Miracle-dz/UniFAR-FTUs huggingface dataset:
Plasma adiponectin concentrations in non-pregnant, normal and overweight pregnant women

Abstract Aims: Adiponectin is an adipokine that has anti-diabetic, anti-atherogenic, anti-inflammatory and angiogenic properties. This hormone has been implicated in both the physiological adaptation to normal pregnancy and in obstetrical complications. The aims of this study were to determine normal maternal plasma concentrations of adiponectin throughout gestation and to explore the relationships between plasma adiponectin concentration, pregnancy, and maternal overweight. Methods: A cross-sectional study was designed to include normal pregnant (normal weight and overweight; 11–42 weeks of gestation), and non-pregnant women. Plasma adiponectin concentration was determined by immunoassay. Non-parametric statistics were used for analysis. Results: (1) Adiponectin was detectable in the plasma of all patients; (2) there was no significant differences in the median adiponectin concentration between pregnant and non-pregnant women; (3) plasma adiponectin concentrations were negatively correlated with gestational age only among normal weight pregnant women; and (4) overweight patients had significantly lower plasma adiponectin concentrations than normal weight women. Conclusions: Consistent with the increased insulin resistance and weight gain that occur in pregnancy, adiponectin concentrations were negatively correlated with gestational age. The results of this study and the nomogram herein presented, can serve as the basis to explore the relationship between adiponectin and pregnancy complications and facilitate the clinical use of this important adipokine.
Sulfotransferase genes: Regulation by nuclear receptors in response to xeno/endo-biotics

Abstract Pregnane X receptor (PXR) and constitutive active/androstane receptor (CAR), members of the nuclear receptor superfamily, are two major xeno-sensing transcription factors. They can be activated by a broad range of lipophilic xenobiotics including therapeutics drugs. In addition to xenobiotics, endogenous compounds such as steroid hormones and bile acids can also activate PXR and/or CAR. These nuclear receptors regulate genes that encode enzymes and transporters that metabolize and excrete both xenobiotics and endobiotics. Sulfotransferases (SULTs) are a group of these enzymes and sulfate xenobiotics for detoxification. In general, inactivation by sulfation constitutes the mechanism to maintain homeostasis of endobiotics. Thus, deciphering the molecular mechanism by which PXR and CAR regulate SULT genes is critical for understanding the roles of SULTs in the alterations of physiological and pathophysiological processes caused by drug treatment or environmental exposures.
Application of Chinese Version of the Dysfunctional Attitude Scale in a Sample of Chinese Adolescents

Objective:To examine the reliability and validity of Dysfunctional Attitude Scale(DAS-A) in a sample of Chinese adolescent students.Methods:A total of 1191 adolescents were asked to complete the Chinese version of Dysfunctional Attitude Scale(DAS -A) and the Beck Depression Inventory(BDI). Results:The internal consistency reliability for the total scale was 0.88 and the four-week test-retest reliability coefficient was 0.84. Exploratory Factor Analysis extracted three factors,namely performance evaluation,need for approval and autonomous attitude.The percentage of variance explained was 41.86%. The DAS-A score in possible depressive adolescents was significant higher than that in non-depression adolescents.There was gender difference in dysfunctional attitude.Conclusion:The Chinese version of the DAS-A had acceptable psychometric quality,can be applied to assess dysfunctional attitudes in Chinese adolescent students.
Proteolytic Degradation of Topoisomerase II (Top2) Enables the Processing of Top2·DNA and Top2·RNA Covalent Complexes by Tyrosyl-DNA-Phosphodiesterase 2 (TDP2)* ♦

