Miracle-dz/UniFAR-FTUs huggingface dataset:
Mode of Action: Inhibition of Histone Deacetylase, Altering WNT-Dependent Gene Expression, and Regulation of Beta-Catenin—Developmental Effects of Valproic Acid

Valproic acid (VPA) has long been known to cause spina bifida, a neural tube defect, and other effects in fetuses of women treated with this drug. Toxicological tests in laboratory mice and rats at human therapeutic doses also show neural tube and other defects. Studies show that VPA alters Wnt signaling in human and animal cells, inducing Wnt-dependent gene expression at doses that cause developmental effects. Structural analogues of VPA that do not have this effect on Wnt signaling do not cause developmental effects. Similarly, Trichostatin A, a compound that mimics VPA in its effects on Wnt gene expression, also causes similar developmental effects. Alteration of Wnt signaling is empirically well supported as the postulated mode of action (MOA) for VPA's developmental effects in animals. VPA causes alteration of Wnt signaling in both human and animal cells systems at the same dose levels. The correspondence of effects on signaling and of effects on development in animals and humans supports the view that alteration of Wnt signaling is a relevant MOA in humans.
AN ELECTROPHYSIOLOGICAL ANALYSIS OF THE EFFECTS OF NORADRENALINE AND α‐RECEPTOR ANTAGONISTS ON NEUROMUSCULAR TRANSMISSION IN MAMMALIAN MUSCULAR ARTERIES

1 The effects of exogenously applied noradrenaline (NA) and α‐adrenoceptor antagonists on the mechanical and intracellularly recorded responses to perivascular nerve stimulation were examined in the rabbit ear artery, rabbit saphenous artery and rat tail artery. 2 Excitatory junction potentials (e.j.ps) and action potentials recorded from these smooth muscles were not blocked or depressed by phentolamine, phenoxybenzamine, prazosin, or labetolol in concentrations as high as 10 μg/ml. Phentolamine (1 to 10 μg/ml) depressed neurally‐evoked contractions of the ear and saphenous, but not the tail artery, and also depressed the contractions produced by direct muscle stimulation in the ear and saphenous arteries. Prazosin and labetolol (0.1 to 10 μg/ml) had no effect on the neurally evoked contractile response in any of the arteries examined. 3 The amplitude of the steady‐state e.j.p. during repetitive stimulation at 0.45 to 2 Hz was increased by phentolamine or phenoxybenzamine but not by prazosin or labetolol. Phentolamine and phenoxybenzamine also increased the amplitude of the e.j.p. evoked by a single stimulus in the majority of the preparations. 4 Concentrations of NA ≥ 1 μg/ml depolarized the smooth muscle while concentrations ≥ 0.5 μg/ml depressed the amplitude of the e.j.ps recorded from these arteries. α‐Antagonists did not suppress either the NA‐induced membrane depolarization or depression of e.j.ps. 5 These observations call into question the physiological relevance of both pre‐ and postsynaptic α‐receptors in regard to adrenergic neuromuscular transmission in muscular arteries.
DENSITY-DEPENDENT SELF-FERTILIZATION AND MALE VERSUS HERMAPHRODITE SIRING SUCCESS IN AN ANDRODIOECIOUS PLANT

Abstract Models of mating-system evolution emphasize the importance of frequency-dependent interactions among mating partners. It is also known that outcross siring success and the selfing rate in self-compatible hermaphrodites can be density dependent. Here, we use array experiments to show that the mating system (i.e., the outcrossing rate) and the siring success of morphs with divergent sex allocation strategies are both density dependent and frequency dependent in androdioecious populations of the wind-pollinated, annual plant Mercurialis annua. In particular, the outcrossing rate is a decreasing function of the mean interplant distance, regulated by a negative exponential pollen fall-off curve. Our results indicate that pollen dispersed from a male inflorescence are over 60% more likely to sire outcrossed progeny than equivalent pollen dispersed from hermaphrodites, likely due to the fact that males, but not hermaphrodites, disperse their pollen from erect inflorescence stalks. Because of this difference, and because males of M. annua produce much more pollen than hermaphrodites, the presence of males in the experimental arrays reduced both the selfing rate and the outcross siring success of hermaphrodites. We use our results to infer a density threshold below which males are unable to persist with hermaphrodites but above which they can invade hermaphroditic populations. We discuss our findings in the context of a metapopulation model, in which males can only persist in well-established populations but are excluded from small, sparse populations, for example, in the early stages of colonization.
Liver Transplantation for Hepatocellular Carcinoma: Five Steps to Prevent Recurrence

