionately and repeatedly invasive and selective for only one ocular hemisphere.


Input: We developed a novel implant that can compensate for the limited conveyance of topical medicine and reduce the repetitive invasiveness of injection from the capsular bag allowing dexamethasone (DXM) delivery to both the anterior and posterior chambers.

dexamethasone

DXM


Input: To establish proof of concept, microparticles were prepared with PLGA [poly (d, l-lactide-co-glycolide), 50: 50, MW. 7000-17000], hydroxypropyl methyl cellulose (HPMC), and DXM by oil-in-water emulsion/solvent evaporation technique.

PLGA

poly (d, l-lactide-co-glycolide)

hydroxypropyl methyl

DXM


Input: Zeatsizer Nano and SEM (scanning electron microscopy) results showed microspheres in the range of 8 +/- 1 micro m.


Input: The target load of DXM in the microparticles was ~ 20. 0% with a% recovery of 99. 9% (w/w).

DXM


Input: Dose related pharmacokinetics with near zero order kinetics was observed for up to 6 weeks in rabbits with intracapsular bag implants.


Input: DXM flow was bidirectional from the endocapsular space and significant concentrations were found in the anterior and posterior chambers after up to 6 weeks.

DXM


Input: Whereas, with topical drops the exposure was minimal in all the ocular tissues with greater systemic exposure.


Input: Intraocular pressure was normal in all of the study groups; slit lamp biomicroscopy examinations revealed that no cells or fibrin formation in the anterior and posterior chamber with implants but flare, cells and fibrin was present in the topical drops group.


Input: Histological examination revealed normal tissues and no signs of inflammation in all the groups.


Input: The implant did not migrate to the center of the eye or obstruct the visual axis.


Input: We believe these findings demonstrate the feasibility of drug delivery from the capsular bag to the anterior and posterior segments effectively compared to topical alternatives.


Input: Meta-analysis of telomere length in 19 713 subjects reveals high heritability, stronger maternal inheritance and a paternal age effect.


Input: Telomere length (TL) has been associated with aging and mortality, but individual differences are also influenced by genetic factors, with previous studies reporting heritability estimates ranging from 34 to 82%.


Input: Here we investigate the heritability, mode of inheritance and the influence of parental age at birth on TL in six large, independent cohort studies with a total of 19 713 participants.


Input: The meta-analysis estimate of TL heritability was 0. 70 (95% CI 0. 64-0. 76) and is based on a pattern of results that is highly similar for twins and other family members.


Input: We observed a stronger mother-offspring (r = 0. 42; P-value = 3. 60 x 10 (-61)) than father-offspring correlation (r = 0. 33; P-value = 7. 01 x 10 (-5)), and a significant positive association with paternal age at offspring birth (beta = 0. 005; P-value = 7. 01 x 10 (-5)).


Input: Interestingly, a significant and quite substantial correlation in TL between spouses (r = 0. 25; P-value = 2. 82 x 10 (-30)) was seen, which appeared stronger in older spouse pairs (mean age >= 55 years; r = 0. 31; P-value = 4. 27 x 10 (-23)) than in younger pairs (mean age < 55 years; r = 0. 20; P-value = 3. 24 x 10 (-10)).


Input: In summary, we find a high and very consistent heritability estimate for TL, evidence for a maternal inheritance component and a positive association with paternal age. European Journal of Human Genetics advance online publication, 16 January 2013; doi: 10. 1038/ejhg. 2012. 303.


Input: Caffeine has greater potency and efficacy than theophylline to reverse the motor impairment caused by chronic but not acute interruption of striatal dopaminergic transmission in rats.

Caffeine

theophylline


Input: In order to assess whether caffeine and theophylline have the same potency and efficacy to reverse the impairment of motor function caused by acute or chronic interruption of striatal dopamine transmission, a comparison of their dose-response relationship was made in the acute model of haloperidol-induced catalepsy, and the chronic model of unilateral lesion of the dopamine nigrostriatal pathway with 6-hydroxydopamine.

caffeine

theophylline

dopamine

haloperidol

dopamine


Input: At equimolar doses, both drugs reduced catalepsy intensity and increased its onset latency in a dose-dependent fashion, showing comparable potencies and attaining the maximal effect at similar doses.


Input: Catalepsy intensity: caffeine ED50 = 24. 1 mu mol/kg [95% CI, 18. 4-31. 5]; theophylline ED50 = 22. 0 mu mol/kg [95% CI, 17. 0-28. 4].

caffeine

theophylline


Input: Catalepsy latency: caffeine ED50 = 27. 0 mu mol/kg [95% CI, 21. 1-34. 6]; theophylline ED50 = 28. 8 mu mol/kg [95% CI, 22. 5-36. 7].

caffeine

theophylline


Input: In one group of hemiparkinsonian rats (n = 5), caffeine caused a dose-dependent recovery of the contralateral forepaw stepping: ED50 = 2. 4 mu mol/kg/day [95% CI, 1. 9-3. 1]), reaching its maximum at the dose of 5. 15 mu mol/kg/day.

caffeine


Input: When the treatment of these same rats was switched to 5. 15 mu mol/kg/day of theophylline, the stepping recovery was only 51 +/- 12% of that induced by caffeine.

theophylline

caffeine


Input: Assessing the dose-response relationship of theophylline in another group of hemiparkinsonian rats (n = 7) revealed that it caused stepping recovery in an all-or-none fashion.

theophylline


Input: Thus, the three lower doses had no effect, but at the dose of 5. 15 mu mol/kg/day theophylline suddenly increased the stepping to 56 +/- 5% of the maximal effect observed when the treatment of these same rats was switched to an equimolar dose of caffeine.

theophylline

caffeine


Input: Increasing the dose of theophylline up to 15. 45 mu mol/kg/day caused no further stepping improvement since it was only 41 +/- 6% of the maximal effect produced by caffeine at the dose of 5. 15 mu mol/kg/day.

theophylline

caffeine


Input: Given that theophylline showed less potency and efficacy than caffeine to reverse the motor impairment caused by chronic, but not acute, interruption of striatal dopaminergic transmission in rats, it is suggested that caffeine would provide more benefits than theophylline to improve the motor function in patients with Parkinson' s disease.

theophylline

caffeine

caffeine

theophylline


Input: Arsenic present in the soil-vine-wine chain in vineyards situated in an old mining area in Trentino, Italy.

Arsenic


Input: The present study follows arsenic (As) transfer through the chain of soil-vine-leaves-grapes-wine to assess the possible risk of arsenic intake related to consuming grapes and wines produced in 10 vineyards located in a mining area rich in this element.

arsenic

As

arsenic


Input: The results are compared with date from 18 uncontaminated areas.


Input: In the soil, the content of As extracted with acqua regia and that extracted with ammonium acetate, were analyzed.

As

ammonium acetate


Input: Leaves and berries were analyzed after washing with acidified aqueous solution and acid mineralization in a closed vessel, whereas wines were simply diluted before analysis.