Background: TDP2 is critical for repairing Top2 cleavage complexes (Top2cc) and as the VPg unlinkase for picornavirus replication. Results: Top2 proteolysis or denaturation is required for TDP2 activity. TDP2 also hydrolyzes Top2cc at ribonucleotides. Conclusion: TDP2 efficiently disjoints relatively large Top2 polypeptide-DNA and -RNA complexes. Significance: Top2 processing is critical prior to its unlinking from DNA or RNA by TDP2. Eukaryotic type II topoisomerases (Top2α and Top2β) are homodimeric enzymes; they are essential for altering DNA topology by the formation of normally transient double strand DNA cleavage. Anticancer drugs (etoposide, doxorubicin, and mitoxantrone) and also Top2 oxidation and DNA helical alterations cause potentially irreversible Top2·DNA cleavage complexes (Top2cc), leading to Top2-linked DNA breaks. Top2cc are the therapeutic mechanism for killing cancer cells. Yet Top2cc can also generate recombination, translocations, and apoptosis in normal cells. The Top2 protein-DNA covalent complexes are excised (in part) by tyrosyl-DNA-phosphodiesterase 2 (TDP2/TTRAP/EAP2/VPg unlinkase). In this study, we show that irreversible Top2cc induced in suicidal substrates are not processed by TDP2 unless they first undergo proteolytic processing or denaturation. We also demonstrate that TDP2 is most efficient when the DNA attached to the tyrosyl is in a single-stranded configuration and that TDP2 can efficiently remove a tyrosine linked to a single misincorporated ribonucleotide or to polyribonucleotides, which expands the TDP2 catalytic profile with RNA substrates. The 1.6-Å resolution crystal structure of TDP2 bound to a substrate bearing a 5′-ribonucleotide defines a mechanism through which RNA can be accommodated in the TDP2 active site, albeit in a strained conformation.
Pathogenesis of Sjögren's syndrome

Purpose of reviewTo summarize recent developments in our understanding of the pathogenesis of Sjögren's syndrome with a focus on the relationship between inflammation and exocrine dysfunction. Recent findingsAnimal models demonstrated the complex interactions between immunologic and nonimmunologic mechanisms in Sjögren's syndrome. Activation of the innate immune system can lead to exocrine dysfunction before or without significant inflammation, whereas in other models, salivary gland function is preserved despite intense inflammatory infiltrates. Primary or inflammation-related abnormalities in water channels contribute to the exocrinopathy. Activation of the innate immunity in patients is demonstrated by the upregulation of type-1 interferon-regulated genes (interferon signature) in peripheral blood and salivary glands and abnormal expression of B cell-activating factor and its receptors. Nonimmune mechanisms that may contribute to exocrine dysfunction include local and systemic androgen deficiency and autonomic nervous system dysfunction. Autoantibodies against the muscarinic acetylcholine receptors would provide a link between autoimmunity and exocrine dysfunction, but the data on the presence, frequency and physiologic affect of these antibodies remain controversial. SummaryRecent discoveries from studies in patients with Sjögren's syndrome and animal models suggest a complex interplay between genetic factors, environmental and stochastic events that involve innate and adaptive immunity, hormonal mechanisms and the autonomic nervous system. Some of these findings suggest that exocrine gland dysfunction may precede autoimmunity or represent a process independent from inflammation in the pathogenesis of Sjögren's syndrome.
Intensive diabetes therapy and glomerular filtration rate in type 1 diabetes.

BACKGROUND An impaired glomerular filtration rate (GFR) leads to end-stage renal disease and increases the risks of cardiovascular disease and death. Persons with type 1 diabetes are at high risk for kidney disease, but there are no interventions that have been proved to prevent impairment of the GFR in this population. METHODS In the Diabetes Control and Complications Trial (DCCT), 1441 persons with type 1 diabetes were randomly assigned to 6.5 years of intensive diabetes therapy aimed at achieving near-normal glucose concentrations or to conventional diabetes therapy aimed at preventing hyperglycemic symptoms. Subsequently, 1375 participants were followed in the observational Epidemiology of Diabetes Interventions and Complications (EDIC) study. Serum creatinine levels were measured annually throughout the course of the two studies. The GFR was estimated with the use of the Chronic Kidney Disease Epidemiology Collaboration formula. We analyzed data from the two studies to determine the long-term effects of intensive diabetes therapy on the risk of impairment of the GFR, which was defined as an incident estimated GFR of less than 60 ml per minute per 1.73 m(2) of body-surface area at two consecutive study visits. RESULTS Over a median follow-up period of 22 years in the combined studies, impairment of the GFR developed in 24 participants assigned to intensive therapy and in 46 assigned to conventional therapy (risk reduction with intensive therapy, 50%; 95% confidence interval, 18 to 69; P=0.006). Among these participants, end-stage renal disease developed in 8 participants in the intensive-therapy group and in 16 in the conventional-therapy group. As compared with conventional therapy, intensive therapy was associated with a reduction in the mean estimated GFR of 1.7 ml per minute per 1.73 m(2) during the DCCT study but during the EDIC study was associated with a slower rate of reduction in the GFR and an increase in the mean estimated GFR of 2.5 ml per minute per 1.73 m(2) (P<0.001 for both comparisons). The beneficial effect of intensive therapy on the risk of an impaired GFR was fully attenuated after adjustment for glycated hemoglobin levels or albumin excretion rates. CONCLUSIONS The long-term risk of an impaired GFR was significantly lower among persons treated early in the course of type 1 diabetes with intensive diabetes therapy than among those treated with conventional diabetes therapy. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; DCCT/EDIC ClinicalTrials.gov numbers, NCT00360815 and NCT00360893.).
Whole Exome Sequencing Identifies Variation in CYB5A and RNF10 Associated with Adiposity and Type 2 Diabetes

