Miracle-dz/UniFAR-FTUs huggingface dataset:
Analysis of Heritability and Genetic Architecture of Pancreatic Cancer: A PanC4 Study

Background: Pancreatic cancer is the fourth-leading cause of cancer death in both men and women in the United States. The currently identified common susceptibility loci account for a small fraction of estimated heritability. We sought to estimate overall heritability of pancreatic cancer and partition the heritability by variant frequencies and functional annotations. Methods: Analysis using the genome-based restricted maximum likelihood method (GREML) was conducted on Pancreatic Cancer Case-Control Consortium (PanC4) genome-wide association study (GWAS) data from 3,568 pancreatic cancer cases and 3,363 controls of European Ancestry. Results: Applying linkage disequilibrium- and minor allele frequency-stratified GREML (GREML-LDMS) method to imputed GWAS data, we estimated the overall heritability of pancreatic cancer to be 21.2% (SE = 4.8%). Across the functional groups (intronic, intergenic, coding, and regulatory variants), intronic variants account for most of the estimated heritability (12.4%). Previously identified GWAS loci explained 4.1% of the total phenotypic variation of pancreatic cancer. Mutations in hereditary pancreatic cancer susceptibility genes are present in 4% to 10% of patients with pancreatic cancer, yet our GREML-LDMS results suggested these regions explain only 0.4% of total phenotypic variance for pancreatic cancer. Conclusions: Although higher than previous studies, our estimated 21.2% overall heritability may still be downwardly biased due to the inherent limitation that the contribution of rare variants in genes with a substantive overall impact on disease are not captured when applying these commonly used methods to imputed GWAS data. Impact: Our work demonstrated the importance of rare and common variants in pancreatic cancer risk.
Proteostasis Environment Shapes Higher-Order Epistasis Operating on Antibiotic Resistance

Epistasis is widely regarded as one of the most important phenomena in genetics. It proposes that the combined effects of mutations cannot be easily predicted from their individual effects. In the present study. Recent studies have affirmed that higher-order epistasis is ubiquitous and can have large effects on complex traits. Yet, we lack frameworks for understanding how epistatic interactions are influenced by central features of cell physiology. In this study, we assess how protein quality control machinery—a critical component of cell physiology—affects epistasis for different traits related to bacterial resistance to antibiotics. Specifically, we disentangle the interactions between different protein quality control genetic backgrounds and two sets of mutations: (i) SNPs associated with resistance to antibiotics in an essential bacterial enzyme (dihydrofolate reductase, or DHFR) and (ii) differing DHFR bacterial species-specific amino acid background sequences (Escherichia coli, Listeria grayi, and Chlamydia muridarum). In doing so, we improve on generic observations that epistasis is widespread by discussing how patterns of epistasis can be partly explained by specific interactions between mutations in an essential enzyme and genes associated with the proteostasis environment. These findings speak to the role of environmental and genotypic context in modulating higher-order epistasis, with direct implications for evolutionary theory, genetic modification technology, and efforts to manage antimicrobial resistance.
Transcriptional Regulation of Early Growth Response Gene-1 (EGR1) is Associated with Progression of Nonalcoholic Fatty Liver Disease (NAFLD) in Patients with Insulin Resistance