Input: All analyses were performed using an inductively coupled plasma mass-spectrometer.


Input: The aqua regia extractable As concentration in soil ranged from 3. 7 to 283 mg/kg, whereas available As varied from 18 to 639 micro g/kg, and As total concentration ranged from 16. 3 to 579 micro g/kg dry weight in leaves and from < 0. 1 to 36. 8 micro g/kg dry weight in grapes.

As

As

As


Input: Arsenic levels in wines were always below 1. 62 micro g/L, with higher concentration in red wines than in white wines.

Arsenic


Input: Significant and positive correlations between the As concentrations in soils, leaves, and berries are highlighted, with the samples collected near the mining area having significantly higher values.

As


Input: Nevertheless, As levels in wines were always well below the limit (200 micro g/L) suggested by the International Organization of Vine and Wine.

As


Input: Reduced Blood Leukocyte and Neutrophil Numbers in the Pathogenesis of Type 1 Diabetes.


Input: Very little is known about the role of the innate immune system in the course of human type 1 diabetes.


Input: Here we investigated neutrophil numbers along with other leukocyte populations in patients at diagnosis of type 1 diabetes and during prediabetes.


Input: Complete and differential blood counts were analyzed from 107 adult patients with newly diagnosed type 1 diabetes, 21 children with persistent islet autoantibodies and a family history of type 1 diabetes, and 1 238 age and gender matched control subjects, all individuals without any signs of acute infection. Adult patients with newly diagnosed type 1 diabetes had significantly lower total WBC (p < 1 x 10-6), neutrophil (p < 1 x 10-6), basophil (p < 1 x 10-6), monocyte (p = 4 x 10-6) and lymphocyte (p < 1 x 10-6) counts compared to control subjects.


Input: Erythrocyte, eosinophil and platelet counts did not differ between groups.


Input: Similarly, children with persistent islet autoantibodies had decreased WBC (p = 0. 001), neutrophils (p = 0. 003), and lymphocytes (p = 0. 006) in comparison to control children.


Input: Our findings demonstrate a perturbation of leukocyte homeostasis at and prior to onset of type 1 diabetes suggesting a general involvement of the innate immune system in the pathogenesis of type 1 diabetes.


Input: A genome-wide siRNA screen reveals positive and negative regulators of the NOD2 and NF-kappa B signaling pathways.


Input: The cytoplasmic receptor NOD2 (nucleotide-binding oligomerization domain 2) senses peptidoglycan fragments and triggers host defense pathways, including activation of nuclear factor kappa B (NF-kappa B) signaling, which lead to inflammatory immune responses.

nucleotide


Input: Dysregulation of NOD2 signaling is associated with inflammatory diseases, such as Crohn' s disease and Blau syndrome.


Input: We used a genome-wide small interfering RNA screen to identify regulators of the NOD2 signaling pathway.


Input: Several genes associated with Crohn' s disease risk were identified in the screen.


Input: A comparison of candidates from this screen with other " omics " data sets revealed interconnected networks of genes implicated in NF-kappa B signaling, thus supporting a role for NOD2 and NF-kappa B pathways in the pathogenesis of Crohn' s disease.


Input: Many of these regulators were validated in secondary assays, such as measurement of interleukin-8 secretion, which is partially dependent on NF-kappa B.


Input: Knockdown of putative regulators in human embryonic kidney 293 cells followed by stimulation with tumor necrosis factor-alpha revealed that most of the genes identified were general regulators of NF-kappa B signaling.


Input: Overall, the genes identified here provide a resource to facilitate the elucidation of the molecular mechanisms that regulate NOD2-and NF-kappa B-mediated inflammation.


Input: Cloning and functional characterization of the pig (Sus scrofa) organic anion transporting polypeptide 1a2.


Input: Abstract 1.


Input: Organic anion transporting polypeptides (OATPs) are a family of transporter proteins that have been extensively recognized as key determinants of absorption, distribution, metabolism and excretion of various drugs.


Input: Human OATP1A2 has been demonstrated to transport wide spectrum of endogenous and exogenous compounds.


Input: Study on OATP1A2 orthologues of other species, however, is still limited.


Input: Here, we described the cloning and functional characterization of a member of the OATP/Oatp family member obtained from pig (Sus scrofa) liver.


Input: Sequence analysis suggested that it has a high homology with human OATP1A2 and bovine Oatp1a2.


Input: Prototypic substrates estrone-3-sulfate (E-3-S) and taurocholic acid were transported by the protein.

taurocholic acid


Input: The transport of these two substrates is pH-dependent, with lower pH showing higher uptake function.


Input: Kinetic study showed the transport of these two substrates have a K (m) of 42. 5 +/- 12. 1 and 33. 1 +/- 8. 7 micro M, respectively.


Input: Pig Slco1a2 has the highest expression level in the liver, and to a less extend in the brain and small intestine.


Input: In conclusion, an OATP member was cloned from pig liver.


Input: Sequence analysis and phylogenic study revealed it as an orthologue of human OATP1A2.


Input: Its kinetic characteristic for prototypic substrates and organ distribution are similar with that of OATP1A2.


Input: Folic acid modified cationic gamma-cyclodextrin-oligoethylenimine star polymer with bioreducible disulfide linker for efficient targeted gene delivery.

Folic acid

gamma-cyclodextrin

oligoethylenimine

disulfide


Input: For an efficient folate-targeted delivery, while the interaction between the folate on the carriers and the folate receptor (FR) on the cells is necessary, the recovering and recycling of FR to maintain a high density level of FR on the cellular membrane is also important.

folate

folate

folate


Input: Herein, we demonstrate a design and synthesis of a new star-shaped cationic polymer containing a gamma-cyclodextrin (gamma-CD) core and multiple oligoethylenimine (OEI) arms with folic acid (FA) linked by a bioreducible disulfide bond for efficient targeted gene delivery.

gamma-cyclodextrin

gamma-CD

oligoethylenimine

OEI

folic acid

disulfide


Input: The newly synthesized cationic polymer, named gamma-CD-OEI-SS-FA, could be cleaved efficiently, and FA was readily released under reductive condition similar to intracellular environment.

gamma-CD-OEI-SS-FA


Input: The gamma-CD-OEI-SS-FA polymer was well-characterized and studied in terms of its gene delivery properties in FR-positive KB cells and FR-negative A549 cells under various conditions, in comparison with cationic polymers such as high molecular weight branched polyethylenimine (PEI), gamma-CD-OEI star-shaped cationic polymer, gamma-CD-OEI-FA polymer where FA was directed linked to the star polymer without disulfide linker.

gamma-CD-OEI-SS-FA

polyethylenimine

PEI

gamma-CD-OEI

gamma-CD-OEI-FA

disulfide


Input: Our data have demonstrated that the new gamma-CD-OEI-SS-FA gene carrier had low cytotoxicity and possessed capacity to target and deliver DNA to specific tumor cells that overexpress FRs, as well as functions to recover and recycle FRs onto cellular membranes to facilitate continuous FR-mediated endocytosis to achieve very high levels of gene expression.

gamma-CD-OEI-SS-FA


Input: This study has expanded the strategy of FA-targeted delivery by combining the smart FR-recycling function to achieve the significant enhancement of gene expression.