Few coding variants in genes associated with type 2 diabetes (T2D) have been identified, and the underlying physiologic mechanisms whereby susceptibility genes influence T2D risk are often unknown. The objective of this study was to identify coding variation that increases risk for T2D via an effect on a pre‐diabetic trait.
Association between swimming lessons and drowning in childhood: a case-control study.

OBJECTIVE To estimate the association between swimming lessons and the risk of drowning among children aged 1 to 19 years. DESIGN Case-control study. SETTING Cases were identified from medical examiners'/coroners' offices between mid-2003 and mid-2005. Jurisdictions included the states of Maryland and North Carolina, 14 districts (33 counties) in Florida, 3 counties in California, 1 county in Texas, and 1 county in New York. PARTICIPANTS Cases were children and adolescents aged 1 to 19 years who died of unintentional drowning. Interviews were conducted with 88 families of children who drowned and 213 matched controls. Main Exposure Swimming lessons. Main Outcome Measure Death due to unintentional drowning. Drownings that were intentional, of undetermined intent, or that occurred under conditions in which swimming ability was unlikely to impact risk (eg, in ice water or bathtubs) were excluded. RESULTS Of the 61 cases in the 1- to 4-year age group, 2 (3%) had participated in formal swimming lessons vs 35 of 134 matched controls (26%) (adjusted odds ratio [OR], 0.12; 95% confidence interval [CI], 0.01-0.97). Among the 27 cases aged 5 to 19 years, 7 (27%) had ever taken formal swimming lessons vs 42 of 79 matched controls (53%) (adjusted OR, 0.36; 95% CI, 0.09-1.51). In adjusted analyses, there was no statistically significant association between informal instruction and drowning risk. CONCLUSIONS Participation in formal swimming lessons was associated with an 88% reduction in the risk of drowning in the 1- to 4-year-old children, although our estimates were imprecise and 95% CIs included risk reductions ranging from 3% to 99%.
Precision medicine for psychopharmacology: a general introduction

ABSTRACT Introduction: Precision medicine is an emerging medical model that can provide accurate diagnoses and tailored therapeutic strategies for patients based on data pertaining to genes, microbiomes, environment, family history and lifestyle. Areas covered: Here, we provide basic information about precision medicine and newly introduced concepts, such as the precision medicine ecosystem and big data processing, and omics technologies including pharmacogenomics, pharamacometabolomics, pharmacoproteomics, pharmacoepigenomics, connectomics and exposomics. The authors review the current state of omics in psychiatry and the future direction of psychopharmacology as it moves towards precision medicine. Expert commentary: Advances in precision medicine have been facilitated by achievements in multiple fields, including large-scale biological databases, powerful methods for characterizing patients (such as genomics, proteomics, metabolomics, diverse cellular assays, and even social networks and mobile health technologies), and computer-based tools for analyzing large amounts of data.
Progress in Fully Automated Abdominal CT Interpretation.