Background The occurrence of nonalcoholic fatty liver disease (NAFLD) is closely related to type 2 diabetes, especially in patients with insulin resistance. The purpose of this research was to elucidate the major genes and transcriptional regulation of insulin resistance in the progression of NAFLD. Material/Methods We downloaded the gene expression matrix of GSE89632 from Gene Expression Omnibus. Then the principal component analysis was used to identify whether the samples were clustered. Differentially expressed genes were identified by limma R package. Enrichment analysis and protein-protein interaction network was used to find potential function and screening hub genes. We further used ChIP-seq data from ENCODE to predict the transcriptional regulation of hub genes. Finally, we verified the functions of hub genes with clinical information. Results These hub genes were significantly enriched in “response to insulin”, “response to glucose”, and “fat cell differentiation”. ChIP-seq data showed that EGR1 (early growth response gene-1) may play an important role in the transcriptional regulation of SOCS1 (suppressor of cytokine signaling 1), SOCS3 (suppressor of cytokine signaling 3), and Fos gene family in the liver, as the low expression of EGR1 in patients with insulin resistance may promote the occurrence and development of NAFLD. Similarly, correlation analysis showed that EGR1 was positively correlated with the expression of SOCS1, SOCS3, and the genes of Fos gene family, and EGR1 was negatively correlated with the degree of steatosis. Conclusions Newly identified hub genes and their transcriptional regulation may promote understanding of the molecular mechanisms underlying insulin resistance related to the progression of NAFLD and provide a new therapy target and biomarkers.
Aaron's Code: Meta-Art, Artificial Intelligence and the Work of Harold Cohen

"Aaron's Code" tells the story of the first profound connection between art and computer technology. Here is the work of Harold Cohen - the renowned abstract painter who, at the height of a celebrated career in the late 1960's, abandoned the international scene of museums and galleries and sequestered himself with the most powerful computers he could get his hands on. What emerged from his long years of solitary struggle is an elaborate computer program that makes drawings autonomously, without human intervention - an electronic apprentice and alter ego called Aaron.
Chronic rhinosinusitis: a qualitative study of patient views and experiences of current management in primary and secondary care

Objectives To explore patient views and perspectives of current management of chronic rhinosinusitis (CRS) in primary and secondary care. Design Semistructured qualitative telephone interviews as part of the MACRO programme (Defining best Management for Adults with Chronic RhinOsinusitis). Setting Primary care and secondary care ear, nose and throat outpatient clinics in the UK. Participants Twenty-five patients consented to in-depth telephone interviews. Transcribed recordings were managed using NVivo software and analysed using inductive thematic analysis. Results CRS has a significant impact on patients’ quality of life, affecting their ability to work effectively, their social interactions and daily living. Patients seek help when symptoms become unmanageable, but can become frustrated with the primary care system with difficulties obtaining an appointment, and lack of continuity of care. Patients perceive that general practitioners can be dismissive of CRS symptoms, and patients often prioritise other concerns when they consult. Health system barriers and poor communication can result in delays in accessing appropriate treatment and referral. Adherence to intranasal steroids is a problem and patients are uncertain about correct technique. Nasal irrigation can be time-consuming and difficult for patients to use. Secondary care consultations can appear rushed, and patients would like specialists to take a more ‘holistic’ approach to their management. Surgery is often considered a temporary solution, appropriate when medical options have been explored. Conclusions Patients are frustrated with the management of their CRS, and poor communication can result in delays in receiving appropriate treatment and timely referral. Patients seek better understanding of their condition and guidance to support treatments decisions in light of uncertainties around the different medical and surgical options. Better coordinated care between general practice and specialist settings and consistency of advice has the potential to increase patient satisfaction and improve outcomes.
Trends in Drug Poisoning Deaths Among Adolescents and Young Adults in the United States, 2006-2015.

OBJECTIVE Despite the rising toll of drug poisoning deaths in the United States, the extent of the problem among adolescents and young adults ages 15-24 years has received relatively little attention. We examined sociodemographic characteristics and state trends in drug poisoning deaths among adolescents and young adults from 2006 to 2015 and estimated the costs of drug poisoning mortality in this population. METHOD We used the National Vital Statistics System's Multiple Cause of Death files from 2006 to 2015. We analyzed trends using Joinpoint regression analysis and calculated total costs of drug poisoning deaths, including medical costs, work loss costs, and quality of life loss, based on widely used cost estimates. RESULTS Drug poisoning death rates (per 100,000 population) in adolescents and young adults increased from 8.1 in 2006 to 9.7 in 2015. The rates increased significantly for Whites (1.7% per year) and Asian/Pacific Islanders (4.3% per year) from 2006 to 2015 and for Blacks (11.8% per year) from 2009 to 2015. By U.S. region, the rates increased significantly in the Midwest (4.4% per year) from 2006 to 2015 and in the Northeast (11.0% per year) from 2009 to 2015. Trends varied by age group, intent for drug poisoning, drug category (i.e., opioids, pharmaceutical drugs excluding opioids, illicit drugs excluding opioids, and unspecified drugs), urbanization level, and state. The estimated costs of drug poisoning deaths among adolescents and young adults totaled approximately $35 billion in 2015. CONCLUSIONS Trends in drug poisoning deaths and estimated costs inform state-specific prevention and intervention efforts.
The use of evaluative expressions in the narratives of adolescents with a history of SLI