Liver transplantation is the best treatment of patients with unresectable early hepatocellular carcinoma, allowing disease‐free survival rates of 60–80% at 5 years. Despite these good results, some 10% of recipients experience a posttransplant HCC recurrence, which leads to death in almost all patients. Recurrence is either due to the growth of occult metastases or to the engraftment of circulating tumor cells. It can be hypothesized that strategies to decrease the engraftment of circulating tumor cells could decrease the risk of recurrence and, in addition, extend access to transplantation to patients with more advanced HCC. These potential strategies can be schematized into five steps, including (1) selecting recipients with low baseline levels of circulating HCC cells, by adding biological markers (such as alpha fetoprotein or molecular signatures) to the accepted combination of morphological criteria; (2) decreasing the perioperative release of HCC cells, with careful perioperative handling of the tumors; (3) preventing the engraftment of circulating HCC cells by decreasing liver graft ischemia‐reperfusion injury, which has been shown to promote cancer cell engraftment and growth; (4) using anticancer drugs, including mammalian target of rapamycin inhibitors and (5) tuning immunity toward HCC clearance.
Capecitabine in gastric cancer

Chemotherapy is an important part of treatment for patients with gastric cancer. Although there is no single globally accepted standard of care for patients with advanced disease, regimens typically include a fluoropyrimidine and a platinum compound with or without a third drug (usually epirubicin or docetaxel). Oral fluoropyrimidines, such as capecitabine, offer clear advantages to patients in terms of convenience, but it is only recently that comprehensive data on their efficacy and safety in patients with gastric cancer have become available. The present article reviews capecitabine in the treatment of advanced and resectable gastric cancer. Ongoing Phase III trials involving capecitabine are also discussed. The data show that capecitabine is now established as an integral part of the multi-agent regimens used in the management of patients with gastric cancers.
Moving beyond legal compliance: innovative approaches to EU multilevel implementation

ABSTRACT Research on implementation in the European Union (EU) is characterized by a strong focus on legal conformance with EU policy. However, this focus has been criticized for insufficiently accounting for the implications of the EU’s multilevel governance structure, thus providing an incomplete picture of EU implementation, its diversity and practice. The contributions of this collection represent a shift towards a more performance-oriented perspective on EU implementation as problem-solving. They approach implementation fundamentally as a process of interpretation of superordinate law by actors who are embedded within multiple contexts arising from the coexistence of dynamics of Europeanization, on the one hand, and what has been termed ‘domestication’, on the other. Moving beyond legal compliance, the contributions provide new evidence on the diversity of domestic responses to EU policy, the roles and motivations of actors implementing EU policy, and the ‘black box’ of EU law in action and its enforcement.
Developing a Network of Community Health Centers With a Common Electronic Health Record: Description of the Safety Net West Practice-based Research Network (SNW-PBRN)

In 2001, community health center (CHC) leaders in Oregon established an organization to facilitate the integration of health information technology, including a shared electronic health record (EHR), into safety net clinics. The Oregon Community Health Information Network (shortened to OCHIN as other states joined) became a CHC information technology hub, supporting a network-wide EHR with one master patient index, now linked across >40 safety net organizations serving >900,000 patients with nearly 800,000 distinct CHC visits. Recognizing the potential of OCHIN′s multiclinic network and comprehensive EHR database for conducting safety net-based research, OCHIN leaders and local researchers formed the Safety Net West practice-based research network (PBRN). The Safety Net West “community- based laboratory,” based at OCHIN, is positioned to become an important resource for many studies including: evaluation of the real-time impact of health care reform on uninsured populations; development of new models of primary care delivery; dissemination and translation of interventions from other EHR-based systems (e.g., Kaiser Permanente) into the community health setting; and analyses of factors influencing disparities in health and health care access. We describe the founding of Safety Net West, its infrastructure development, current projects, and the future goals of this community-based PBRN with a common EHR.
How to Perform Permanent His Bundle Pacing: Tips and Tricks