OBJECTIVE Automated analysis of abdominal CT has advanced markedly over just the last few years. Fully automated assessment of organs, lymph nodes, adipose tissue, muscle, bowel, spine, and tumors are some examples where tremendous progress has been made. Computer-aided detection of lesions has also improved dramatically. CONCLUSION This article reviews the progress and provides insights into what is in store in the near future for automated analysis for abdominal CT, ultimately leading to fully automated interpretation.
Anti-Infectious Drug Repurposing Using an Integrated Chemical Genomics and Structural Systems Biology Approach

The emergence of multi-drug and extensive drug resistance of microbes to antibiotics poses a great threat to human health. Although drug repurposing is a promising solution for accelerating the drug development process, its application to anti-infectious drug discovery is limited by the scope of existing phenotype-, ligand-, or target-based methods. In this paper we introduce a new computational strategy to determine the genome-wide molecular targets of bioactive compounds in both human and bacterial genomes. Our method is based on the use of a novel algorithm, ligand Enrichment of Network Topological Similarity (ligENTS), to map the chemical universe to its global pharmacological space. ligENTS outperforms the state-of-the-art algorithms in identifying novel drug-target relationships. Furthermore, we integrate ligENTS with our structural systems biology platform to identify drug repurposing opportunities via target similarity profiling. Using this integrated strategy, we have identified novel P. falciparum targets of drug-like active compounds from the Malaria Box, and suggest that a number of approved drugs may be active against malaria. This study demonstrates the potential of an integrative chemical genomics and structural systems biology approach to drug repurposing.
The genetics of dystonia: new twists in an old tale

Dystonia is a common movement disorder seen by neurologists in clinic. Genetic forms of the disease are important to recognize clinically and also provide valuable information about possible pathogenic mechanisms within the wider disorder. In the past few years, with the advent of new sequencing technologies, there has been a step change in the pace of discovery in the field of dystonia genetics. In just over a year, four new genes have been shown to cause primary dystonia (CIZ1, ANO3, TUBB4A and GNAL), PRRT2 has been identified as the cause of paroxysmal kinesigenic dystonia and other genes, such as SLC30A10 and ATP1A3, have been linked to more complicated forms of dystonia or new phenotypes. In this review, we provide an overview of the current state of knowledge regarding genetic forms of dystonia—related to both new and well-known genes alike—and incorporating genetic, clinical and molecular information. We discuss the mechanistic insights provided by the study of the genetic causes of dystonia and provide a helpful clinical algorithm to aid clinicians in correctly predicting the genetic basis of various forms of dystonia.
Testing the reflection assumption: an examination of the external validity of published studies on lineup identification accuracy.

The purpose of this project was to draw attention to the problem of eyewitness ecology, a term that we use to refer to the relationship between the eyewitness and the criminal environment, which includes characteristics of perpetrators, witnessing conditions and the identification test. Our goal was to compare the range of eyewitness ecologies found in real world cases with those found in laboratory studies of eyewitness identification. Toward this end, we coded the characteristics of the published literature on criminal identification in the laboratory (N = 290). The results were compared to the characteristics of a stratified random sample of felony cases (N = 721) obtained from a large metropolitan district in the United States. The results provide a systematic overview of the methods and procedures that have been used to study eyewitness identification in the laboratory, and suggest areas in which further research is needed to better reflect the range of eyewitness ecologies that are found in actual criminal cases
Coordinate Regulation of DNA Methylation and H3K27me3 in Mouse Embryonic Stem Cells

Chromatin is separated into functional domains distinguished by combinatorial patterns of post-translational histone modifications and DNA methylation. Recent studies examining multiple histone modifications have found numerous chromatin states with distinct profiles of chromatin marks and functional enrichments. There are data showing coordinate regulation between DNAme and H3K27me3, which are both involved in the establishment and maintenance of epigenetic gene silencing, but the data are conflicting. Multiple studies have presented evidence to support the theory that PRC2 and DNAme cooperate to achieve silencing, or alternatively that H3K27me3 and DNAme act antagonistically. Here we examine the effect loss of either PRC2 or DNA methyltransferase activity has on the placement of the reciprocal mark in mouse ES cells. We find that DNAme is acting globally to antagonize the placement of H3K27me3, in accordance with recently published results. At least 471,011 domains in the mouse genome acquire H3K27me3 when DNAme is diminished. Of these 466,563 have been shown to be fully methylated in wildtype ES cells, indicating the effects of DNAme on H3K27me3 are direct. In a reciprocal experiment, we examine the effect loss of PRC2 has on the placement of DNAme. In contrast to the global antagonism DNAme has on the placement of H3K27me3, loss of H3K27me3 has a modest effect on DNAme, with only 4% of genes undergoing changes in DNAme, including 861 showing increases and 552 showing losses of overall DNAme. We anticipate that integrating genomic datasets where the effect of loss of a particular epigenetic mark has on the placement of other marks will help elucidate the rules governing epigenetic regulation and what role coordinate regulation of epigenetic marks plays in development and disease.
The Role of Comorbidities in Cardioprotection