ABSTRACT Typically, young children diagnosed with specific language impairment (SLI; also called Developmental language disorder, DLD) have been found to show weakness in narrative development, and such weakness has been judged to be unlikely to resolve over time. However, developmental outcomes for adolescents with a prior SLI diagnosis have not been thoroughly studied. In particular, studies on the evaluative aspects of narratives of such persons are almost non-existent. Here we examine the question whether narrative evaluation of adolescents formerly diagnosed with SLI remains problematic into adolescence or comes to resemble more typical narrative performance. We compare the use of evaluative expressions in the narratives of 19 adolescents diagnosed with SLI against 19 typically language developing (TLD) peers. Spoken narratives by the SLI group (Mean age = 14.3; SD = 0.64) and TLD group (Mean age = 14.5; SD = 0.84) using the wordless picture storybook “Frog, where are you? ” (https://childes.talkbank.org/access/Clinical-MOR/Conti/Conti4.html) were analysed. Each narrative was coded for evaluative clauses, types of evaluative devices (frames of mind, character speech, hedges, negatives, and causal connectives), as well as evaluative perspectives (global vs. local). Although the quantitative analysis did not reveal any significant differences between the two groups, the qualitative analysis showed certain notable strengths in the narrative skills of the focal group of SLI adolescents. Results suggest that adolescents with a history of SLI may approximate TLD narrative skill in evaluating their own narratives, but additional work with more sensitive measures applied at intervals are needed to illuminate developmental pathways of narrative production and of evaluative capacities in adolescents formerly diagnosed with SLI.
Socioeconomic position and use of healthcare in the last year of life: A systematic review and meta-analysis

Background Low socioeconomic position (SEP) is recognized as a risk factor for worse health outcomes. How socioeconomic factors influence end-of-life care, and the magnitude of their effect, is not understood. This review aimed to synthesise and quantify the associations between measures of SEP and use of healthcare in the last year of life. Methods and findings MEDLINE, EMBASE, PsycINFO, CINAHL, and ASSIA databases were searched without language restrictions from inception to 1 February 2019. We included empirical observational studies from high-income countries reporting an association between SEP (e.g., income, education, occupation, private medical insurance status, housing tenure, housing quality, or area-based deprivation) and place of death, plus use of acute care, specialist and nonspecialist end-of-life care, advance care planning, and quality of care in the last year of life. Methodological quality was evaluated using the Newcastle-Ottawa Quality Assessment Scale (NOS). The overall strength and direction of associations was summarised, and where sufficient comparable data were available, adjusted odds ratios (ORs) were pooled and dose-response meta-regression performed. A total of 209 studies were included (mean NOS quality score of 4.8); 112 high- to medium-quality observational studies were used in the meta-synthesis and meta-analysis (53.5% from North America, 31.0% from Europe, 8.5% from Australia, and 7.0% from Asia). Compared to people living in the least deprived neighbourhoods, people living in the most deprived neighbourhoods were more likely to die in hospital versus home (OR 1.30, 95% CI 1.23–1.38, p < 0.001), to receive acute hospital-based care in the last 3 months of life (OR 1.16, 95% CI 1.08–1.25, p < 0.001), and to not receive specialist palliative care (OR 1.13, 95% CI 1.07–1.19, p < 0.001). For every quintile increase in area deprivation, hospital versus home death was more likely (OR 1.07, 95% CI 1.05–1.08, p < 0.001), and not receiving specialist palliative care was more likely (OR 1.03, 95% CI 1.02–1.05, p < 0.001). Compared to the most educated (qualifications or years of education completed), the least educated people were more likely to not receive specialist palliative care (OR 1.26, 95% CI 1.07–1.49, p = 0.005). The observational nature of the studies included and the focus on high-income countries limit the conclusions of this review. Conclusions In high-income countries, low SEP is a risk factor for hospital death as well as other indicators of potentially poor-quality end-of-life care, with evidence of a dose response indicating that inequality persists across the social stratum. These findings should stimulate widespread efforts to reduce socioeconomic inequality towards the end of life.
Evidence of Altered Habenular Intrinsic Functional Connectivity in Pediatric ADHD