Input: The new FA-targeted and bioreducible carrier may be a promising efficient gene delivery system for potential cancer gene therapy.


Input: Diterpenoid alkaloids from Aconitum kirinense.

Diterpenoid alkaloids


Input: A new C (18)-diterpenoid alkaloid, kirinenine A (1), was isolated from the root of Aconitum kirinense, along with eight known diterpenoid alkaloids.

C (18)-diterpenoid alkaloid

kirinenine A

diterpenoid alkaloids


Input: The structures of all compounds were characterized on the basis of extensive NMR and MS analyses and by comparison with literature values, and the new one was further confirmed by X-ray crystallographic diffraction.


Input: All the compounds were isolated from the title plant for the first time.


Input: A new compound from liquid fermentation broth of Armillaria mellea and the determination of its absolute configuration.


Input: A new 2, 5-diketopiperazine, (R)-2-(2-(furan-2-yl)-oxoethyl)-octahydropyrrolo [1, 2-a] pyrazine-1, 4-dione, and seven known compounds were isolated from the ethyl acetate extract of liquid fermentation broth of Armillaria mellea.

2, 5-diketopiperazine

(R)-2-(2-(furan-2-yl)-oxoethyl)-octahydropyrrolo [1, 2-a] pyrazine-1, 4-dione

ethyl acetate


Input: The structures of the isolated compounds were established from NMR and HR-MS data.


Input: The absolute configuration of the new compound was established by comparing the experimental electronic circular dichroism (ECD) spectrum with the calculated ECD data.


Input: Dissecting single-molecule signal transduction in carbon nanotube circuits with protein engineering.

carbon


Input: Single-molecule experimental methods have provided new insights into biomolecular function, dynamic disorder, and transient states that are all invisible to conventional measurements.


Input: A novel, nonfluorescent single-molecule technique involves attaching single molecules to single-walled carbon nanotube field-effective transistors (SWNT FETs).

carbon


Input: These ultrasensitive electronic devices provide long-duration, label-free monitoring of biomolecules and their dynamic motions.


Input: However, generalization of the SWNT FET technique first requires design rules that can predict the success and applicability of these devices.


Input: Here, we report on the transduction mechanism linking enzymatic processivity to electrical signal generation by a SWNT FET.


Input: The interaction between SWNT FETs and the enzyme lysozyme was systematically dissected using eight different lysozyme variants synthesized by protein engineering.


Input: The data prove that effective signal generation can be accomplished using a single charged amino acid, when appropriately located, providing a foundation to widely apply SWNT FET sensitivity to other biomolecular systems.

amino acid


Input: A new di-O-prenylated flavone from an actinomycete Streptomyces sp.

di-O-prenylated flavone


Input: A new di-O-prenylated flavone, named 7, 3'-di-(gamma, gamma-dimethylallyloxy)-5-hydroxy-4'-methoxyflavone (1), was isolated from the culture broth of the endophytic actinomycete Streptomyces sp.

di-O-prenylated flavone

7, 3'-di-(gamma, gamma-dimethylallyloxy)-5-hydroxy-4'-methoxyflavone


Input: MA-12 isolated from the root of the semi-mangrove plant Myoporum bontioides A.


Input: Gray.


Input: The structure of 1 was determined by comprehensive spectroscopic methods, including 1D and 2D NMR experiments (COSY, HMQC, and HMBC).


Input: Primary bioassays showed that 1 at concentration of 0. 25 mM had moderate inhibitory activity against three plant pathogenic fungi including Colletotrichum musae, Gibberella zeae (Schweinitz) Petch, and Penicillium citrinum Thom.


Input: New tetraterpene glycosides from the fruits of Lycium chinense.

tetraterpene glycosides


Input: Two new compounds lyciumtetraterpenic hexaarabinoside (1) and tetraterpenyl hexaarabinoside (2), along with two known compounds, were isolated from the methanol extract of the fruits of Lycium chinense Miller (Solanaceae), and their structures have been elucidated as 6-(1, 1, 5-trimethyl-5 alpha-hydroxycyclohexanyl)-6'-(1', 1', 5'-trimethyl-2' beta-hydroxycyclohexanyl)-9, 13, 9', 13'-tetramethyloctadec-7, 9, 11, 13, 15, 7', 9', 11', 13'-nonene-5 alpha-D-arabinopyranosyl (2a --> 1b)-beta-D-arabinopyranosyl-(2b --> 1c)-beta-D-arabinopyranosyl-2'-beta-D-arabinopyranosyl-(2d --> 1e)-alpha-D-arabinopyranosyl-(2e --> 1f)-alpha-D-arabinopyranoside (1) and 1 (6), 11 (12), 13 (14), 1' (6'), 11' (12'), 13' (14')-dodecahydro-beta-caroten-4 beta, 4' beta-diol-4 beta-L-arabinopyranosyl-(2a --> 1b)-beta-L-arabinopyranosyl-(2b --> 1c)-beta-D-arabinopyranosido-4' beta-L-arabinopyranosyl-(2d --> 1e)-beta-L-arabinopyranosyl-(2e --> 1f)-beta-D-arabinopyranoside (2) on the basis of spectral data analysis and chemical reactions.

lyciumtetraterpenic hexaarabinoside

tetraterpenyl hexaarabinoside

methanol

6-(1, 1, 5-trimethyl-5 alpha-hydroxycyclohexanyl)-6'-(1', 1', 5'-trimethyl-2' beta-hydroxycyclohexanyl)-9, 13, 9', 13'-tetramethyloctadec-7, 9, 11, 13, 15, 7', 9', 11', 13'-nonene-5 alpha-D-arabinopyranosyl (2a --> 1b)-beta-D-arabinopyranosyl-(2b --> 1c)-beta-D-arabinopyranosyl-2'-beta-D-arabinopyranosyl-(2d --> 1e)-alpha-D-arabinopyranosyl-(2e --> 1f)-alpha-D-arabinopyranoside

1 (6), 11 (12), 13 (14), 1' (6'), 11' (12'), 13' (14')-dodecahydro-beta-caroten-4 beta, 4' beta-diol-4 beta-L-arabinopyranosyl-(2a --> 1b)-beta-L-arabinopyranosyl-(2b --> 1c)-beta-D-arabinopyranosido-4' beta-L-arabinopyranosyl-(2d --> 1e)-beta-L-arabinopyranosyl-(2e --> 1f)-beta-D-arabinopyranoside


Input: Evolution of novel tricyclic CRTh2 receptor antagonists from a (E)-2-cyano-3-(1H-indol-3-yl) acrylamide scaffold.