Cardioprotective strategies such as pre- and postconditioning result in a robust reduction in infarct size in young, healthy male animals. However, there are data suggesting that the protection is diminished in animals with comorbidities such as hypertension, hypercholesterolemia, and diabetes. It is important to understand at a mechanistic level the reasons for these differences. The effects of sex and diseases need to be considered in design of cardioprotective interventions in animal studies and clinical trials.
Mapping Pitch Representation in Neural Ensembles with fMRI

Functional magnetic resonance imaging (fMRI) in humans and macaques allows a test of the hypothesis that there is a specialized neural ensemble for pitch within auditory cortex: a pitch center. fMRI measures the blood oxygenation level-dependent (BOLD) response related to regional synaptic activity (Logothetis et al., 2001). The distinction between synaptic activity and spike firing, and species differences encourage caution when comparing BOLD activity in humans and macaques to recordings from single neurons in ferret and marmoset in the previous mini-review. The BOLD data provide support for the pitch-center concept, with ongoing debate about its location.
New FDA breakthrough-drug category--implications for patients.

U.S. pharmaceutical regulations are based on the principle that patients should not be exposed to new prescription drugs until their efficacy and safety have been shown. Since 1962, the Food and Drug Administration (FDA) and Congress have balanced the efficient review of investiga­ tional drugs with the need to withhold judgment until sufficient evidence is available to clarify the benefit–risk relationship. Misjudging these competing interests in either direction causes important problems. On the one hand, the evi­ dentiary hurdles of the FDA are often criticized by pharmaceutical companies and patient advo­ cacy groups for slowing access to promising therapies. On the other hand, truncated premar­ ket review can lead to the approval of drugs that are ineffective, unsafe, or both. These dangers were once again made clear in October 2013 when approval was briefly sus­ pended for ponatinib, a medication to treat leu­ kemia that had been approved just the year be­ fore on an accelerated basis. Emerging data showed that 24% of the patients who had been followed for a median of 1.3 years and 48% of those who had been followed for a median of 2.7 years had serious thromboembolic events, including myocardial infarction and stroke.1 The drug was allowed back on the market in December 2013 with more limited indications and a restricted distribution system. The latest development in the FDA approach to ensuring the safety and effectiveness of mar­ keted prescription drugs occurred in July 2012, when Congress created a new category of “break­ through therapy” in the FDA Safety and Inno­ vation Act (FDASIA). A breakthrough therapy was defined as a new product to treat a serious disease for which preliminary clinical evidence suggested substantial superiority over existing options on one or more clinically significant end points.2 Lawmakers intended the designation to speed to market a limited number of prod­ ucts that showed “exceptional results for pa­ tients. ”3 Lauded by policymakers,4 consumer advocates,5,6 and the FDA itself,7 the break­ through­drug pathway has been embraced by industry8 and has produced early results far ex­ ceeding predictions. From October 2012 through September 2013, the FDA received 92 applica­ tions for the breakthrough­therapy designation, of which 27 were approved and 41 denied (24 applications were still pending). 9 Although some of these agents may end up being truly transfor­ mative for patient care, the breakthrough­therapy designation also raises the possibility of a surge in new drugs that have been approved on the basis of limited clinical data. There is ongoing controversy over the FDA standards for the approval of investigational drugs. In this article, we briefly summarize pri­ or government efforts to expedite the availabil­ ity of new therapeutics, and we discuss the clin­ ical, ethical, and regulatory implications of the breakthrough­therapy designation.