Right ventricular pacing can cause ventricular dyssynchrony and result in reduced left ventricular systolic function and heart failure. Permanent His bundle pacing is a more physiologic form of pacing, but can be technically challenging. In this article, we describe our technique for permanent His bundle pacing including special considerations and limitations associated with His bundle pacing.
Combination of a spinning disc confocal unit with frequency‐domain fluorescence lifetime imaging microscopy

Wide‐field frequency‐domain fluorescence lifetime imaging microscopy (FLIM) is an established technique to determine fluorescence lifetimes. Disadvantage of wide‐field imaging is that measurements are compromised by out‐of‐focus blur. Conventional scanning confocal typically means long acquisition times and more photo bleaching. An alternative is spinning‐disc confocal whereby samples are scanned simultaneously by thousands of pinholes, resulting in a virtually instantaneous image with more than tenfold reduced photo bleaching.
Regulation of Cl− secretion in seawater fish (Dicentrarchus labrax) gill respiratory cells in primary culture

1 Primary cultures of sea bass (Dicentrarchus labrax) gill cells grown on permeable membranes form a highly differentiated tight epithelium composed of respiratory‐like cells. This preparation was also found to provide a functional model for investigating the hormonal regulation of Cl− secretion. 2 In control conditions, i.e. in the absence of hormones or other stimuli, the cultured epithelium showed a short‐circuit current (Isc) of 8·8 ± 0·4 μA cm−2, a transepithelial potential (Vt) of 28·6 ± 0·6 mV (serosal side positive), and a transepithelial resistance (Rt) of 5026 ± 127 Ω cm2. Addition of 50 nM PGE2 caused a stimulation of Isc, Vt and transepithelial conductance, Gt. The increase in Isc was probably due to the elevation in Cl− secretion, since it could be correlated with the stimulation of serosal to mucosal 36Cl− flux. Application of the neurohypophyseal peptide arginine vasotocin (AVT; 50 nM) or the β‐adrenergic agonist isoproterenol (isoprenaline; 0·5 μM) evoked a stimulation in Cl− secretion, as was shown by the increases in Isc and Gt. The excitatory effect of isoproterenol followed by the inhibitory action of propranolol, a β‐adrenergic antagonist, suggested the presence of β‐adrenergic receptors. Noradrenaline (0·1 μM) elicited a reduction in Isc, Vt and Gt, which was counterbalanced by the addition of phentolamine, an α‐adrenergic antagonist. This suggested an activation of α‐adrenergic receptors. 3 This study provides evidence for hormonal control of the Cl− secretion in sea bass gill respiratory cells in culture, involving AVT, prostaglandin (PGE2), and β‐ and α‐adrenergic receptors.
The Changing Role of the Chief Executive

Role and Authority With a simple addition extending that definition into commerce, and the public service it is my general view that this comment is adequate in considering the Chief Executive's role. Certainly our Bradford discussions tended to confirm that. Clearly, in industry, commerce, and the public service, the authority structure and the accountability of the Chief Executive vary greatly. The Vice-Chancellor of a University, the Chief Executive of a Local Authority, the Chief Executive A. Brearley *
(5E)-5-(4-Hydroxy-3-methoxybenzylidene)-2-thioxo-1,3-thiazolidin-4-one methanol monosolvate

In the title compound, C11H9NO3S2·CH4O, the dihedral angle between the aromatic rings is 3.57 (16)° and intramolecular O—H⋯O and C—H⋯S interactions occur. In the crystal, the thiazolidin-4-one molecules are linked by N—H⋯O hydrogen bonds, forming chains. The hydrogen-bond motifs lead to S(5), S(6) and R 3 3(8) ring motifs. There exist C=O⋯π interactions between the heterocyclic rings and π–π interactions between the heterocyclic and benzene rings at distances of 3.455 (2) and 3.602 (2) Å, respectively. The methanol solvent molecule is disordered over two sets of sites in a 0.542 (9):0.458 (9) ratio.
IL-22 Regulates Iron Availability In Vivo through the Induction of Hepcidin