(E)-2-cyano-3-(1H-indol-3-yl) acrylamide


Input: (E)-2-(3-(3-((3-Bromophenyl) amino)-2-cyano-3-oxoprop-1-en-1-yl)-1H-indol-1-yl) acetic acid (1) was discovered in a HTS campaign for CRTh2 receptor antagonists.

(E)-2-(3-(3-((3-Bromophenyl) amino)-2-cyano-3-oxoprop-1-en-1-yl)-1H-indol-1-yl) acetic acid


Input: An SAR around this hit could be established and representatives with interesting activity profiles were obtained.


Input: Ring closing tactics to convert this hit series into a novel 2, 3, 4, 5-tetrahydro-1H-pyrido [4, 3-b] indole based CRTh2 receptor antagonist series is presented.

2, 3, 4, 5-tetrahydro-1H-pyrido [4, 3-b] indole


Input: Genetic association study of WNT10B polymorphisms with BMD and adiposity parameters in Danish and Belgian males.


Input: Because of the importance of the Wnt pathway in the development and maintenance of both adipose and bone tissue, we wanted to evaluate the involvement of WNT10B, a Wnt pathway activator, in adipogenesis and osteoblastogenesis in humans.


Input: Genetic association between WNT10B polymorphisms and adiposity parameters as well as bone mineral density (BMD) measurements was analysed in two independent populations.


Input: The first is a population of 1, 228 Danish men (702 aged 20-29 years; 532 aged 60-74 years) from the Odense Androgen Study (OAS), which was designed as a cross-sectional, population-based study.

Androgen


Input: The second population, called SIBLOS, includes 922 Belgian men (34 +/- 5 years old) and contains siblings selected from over 500 families.


Input: Four tagSNPs (rs833840, rs833841, rs10875902 and rs4018511) that capture variation of ten SNPs (MAF > 5%) in a 15. 2 kb region spanning the WNT10B gene and its flanking regions were genotyped.


Input: Although no association with body mass index was found, we found all tagSNPs to be associated with BMD parameters (BMD whole body, total hip and femoral neck) and height in the OAS population.


Input: The association of rs10875902 was most prominent (nominal p = 0. 012) and confirmed a previously shown negative effect on BMD.


Input: No significant associations were observed in the SIBLOS population.


Input: In the present study, no association between WNT10B polymorphisms and adiposity parameters was found.


Input: However, our results clearly illustrate a role for WNT10B variants in determining human BMD.


Input: The effect of WNT10B polymorphisms on height should be evaluated in additional populations.


Input: The 5-HT1D/1B receptor agonist sumatriptan enhances fear of simulated speaking and reduces plasma levels of prolactin.

sumatriptan


Input: This study measured the effects of the preferential 5-HT1D/1B receptor agonist sumatriptan in healthy volunteers who performed the Simulated Public Speaking Test (SPST), which recruits the neural network involved in panic disorder and social anxiety disorder.

sumatriptan


Input: In a double-blind, randomised experiment, 36 males received placebo (12), 50 mg (12) or 100 mg (12) of sumatriptan 2 h before the SPST.

sumatriptan


Input: Subjective, physiological and hormonal measures were taken before, during and after the test.


Input: The dose of 100 mg of sumatriptan increased speech-induced fear more than either a 50mg dose of the drug or placebo.

sumatriptan


Input: The largest dose of sumatriptan also enhanced vigilance more than placebo, without any change in blood pressure, heart rate or electrical skin conductance.

sumatriptan


Input: Sumatriptan decreased plasma levels of prolactin.

Sumatriptan


Input: A significant but moderate increase in plasma cortisol after SPST occurred, independent of treatment.

cortisol


Input: Because sumatriptan decreases 5-HT release into the extracellular space, the potentiation of SPST-induced fear caused by the drug supports the hypothesis that 5-HT attenuates this emotional state.

sumatriptan


Input: As acute administration of antidepressants has also been shown to enhance speaking fear and increase plasma prolactin, in contrast to sumatriptan, the 5-HT regulation of stress-hormone release is likely to be different from that of emotion.

sumatriptan


Input: Increases in triglyceride levels are associated with clinical response to clozapine treatment.

triglyceride

clozapine


Input: Increases in serum triglyceride (TG) levels are associated with clinical response to clozapine treatment.

triglyceride

clozapine


Input: Clozapine is the most efficacious therapy for treatment of refractory schizophrenia, although its use is well recognised to be associated with substantial metabolic dysfunction.

Clozapine


Input: Interestingly, there is some evidence that the therapeutic benefit of clozapine is associated with treatment-emergent weight gain and dyslipidaemia, specifically hypertriglyceridaemia.

clozapine


Input: In this prospective observational study, we examine associations between therapeutic response to clozapine in 49 patients with treatment-resistant schizophrenia and lipid dysregulation.

clozapine


Input: An increase in TG levels was strongly predictive of clinical improvement (B = 9. 33, t = 3. 56, df = 4, p < 0. 001) and of improvement in positive PANSS scores (B = 2. 85, t = 3. 61, df = 4, p = 0. 001) as well as negative PANSS scores (B = 1. 93, t = 2. 36, df = 4, p = 0. 02), when controlling for potential confounds of weight gain, change in waist circumference, baseline antipsychotic polypharmacy and serum clozapine levels.

clozapine


Input: This finding suggests that clozapine' s therapeutic efficacy is linked to serum lipid changes.

clozapine


Input: Hypertriglyceridaemia as a predictor of clinical response in patients treated with clozapine merits further investigation in order to better elucidate its effect on the pharmacological activity of clozapine.

clozapine

clozapine


Input: Design and synthesis of some new quinazolin-4-(3H)-ones as anticonvulsant and antidepressant agents.


Input: A series of 3-[(4-substituted-benzylidene)-amino]-2-phenyl-3H-quinazolin-4-ones (5a-k) were synthesized by reacting 3-amino-2-phenyl-1H-quinazolin-4-one with p-hydroxybenzaldehyde, and then further with various alkyl/benzyl halides or substituted phenacyl bromides.

3-[(4-substituted-benzylidene)-amino]-2-phenyl-3H-quinazolin-4-ones

p-hydroxybenzaldehyde

alkyl/benzyl halides

phenacyl bromides


Input: The structures of the compounds were confirmed on the basis of IR, NMR, MS and elemental analysis.


Input: Anticonvulsant activities were evaluated using the MES and scPTZ tests.


Input: Some of the selected compounds were evaluated for antidepressant activity by forced swim pool test.


Input: Compound 3-[(4-butoxy-benzylidene)-amino]-2-phenyl-3H-quinazolin-4-one was emerged as the most promising anticonvulsant agent without any motor impairment effect.