Objective: The habenula is a small region in the epithalamus that contributes to the regulation of midbrain dopaminergic circuits implicated in attention-deficit hyperactivity disorder (ADHD). This investigation aims to evaluate the intrinsic functional connectivity (iFC) of the habenula in children with ADHD. Method: A total of 112 children (5-9 years; 75 ADHD, 37 healthy comparisons) completed anatomical and resting-state functional magnetic resonance imaging (MRI) scans. Habenula regions of interest (ROIs) were identified individually on normalized T1-weighted anatomical images. Seed-based iFC analyses and group comparisons were conducted for habenula ROIs, as well as thalamic ROIs to test the specificity of habenula findings. Results: Children with ADHD exhibited reduced habenula–putamen iFC compared with healthy comparisons. Group differences in thalamic iFC showed no overlap with habenular findings. Conclusion: These preliminary findings suggest that habenula–putamen iFC may be disrupted in children with ADHD. Further work is needed to confirm and elucidate the role of this circuit in ADHD pathophysiology.
Genes, geology and germs: gut microbiota across a primate hybrid zone are explained by site soil properties, not host species

Gut microbiota in geographically isolated host populations are often distinct. These differences have been attributed to between-population differences in host behaviours, environments, genetics and geographical distance. However, which factors are most important remains unknown. Here, we fill this gap for baboons by leveraging information on 13 environmental variables from 14 baboon populations spanning a natural hybrid zone. Sampling across a hybrid zone allowed us to additionally test whether phylosymbiosis (codiversification between hosts and their microbiota) is detectable in admixed, closely related primates. We found little evidence of genetic effects: none of host genetic ancestry, host genetic relatedness nor genetic distance between host populations were strong predictors of baboon gut microbiota. Instead, gut microbiota were best explained by the baboons' environments, especially the soil's geologic history and exchangeable sodium. Indeed, soil effects were 15 times stronger than those of host–population FST, perhaps because soil predicts which foods are present, or because baboons are terrestrial and consume soil microbes incidentally with their food. Our results support an emerging picture in which environmental variation is the dominant predictor of host-associated microbiomes. We are the first to show that such effects overshadow host species identity among members of the same primate genus.
Ab Initio Determination on Diffusion Coe�cient and Viscosity of FeNi Fluid Under Earth’s Core Condition

: The Earth’s outer core is mainly composed of Fe and Ni. The compositional stratification and 16 geodynamo of the Earth’s core are closely correlated with the transport properties of the fluid in the Earth core. We selected the typical FeNi fluid, and systemically calculated its diffusion coefficient and viscosity 18 under Earth’s core condition by quantum molecular dynamics simulation. The diffusion coefficients and viscosity are almost constant along the core adiabatic curve. The self-diffusion coefficients of Ni along 20 the core adiabatic range from 8.37 × 10 -9 m 2 s -1 to 8.87 × 10 -9 m 2 s -1 . The diffusion coefficient increases with 21 temperature increase, while viscosity decrease with temperature increase. The calculations on the 22 transport properties suggest that the Ni impurities have a negligible effect on the diffusion coefficient 23 and viscosity of Earth’s core. Combining the self-diffusion coefficient of Ni and the diffusion equation, the thickness of compositional stratification at the top of the core is 138.5 km.
Identification of key transcription factors associated with cerebral ischemia-reperfusion injury based on gene-set enrichment analysis