Iron is a trace element important for the proper folding and function of various proteins. Physiological regulation of iron stores is of critical importance for RBC production and antimicrobial defense. Hepcidin is a key regulator of iron levels within the body. Under conditions of iron deficiency, hepcidin expression is reduced to promote increased iron uptake from the diet and release from cells, whereas during conditions of iron excess, induction of hepcidin restricts iron uptake and movement within the body. The cytokine IL-6 is well established as an important inducer of hepcidin. The presence of this cytokine during inflammatory states can induce hepcidin production, iron deficiency, and anemia. In this study, we show that IL-22 also influences hepcidin production in vivo. Injection of mice with exogenous mouse IgG1 Fc fused to the N terminus of mouse IL-22 (Fc–IL-22), an IL-22R agonist with prolonged and enhanced functional potency, induced hepcidin production, with a subsequent decrease in circulating serum iron and hemoglobin levels and a concomitant increase in iron accumulation within the spleen. This response was independent of IL-6 and was attenuated in the absence of the IL-22R–associated signaling kinase, Tyk2. Ab-mediated blockade of hepcidin partially reversed the effects on iron biology caused by IL-22R stimulation. Taken together, these data suggest that exogenous IL-22 regulates hepcidin production to physiologically influence iron usage.
Epidemiology and Clinical Management of Traumatic Spine Injuries at a Major Government Hospital in Cambodia

Study Design Cross sectional study. Purpose To characterize the pattern of injury, describe the current clinical management, and determine the outcomes in traumatic spine injury (TSI) patients presenting to a major government hospital in Phnom Penh, Cambodia. Overview of Literature There is a paucity of literature on epidemiology or current clinical practices for TSIs in Cambodia. The findings from this study can thus serve as a valuable resource for future progress in treating TSIs in low-income countries. Methods This study was a cross-sectional study of TSI patients admitted to Preah Kossamak Hospital in Phnom Penh, Cambodia. Demographics, cause of spinal injury, spinal level of injury, surgical procedures and techniques, complications, and American Spinal Injury Association (ASIA) grades were recorded and analyzed. Results Eighty patients were admitted with TSI between October 2013 and June 2014. Falls from heights were the most common cause of TSI, followed by road traffic accidents. 78% of the admitted patients underwent at least one surgical procedure. Without intraoperative imaging, 4 patients (6%) had wrong level surgery, and 1 patient (2%) had misplacement of pedicle screws. Sacral decubitus ulcers were the most common non-surgically related complication. Antibiotics were administered to >90% of patients. There were no in-hospital mortalities. Of the 60 spinal cord injury (SCI) patients, 32% (19/60) showed improvement in their ASIA grade at the time of discharge, and 52% (31/60) showed no change. At follow-up, 32% (19/60) of SCI patients reported improvement, and 8% (5/60) reported no change. However, 36 SCI patients (60%) were lost to follow-up. Conclusions Despite technological limitations, outcomes of TSI patients in Cambodia appear favorable with evidence of clinical improvement and low mortality.
Activation of MHC Class I, II, and CD40 Gene Expression by Histone Deacetylase Inhibitors1

Epigenetic mechanisms are involved in regulating chromatin structure and gene expression through repression. In this study, we show that histone deacetylase inhibitors (DAIs) that alter the acetylation of histones in chromatin enhance the expression of several genes on tumor cells including: MHC class I, II, and the costimulatory molecule CD40. Enhanced transcription results in a significant increase in protein expression on the tumor cell surface, and expression can be elicited on some tumors that are unresponsive to IFN-γ. The magnitude of induction of these genes cannot be explained by the effect of DAIs on the cell cycle or enhanced apoptosis. Induction of class II genes by DAIs was accompanied by activation of a repressed class II transactivator gene in a plasma cell tumor but, in several other tumor cell lines, class II was induced in the apparent absence of class II transactivator transcripts. These findings also suggest that the abnormalities observed in some tumors in the expression of genes critical to tumor immunity may result from epigenetic alterations in chromatin and gene regulation in addition to well-established mutational mechanisms.
Transcription factors that interact with p53 and Mdm2