3-[(4-butoxy-benzylidene)-amino]-2-phenyl-3H-quinazolin-4-one


Input: The whole brain GABA estimation of brain homogenate indicated that the anticonvulsant activity of above mentioned quinazolinone derivatives might be due to an increased GABA concentration.

GABA

quinazolinone

GABA


Input: An autonomous chromatin/DNA-PK mechanism for localized DNA damage signaling in mammalian cells.


Input: Rapid phosphorylation of histone variant H2AX proximal to DNA breaks is an initiating event and a hallmark of eukaryotic DNA damage responses.


Input: Three mammalian kinases are known to phosphorylate H2AX in response to DNA damage.


Input: However, the mechanism (s) for damage-localized phosphorylation remains incompletely understood.


Input: The DNA-dependent protein kinase (DNA-PK) is the most abundant H2AX-modifying kinases and uniquely activated by binding DNA termini.


Input: Here, we have developed a novel approach to examine enzyme activity and substrate properties by executing biochemical assays on intact cellular structures.


Input: We apply this approach to examine the mechanisms of localized protein modification in chromatin within fixed cells.


Input: DNA-PK retains substrate specificity and independently generates break-localized gamma H2AX foci in chromatin.


Input: In situ DNA-PK activity recapitulates localization and intensity of in vivo H2AX phosphorylation and requires no active cellular processes.


Input: Nuclease treatments or addition of exogenous DNA resulted in genome-wide H2AX phosphorylation, showing that DNA termini dictated the locality of H2AX phosphorylation in situ.


Input: DNA-PK also reconstituted focal phosphorylation of structural maintenance of chromatin protein 1, but not activating transcription factor 2.


Input: Allosteric regulation of DNA-PK by DNA termini protruding from chromatin constitutes an autonomous mechanism for break-localized protein phosphorylation that generates sub-nuclear foci.


Input: We discuss generalized implications of this mechanism in localizing mammalian DNA damage responses.


Input: Use of a Routh-Russel deformation map to achieve film formation of a latex with a high glass transition temperature.


Input: In the film formation of latex, particle deformation can occur by processes of wet sintering, dry sintering, or capillary action.


Input: When latex films dry nonuniformly and when particles deform and coalesce while the film is still wet, a detrimental skin layer will develop at the film surface.


Input: In their process model, Routh and Russel proposed that the operative particle deformation mechanism can be determined by the values of control parameters on a deformation map.


Input: Here, the film formation processes of three methyl methacrylate/butyl acrylate copolymer latexes with high glass transition temperatures (T (g)), ranging from 45 to 64 degrees C, have been studied when heated by infrared radiation.

methyl methacrylate

butyl acrylate


Input: Adjusting the infrared (IR) power density enables the film temperature, polymer viscosity, and evaporation rate during latex film formation to be controlled precisely.


Input: Different polymer particle deformation mechanisms have been demonstrated for the same latex under a variety of film formation process conditions.


Input: When the temperature is too high, a skin layer develops.


Input: On the other hand, when the temperature is too low, particles deform by dry sintering, and the process requires extended time periods.


Input: The deduced mechanisms can be interpreted and explained by the Routh-Russel deformation maps.


Input: Film formation of hard (high T (g)) coatings is achieved without using coalescing aids that emit volatile organic compounds (VOCs), which is a significant technical achievement.


Input: Dynamic Domains in Polymersomes: Mixtures of Polyanionic and Neutral Diblocks Respond More Rapidly to Changes in Calcium than to pH.

Calcium


Input: Chemical triggering of membrane domain dynamics is of broad relevance to cell signaling through lipid bilayers and might also be exploited in application of phase-separated vesicles.


Input: Here we describe the morphodynamics and remixing kinetics of spotted polymersomes made with mixtures of polyanionic and neutral amphiphiles plus calcium.

calcium


Input: Addition of the calcium chelator EDTA to vesicle dispersions produced a decrease in domain size within minutes, whereas increasing the pH with NaOH led to the viscous fingering of domains and decreased domain size over hours.

calcium

EDTA

NaOH


Input: Although the latter suggests that the charge of the polyanion contributes to domain formation, the remixing of more negative chains at high pH is surprising.


Input: Domain roughening at high pH is also accelerated by EDTA, which highlights the dominance of cross-bridging.

EDTA


Input: Importantly, even though vesicles were perturbed only externally, the inner and outer leaflets remain coupled throughout, consistent with molecular dynamics simulations and suggestive of an order-disorder transition that underlies the remixing kinetics.


Input: Quasiclassical Trajectory Study of CH (3) NO (2) Decomposition via Roaming Mediated Isomerization Using a Global Potential Energy Surface.

CH (3) NO (2)


Input: We report a global potential energy surface (PES) for CH (3) NO (2) based on fitting roughly 114 000 density functional theory (UB3LYP/6-311 + g (d, p)) electronic energies.

CH (3) NO (2)


Input: The PES is a precise, permutationally invariant fit to these energies.


Input: Properties of the PES are described, as are some preliminary quasiclassical trajectory calculations.


Input: An isomerization-roaming pathway to the CH (3) ONO isomer and then to the CH (3) O + NO products is found.

CH (3) ONO

CH (3) O

NO


Input: Although the pathway occurs at larger distances than a related loose saddle-point on the PES, the pathway supports the supposition of such a pathway based on locating a loose first-order saddle point and associated IRC, reported previously by Zhu and Lin [Zhu, R. S. and Lin, M. C. Chem. Phys. Lett. 2009, 478, 11].


Input: Selective inhibition of extracellular thioredoxin by asymmetric disulfides.

disulfides


Input: Whereas the role of mammalian thioredoxin (Trx) as an intracellular protein cofactor is widely appreciated, its function in the extracellular environment is not well-understood.


Input: Only few extracellular targets of Trx-mediated thiol-disulfide exchange are known.

thiol-disulfide


Input: For example, Trx activates extracellular transglutaminase 2 (TG2) via reduction of an intramolecular disulfide bond.

disulfide


Input: Because hyperactive TG2 is thought to play a role in various diseases, understanding the biological role of extracellular Trx may provide critical insight into the pathogenesis of these disorders.


Input: Starting from a clinical-stage asymmetric disulfide lead, we have identified analogs with > 100-fold specificity for Trx.

disulfide


Input: Structure-activity relationship and computational docking model analyses have provided insights into the features important for enhancing potency and specificity.


Input: The most active compound identified had an IC (50) below 0. 1 mu M in cell culture and may be appropriate for in vivo use to interrogate the role of extracellular Trx in health and disease.


Input: Invasive lobular carcinoma stable for 4. 5 years in a postmenopausal woman user of hormone therapy for 25 years.


Input: We present a case of a 72-year-old woman referred to the breast disorder service due to abnormalities on mammography and breast ultrasound.


Input: The patient reported using different hormone therapy (HT) formulations during 25 years and had stopped taking HT for 4 years.


Input: Physical examination showed no alterations in the breasts or axilla.