Cerebral ischemia-reperfusion injury (CIRI) usually causes detrimental complications following reperfusion therapy in stroke patients. The present study systematically investigated the regulatory mechanism involved in the pathogenesis of CIRI using gene set enrichment analysis of the transient middle cerebral artery occlusion mouse stroke model. The results revealed a total of 13 CIRI-related transcription factors (TFs), including CCAAT enhancer binding protein b (Cebpb), Cebpa, early growth response-1, Fos, Rela, Jund, signal transduction and activator of transcription 5a/b, transformation related protein 53, GLI family zinc finger 2 (Gli2), Sp3, TF AP-2 α (Tfap2a) and spleen focus forming virus proviral integration oncogene (Spi1). To the best of our knowledge, five TFs (Cebpa, Gli2, Sp3, Tfap2a and Spi1) were the first to be reported associated with CIRI in the present study. The five novel CIRI-related TFs were mainly associated with pathways of inflammation and responses to reperfusion, including the tumor necrosis factor signaling pathway (Gli2, Spi1 and Tfap2a, P=0.0035, 0.0035 and 0.048, respectively), interleuking-17 signaling pathway (Cebpa, Gli2, Sp3, Spi1 and Tfap2a, P=0.019, 0.047, 0.019, 0.035 and 0.005, respectively) and fluid shear stress and atherosclerosis (Gli2, Sp3, Spi1 and Tfap2a, P=0.047, 0.046, 0.013 and 0.003, respectively). These results may improve understanding of the potential molecular mechanism underlying the pathogenesis of CIRI at the genome-wide level.
Mesopore-Rich Activated Carbons for Electrical Double-Layer Capacitors by Optimal Activation Condition

In this study, activated polymer-based hard carbon using steam activation (APHS) with mesopore-rich pore structures were prepared for application as electrodes in electrical double-layer capacitors (EDLC). The surface morphologies and structural characteristics of APHS were observed using scanning electron microscopy and X-ray diffraction analysis, respectively. The textural properties were described using Brunauer-Emmett-Teller and Barrett-Joyner-Halenda equations with N2/77 K adsorption isotherms. APHS were prepared under various steam activation conditions to find optimal ones, which were then applied as electrode materials for the EDLC. The observed specific surface areas and total pore volumes of the APHS were in the range 1170–2410 m2/g and 0.48–1.22 cm3/g, respectively. It was observed that pore size distribution mainly depended on the activation time and temperature, and that the volume of pores with size of 1.5–2.5 nm was found to be a key factor determining the electrochemical capacity.
Investigation of the effects of natural compounds isolated from Arum rupicola var. rupicola on glutathione reductase enzyme purified from bovine liver.

Glutathione reductase (GR, E.C. 1.8.1.7), a flavoenzyme, is responsible for recycling of oxidized glutathione disulfide. This study was performed in two main sections. In the first GR was purified from bovine liver by affinity column chromatography and the purification rate and specific activity of the enzyme were calculated as 1832-fold and 141 EU/mg protein, respectively. The subunit molecular weight of the enzyme was determined as 55 kDa by means of SDS-PAGE. The second section isolated natural components of Arum rupicola Boiss. var. rupicola using column chromatography. The isolation protocol for this plant was performed with a series of different-sized columns with hexane-ethyl acetate. According to the thin-layer chromatography plate, seven substances (R1-R7) were isolated. Our study's aim was to find new activators or inhibitors for GR activity. With this aim, all isolated substances were tested for GR activity. R6 showed competitive inhibition, while R4 had noncompetitive inhibition of GR activity. R1 played a role as an activator of GR activity. The inhibitory activity percentage vs. concentration graph was plotted. Values of IC50 for R4 and R6 were calculated as 0.193 mg/mL and 3.98 μg/mL, respectively, from the equation of this graph.