The tumor suppressor p53 is activated upon cellular stresses such as DNA damage, oncogene activation, hypoxia, which transactivates sets of genes that induce DNA repair, cell cycle arrest, apoptosis, or autophagy, playing crucial roles in the prevention of tumor formation. The central regulator of the p53 pathway is Mdm2 which inhibits transcriptional activity, nuclear localization and protein stability. More than 30 cellular p53‐binding proteins have been isolated and characterized including Mdm2, Mdm4, p300, BRCA1/2, ATM, ABL and 53BP‐1/2. Most of them are nuclear proteins; however, not much is known about p53‐binding transcription factors. In this review, we focus on transcription factors that directly interact with p53/Mdm2 through direct binding including Dmp1, E2F1, YB‐1 and YY1. Dmp1 and YB‐1 bind only to p53 while E2F1 and YY1 bind to both p53 and Mdm2. Dmp1 has been shown to bind to p53 and block all the known functions for Mdm2 on p53 inhibition, providing a secondary mechanism for tumor suppression in Arf‐null cells. Although E2F1‐p53 binding provides a checkpoint mechanism to silence hyperactive E2F1, YB‐1 or YY1 interaction with p53 subverts the activity of p53, contributing to cell cycle progression and tumorigenesis. Thus, the modes and consequences for each protein‐protein interaction vary from the viewpoint of tumor development and suppression.
Is the effect of low birth weight on cardiovascular mortality mediated through high blood pressure?

OBJECTIVE To explore whether the inverse association between birth weight and mortality from circulatory diseases is mediated through blood pressure in men aged 50-75 years. DESIGN Cohort study with retrospectively collected data on size at birth. SUBJECTS AND SETTING The study included 1334 men born during 1920-1924, living in Uppsala, Sweden, who were examined at the ages of 50 and 60 years, and followed-up to the end of 1995. MAIN OUTCOME MEASURES Mortality from circulatory diseases based on routine death registration. RESULTS Birth weight showed a specific, inverse association with mortality from circulatory diseases: the rate ratio was 0.67 (95% confidence interval 0.50 to 0.89) per 1000 g increase in birth weight. This association was not appreciably affected by adjustment for sociodemographic characteristics or smoking, but was strengthened slightly by adjustment for body mass index at the ages of 50 and 60 years. Adjustment for systolic blood pressure at the age of 50 years only slightly reduced the strength of the inverse association between birth weight and mortality from ischaemic heart disease, and did not affect the inverse association between birth weight and mortality from stroke. Adjustments for systolic and diastolic blood pressure and hypertension treatment at the ages of 50 and 60 years did not reduce the strength of the association between birth weight and mortality from circulatory diseases at the age of 60-75 years. CONCLUSIONS The inverse association between birth weight and mortality from circulatory diseases in men aged 50-75 years is independent of adult sociodemographic characteristics, smoking and adult obesity and does not seem to be mediated through an increased blood pressure in those with low birth weight.
Callitrichid Hepatitis: Epizootiology of a Fatal Hepatitis in Zoo Tamarins and Marmosets

Epizootics of an acute, fatal hepatitis affecting tamarins and marmosets (family Cal litrichidae) have been reported in two zoos in the U.S. and Europe. Two new epizootics of hepatitis affecting seven golden lion tamarins (Leontopithecus rosalia) and three emperor tamarins (Saguinus Imperator) were identified at the Oklahoma City Zoo in 1984 and 1986. Livers from these animals showed hepatocellular swelling and necrosis accompanied by inflammatory cells and acidophilic bodies. Virus-like particles 85-105 nm in diameter were seen in hepatocytes. Using pathologic and clinical criteria, a case definition of the disease now called callitrichid hepatitis (CH) was developed. Health records of tamarins in zoos in the U.S. were surveyed for the occurrence of CH, and 12 outbreaks of CH were retrospectively identified at 10 zoos or animal parks. These studies show that CH is a highly infectious disease with a high mortality rate. This disease is apparently much more prevalent in zoos than previously recognized, and may therefore pose a serious threat to the survival of captive tamarins, particularly endangered species.