Input: Mammography from 2012 detected asymmetry at the 3 o' clock position in the anterior right breast.


Input: Ultrasound revealed an irregular, hypoechoic mass with indistinct margins, and posterior acoustic shadowing.


Input: A retrospective analysis of mammographies from 2007, 2009 and 2010 showed that a very subtle asymmetry had existed since 2007.


Input: Follow-up imaging demonstrated no change in asymmetry during 4. 5 years.


Input: The patient underwent breast-conserving therapy and sentinel lymph node biopsy.


Input: Histopathologic examination demonstrated classic invasive lobular carcinoma.


Input: There were no sentinel node metastases.


Input: The patient received radiotherapy and endrocrine therapy.


Input: This case demonstrates that breast cancer may remain stable and not grow for many years.


Input: This aspect should be kept in mind by all professionals dealing with women' s healthcare, in particular HT users who may develop breast cancer with a less aggressive behavior.


Input: Any suspicious finding on mammography, despite being unchanged for a number of years, must be investigated.


Input: Dibenzocyclooctadiene lignans and norlignans from fruits of Schisandra wilsoniana.

Dibenzocyclooctadiene lignans

norlignans


Input: Seven new dibenzocyclooctadiene lignans, marlignans M-S (1-7), four new norlignans, marphenols C-F (8-11), and 21 known compounds (12-32) were isolated from the fruits of Schisandra wilsoniana.

dibenzocyclooctadiene lignans

marlignans M-S

norlignans

marphenols C-F


Input: The structures of 1-11 were elucidated by spectroscopic methods including 1D-and 2D-NMR techniques and CD experiments.


Input: Compounds 1-11 were evaluated for their anti-HIV activities and showed EC (50) values in the range 2. 97-6. 18 mu g/mL and therapeutic index values of 5. 33-29. 13.


Input: Acutely administered antipsychotic drugs are highly selective for dopamine D2 over D3 receptors.

dopamine


Input: We showed previously, using [(3) H]-(+)-4-propyl-9-hydroxynaphthoxazine ([(3) H]-(+)-PHNO) autoradiography, that several antipsychotic drugs do not occupy dopamine D3 receptors at clinically-relevant doses in rat.

[(3) H]-(+)-4-propyl-9-hydroxynaphthoxazine

[(3) H]-(+)-PHNO

dopamine


Input: This is an unexpected finding considering the near-equivalent in vitro affinity of these drugs for D2 and D3 receptors.


Input: The purpose of the current study was to address two possible methodological limitations of our previous report, namely that (1) [(3) H]-(+)-PHNO may have been administered at non-tracer dose, potentially causing underestimate of D3 receptor occupancy, and (2) antipsychotic drugs were administered chronically, potentially causing increased D3 receptor expression not accounted for in the vehicle-treated control group.

[(3) H]-(+)-PHNO


Input: We found that decreasing [(3) H]-(+)-PHNO dose from 5. 6nmol/kg (our previous dose) to 0. 6nmol/kg caused a > 60% increase in [(3) H]-(+)-PHNO binding to D3 receptors in cerebellar lobes 9 and 10, indicating that our previous study was indeed conducted under non-tracer dose conditions.

[(3) H]-(+)-PHNO

[(3) H]-(+)-PHNO


Input: However, neither reducing [(3) H]-(+)-PHNO dose further to 0. 3nmol/kg (a tracer dose), nor administering antipsychotics acutely affected antipsychotic receptor occupancy.

[(3) H]-(+)-PHNO


Input: At clinically-relevant levels of D2 occupancy (57-82% inhibition of striatal binding), neither olanzapine nor haloperidol occupied D3 receptors, while clozapine occupied D3 receptors at levels similar to our previous report (33%).

olanzapine

haloperidol

clozapine


Input: Risperidone moderately occupied D3 receptors (40%), but at a dose occupying > 90% of D2 receptors and therefore of questionable clinical relevance.

Risperidone


Input: These findings demonstrate that the lack of antipsychotic occupancy of D3 receptors is not attributable to limitations of our previous study.


Input: These results suggest that D3 receptor blockade is not necessary for the therapeutic effects of the antipsychotic drugs examined.


Input: Lifestyle and osteoporosis in middle-aged and elderly women: Chiba bone survey.


Input: Osteoporosis causes an enormous health and economic impact in Japan.


Input: We investigated the relation between lifestyle and bone fracture in middle-aged and elderly women.


Input: This was a population-based, multicenter, cross-sectional survey for postmenopausal osteoporosis in Chiba City, Japan (Chiba bone survey).


Input: This survey included 64, 809 Japanese women aged > 40 years.


Input: All participants underwent anthropometric measurements including bone mineral density (BMD) and completed a structured, nurse-assisted, self-administered questionnaire also including patient lifestyle.


Input: Bone fracture during the recent 5 years was observed in 5. 3%, and the fracture group had significantly higher age, BMI, and number of births, family histories of kyphosis and hip fracture, diabetes mellitus (DM), dyslipidemia, kidney disease, exercise, fall, and osteoporosis, and had significantly lower BMD and proportion of menstruating participants.


Input: Logistic regression analysis revealed that bone fracture was closely associated with not only low bone mass but also age, fall, family histories of kyphosis and hip fracture, DM, kidney disease, menopause, and lifestyle factors of dieting, exercise, and alcohol.

alcohol


Input: Women' s health care focusing on lifestyle-related fracture risks such as dieting, exercise, and alcohol appears necessary to prevent bone fracture in postmenopausal osteoporosis.

alcohol


Input: Transport by OATP1B1 and OATP1B3 enhances the cytotoxicity of epigallocatechin 3-O-gallate and several quercetin derivatives.

epigallocatechin 3-O-gallate

quercetin


Input: Organic anion transporting polypeptides (OATPs) 1B1 and 1B3 are transporters that are expressed selectively in human hepatocytes under normal conditions.


Input: OATP1B3 is also expressed in certain cancers.


Input: Flavonoids such as green tea catechins and quercetin glycosides have been shown to modulate the function of some OATPs.

Flavonoids

catechins

quercetin glycosides


Input: In the present study, the extent to which six substituted quercetin derivatives (1-6) affected the function of OATP1B1 and OATP1B3 was investigated.

quercetin


Input: Uptake of the radiolabeled model substrates estradiol 17 beta-glucuronide, estrone 3-sulfate, and dehydroepiandrosterone sulfate (DHEAS) was determined in the absence and presence of compounds 1-6 using Chinese hamster ovary (CHO) cells stably expressing either OATP1B1 or OATP1B3.

estradiol 17 beta-glucuronide

estrone 3-sulfate

dehydroepiandrosterone sulfate

DHEAS


Input: Several of compounds 1-6 inhibited OATP-mediated uptake of all three model substrates, suggesting that they could also be potential substrates.


Input: Compound 6 stimulated OATP1B3-mediated estradiol 17 beta-glucuronide uptake by increasing the apparent affinity of OATP1B3 for its substrate.

estradiol 17 beta-glucuronide


Input: Cytotoxicity assays demonstrated that epigallocatechin 3-O-gallate (EGCG) and most of compounds 1-6 killed preferentially OATP-expressing CHO cells.

epigallocatechin 3-O-gallate

EGCG


Input: EGCG, 1, and 3 were the most potent cytotoxic compounds, with EGCG and 3 selectively killing OATP1B3-expressing cells.

EGCG

EGCG


Input: Given that OATP1B3 is expressed in several cancers, EGCG and some of the quercetin derivatives studied might be promising lead compounds for the development of novel anticancer drugs.

EGCG

quercetin


Input: Labdane-type diterpenoids from the fruits of Vitex trifolia.

Labdane

diterpenoids


Input: Seven new labdane-type diterpenoids, vitextrifolins A-G (1-7), along with eight previously reported analogues, were isolated from the fruits of Vitex trifolia.

labdane

diterpenoids

vitextrifolins A-G


Input: The structures of 1-7 were elucidated by spectroscopic data interpretation.


Input: The isolates were evaluated for their cytotoxicity against four human cancer cell lines (A549, HCT116, HL-60, and ZR-75-30), but all were inactive (IC (50) < 5 mu g/mL).


Input: Injectable hyaluronic acid-tyramine hydrogels incorporating interferon-alpha 2a for liver cancer therapy.

tyramine


Input: We report an injectable hydrogel system that incorporates interferon-alpha 2a (IFN-alpha 2a) for liver cancer therapy.


Input: IFN-alpha 2a was incorporated in hydrogels composed of hyaluronic acid-tyramine (HA-Tyr) conjugates through the oxidative coupling of Tyr moieties with hydrogen peroxide (H2O2) and horseradish peroxidase (HRP).

tyramine

Tyr

Tyr

hydrogen peroxide


Input: IFN-alpha 2a-incorporated HA-Tyr hydrogels of varying stiffness were formed by changing the H2O2 concentration.

Tyr


Input: The incorporation of IFN-alpha 2a did not affect the rheological properties of the hydrogels.


Input: The activity of IFN-alpha 2a was furthermore well-maintained in the hydrogels with lower stiffness.


Input: Through the caspase-3/7 pathway in vitro, IFN-alpha 2a released from HA-Tyr hydrogels inhibited the proliferation of liver cancer cells and induced apoptosis.

Tyr


Input: In the study of the pharmacokinetics, a higher concentration of IFN-alpha 2a was shown in the plasma of mice treated with IFN-alpha 2a-incorporated hydrogels after 4h post injection, with a much higher amount of IFN-alpha 2a delivered at the tumor tissue comparing to that of injecting an IFN-alpha 2a solution.


Input: The tumor regression study revealed that IFN-alpha 2a-incorporated HA-Tyr hydrogels effectively inhibited tumor growth, while the injection of an IFN-alpha 2a solution did not demonstrate antitumor efficacy.

Tyr


Input: Histological studies confirmed that tumor tissues in mice treated with IFN-alpha 2a-incorporated HA-Tyr hydrogels showed lower cell density, with more apoptotic and less proliferating cells compared with tissues treated with an IFN-alpha 2a solution.

Tyr


Input: In addition, the IFN-alpha 2a-incorporated hydrogel treatment greatly inhibited the angiogenesis of tumor tissues.


Input: Nonalcoholic fatty liver disease: current issues and novel treatment approaches.


Input: Nonalcoholic fatty liver disease (NAFLD) is considered the most common liver disorder in the Western world.


Input: It is commonly associated with insulin resistance, obesity, dyslipidaemia, type 2 diabetes mellitus (T2DM) and cardiovascular disease.


Input: Nonalcoholic steatohepatitis (NASH) is characterized by steatosis with necroinflammation and eventual fibrosis, which can lead to end-stage liver disease and hepatocellular carcinoma.


Input: Its pathogenesis is complex, and involves a state of' lipotoxicity' in which insulin resistance, with increased free fatty acid release from adipose tissue to the liver, play a key role in the onset of a' lipotoxic liver disease' and its progression to NASH.

free fatty acid


Input: The diagnosis of NASH is challenging, as most affected patients are symptom free and the role of routine screening is not clearly established.


Input: A complete medical history is important to rule out other causes of fatty liver disease (alcohol abuse, medications, other).

alcohol


Input: Plasma aminotransferase levels and liver ultrasound are helpful in the diagnosis of NAFLD/NASH, but a liver biopsy is often required for a definitive diagnosis.


Input: However, there is an active search for plasma biomarkers and imaging techniques that may non-invasively aid in the diagnosis.


Input: The treatment of NASH requires a multifaceted approach.


Input: The goal is to reverse obesity-associated lipotoxicity and insulin resistance via lifestyle intervention.


Input: Although there is no pharmacological agent approved for the treatment of NAFLD, vitamin E (in patients without T2DM) and the thiazolidinedione pioglitazone (in patients with and without T2DM) have shown the most consistent results in randomized controlled trials.

vitamin E

pioglitazone


Input: This review concentrates on our current understanding of the disease, with a focus on the existing therapeutic approaches and potential future pharmacological developments for NAFLD and NASH.


Input: Ranolazine: a review of its use as add-on therapy in patients with chronic stable angina pectoris.

Ranolazine


Input: Extended-release ranolazine (ranolazine ER) [Ranexa ((R))] is an antianginal agent that achieves its effects via a novel mechanism of action (inhibition of the late phase of the inward sodium current), without affecting heart rate or blood pressure (BP).

Extended-release ranolazine

ranolazine ER

Ranexa

sodium


Input: This article reviews the efficacy, safety and tolerability of ranolazine ER as add-on therapy in patients with chronic stable angina pectoris, as well as summarizing its pharmacological properties and its use in non-ST-elevation acute coronary syndromes.

ranolazine ER


Input: In the CARISA and ERICA trials, add-on therapy with ranolazine ER improved exercise tolerance and/or reduced angina frequency and nitroglycerin use in patients with chronic stable angina; benefits were seen across a variety of patient subgroups.

ranolazine ER

nitroglycerin


Input: Although results of the MERLIN-TIMI 36 trial do not support the use of ranolazine ER in the acute management of non-ST-elevation acute coronary syndromes, they do support its use as an antianginal therapy.

ranolazine ER


Input: Ranolazine ER was generally well tolerated, with the most commonly reported adverse events including dizziness, nausea, asthenia and constipation.

Ranolazine ER


Input: Despite being associated with modest increases in the corrected QT interval, ranolazine ER demonstrated antiarrhythmic effects in the MERLIN-TIMI 36 trial.

ranolazine ER


Input: In conclusion, ranolazine ER provides an important option for use as add-on therapy to reduce symptoms in patients with chronic stable angina.

ranolazine ER


Input: Recognition of viral RNA stem-loops by the tandem double-stranded RNA binding domains of PKR.


Input: In humans, the double-stranded RNA (dsRNA)-activated protein kinase (PKR) is expressed in late stages of the innate immune response to viral infection by the interferon pathway.


Input: PKR consists of tandem dsRNA binding motifs (dsRBMs) connected via a flexible linker to a Ser/Thr kinase domain.

Ser

Thr


Input: Upon interaction with viral dsRNA, PKR is converted into a catalytically active enzyme capable of phosphorylating a number of target proteins that often results in host cell translational repression.


Input: A number of high-resolution structural studies involving individual dsRBMs from proteins other than PKR have highlighted the key features required for interaction with perfectly duplexed RNA substrates.


Input: However, viral dsRNA molecules are highly structured and often contain deviations from perfect A-form RNA helices.


Input: By use of small-angle X-ray scattering (SAXS), we present solution conformations of the tandem dsRBMs of PKR in complex with two imperfectly base-paired viral dsRNA stem-loops; HIV-1 TAR and adenovirus VA (I)-AS.


Input: Both individual components and complexes were purified by size exclusion chromatography and characterized by dynamic light scattering at multiple concentrations to ensure monodispersity.


Input: SAXS ab initio solution conformations of the individual components and RNA-protein complexes were determined and highlight the potential of PKR to interact with both stem and loop regions of the RNA.


Input: Excellent agreement between experimental and model-based hydrodynamic parameter determination heightens our confidence in the obtained models.


Input: Taken together, these data support and provide a framework for the existing biochemical data regarding the tolerance of imperfectly base-paired viral dsRNA by PKR.


Input: Nuclear receptors in bile acid metabolism.

bile acid


Input: Bile acids are signaling molecules that activate nuclear receptors, such as farnesoid X receptor, pregnane X receptor, constitutive androstane receptor, and vitamin D receptor, and play a critical role in the regulation of lipid, glucose, energy, and drug metabolism.

Bile acids

pregnane

androstane

vitamin D

glucose


Input: These xenobiotic/endobiotic-sensing nuclear receptors regulate phase I oxidation, phase II conjugation, and phase III transport in bile acid and drug metabolism in the digestive system.

bile acid


Input: Integration of bile acid metabolism with drug metabolism controls absorption, transport, and metabolism of nutrients and drugs to maintain metabolic homeostasis and also protects against liver injury, inflammation, and related metabolic diseases, such as nonalcoholic fatty liver disease, diabetes, and obesity.

bile acid


Input: Bile-acid-based drugs targeting nuclear receptors are in clinical trials for treating cholestatic liver diseases and fatty liver disease.

Bile-acid


Input: Bioanalytical assay strategies for the development of antibody-drug conjugate biotherapeutics.


Input: Antibody-drug conjugates (ADCs) are monoclonal antibodies with covalently bound cytotoxic drugs.


Input: They are designed to target tumor antigens selectively and offer the hope of cancer treatment without the debilitating side-effects of conventional therapies.


Input: The concept of ADCs is not new; however, development of these therapeutics is challenging and only recently are promising clinical data emerging.


Input: These challenges include ADC bioanalysis, such as quantifying in serum/plasma for PK studies and strategies for assessing immunogenicity.


Input: ADCs have complex molecular structures incorporating large-and small-molecule characteristics and require diverse analytical methods, including ligand-binding assays and MS-based methods.


Input: ADCs are typically mixtures with a range of drug-to-antibody ratios.


Input: Biotransformations in vivo can lead to additional changes in drug-to-antibody ratios resulting in dynamically changing mixtures.


Input: Thus, a standard calibration curve consisting of the reference standard may not be appropriate for quantification of analytes in vivo and represents a unique challenge.


Input: This paper will share our perspective on why ADC bioanalysis is so complex and describe the strategies and rationale that we have used for ADCs, with highlights of original data from a variety of nonclinical and clinical case studies.


Input: Our strategy has involved novel protein structural characterization tools to help understand ADC biotransformations in vivo and use of the analyte knowledge gained to guide the development of quantitative bioanalytical assays.


Input: Electrokinetic charging and evidence for charge evaporation in liquid microjets of aqueous salt solution.


Input: Electrokinetic charging of aqueous microjets was characterized by measuring streaming currents as a function of sodium iodide salt concentration.

sodium iodide


Input: Measured streaming currents at high salt concentrations (up to 0. 5 M) varied nonmonotonically with the jet velocity and can be explained by a multipolar charge distribution at the nozzle-water interface.


Input: In the case of potassium fluoride no multipolar charge distribution is observed.

potassium fluoride


Input: Electrokinetic potentials were estimated from the streaming currents, under the assumption that all excess charges are confined within the liquid jet.


Input: Measured photoelectron spectra indicate much smaller streaming potentials.


Input: To resolve the apparent discrepancy, we propose that a significant fraction of excess charges evaporates in the form of ion-water clusters.


Input: Multilayered hierarchical capsules providing cell adhesion sites.


Input: Liquified capsules featuring (i) an external shell by layer-by-layer assembly of poly (l-lysine), alginate, and chitosan, and encapsulating (ii) surface functionalized poly (l-lactic acid) (PLLA) microparticles were developed.

poly (l-lysine)

poly (l-lactic acid)

PLLA


Input: We hypothesize that, while the liquified environment enhances the diffusion of essential molecules for cell survival, microparticles dispersed in the liquified core of capsules provide the physical support required for cellular functions of anchorage-dependent cells.


Input: The influence of the incorporation of PLL on the regime growth, thickness, and stability was analyzed.

PLL


Input: Results show a more resistant and thicker film with an exponential build-up growth regime.


Input: Moreover, capsules ability to support cell survival was assessed.


Input: Capsules containing microparticles revealed an enhanced biological outcome in cell metabolic activity and proliferation, suggesting their potential to boost the development of innovative biomaterial designs for bioencapsulation systems and tissue engineering products.


Input: Interaction between group IIb divalent transition-metal cations and 3-mercaptopropionic acid: a computational and topological perspective.

group IIb divalent transition-metal

3-mercaptopropionic acid


Input: Density functional theory was applied to study the interaction of group IIb transition-metal cations (Zn (2 +), Cd (2 +), and Hg (2 +)) with one and two fully or partially deprotonated 3-mercaptopropionic acid ligands.

group IIb transition-metal

Zn (2 +)

Cd (2 +)

Hg (2 +)

3-mercaptopropionic acid


Input: In this investigation, we determined the geometries of all possible complexes resulting from the coordination of the metal ions with the ligands at different binding sites selected on each ligand.


Input: The relative energies of the complexes, metal-ion affinities, free energies, and entropies were also determined.


Input: The natures of the bonds were critically analyzed by natural bond orbital (NBO) analysis and clarified further using the atoms-in-molecules (AIM) approach.