Miracle-dz/UniFAR-FTUs huggingface dataset:
Mental wellbeing among people in prison in Scotland: an analysis of repeat cross-sectional surveys

ABSTRACT Background Mental wellbeing among people in prison is poorly studied, despite featuring in many health and justice policies. We aimed to describe for the first time mental wellbeing among an unselected national prison sample. Methods Since 2013, the Scottish Prisoner Survey—a biennial survey of people in custody in Scotland—has included the Warwick-Edinburgh mental wellbeing scale (WEMWBS), a 14-item scale with higher scores indicating greater wellbeing. We analysed data from sweeps in 2013 (n = 3158), 2015 (n = 2892) and 2017 (n = 2405) using Student’s t-test, ANOVA and multiple linear regression. We also used WEMWBS data from the Scottish Health Survey stratified by age, gender and deprivation to compare with the population at liberty. Results Mean WEMWBS scores overall were 43.4 in 2013 (SD = 12.2), 41.8 (SD = 11.9) in 2015 and 41.2 (SD = 12.3) in 2017. Mean scores were lower among people on remand and with multiple prison episodes. Age-standardized mean scores were lower among people in prison than their peers at liberty. Conclusions Poor mental wellbeing is an important, under-studied facet of the extreme health inequalities associated with imprisonment. These results identify that people on remand or with multiple episodes are particularly disadvantaged and provide a baseline for monitoring impacts of service or policy interventions.
Transforming growth factor‐β signaling confers hepatic stellate cells progenitor features after partial hepatectomy

Liver regeneration involves not only hepatocyte replication but progenitor aggregation and scarring. Partial hepatectomy (PH), an established model for liver regeneration, reactivates transforming growth factor‐β (TGF‐β) signaling. Hepatic stellate cells (HSCs) are primarily responding cells for TGF‐β and resident in stem cell niche. In the current study, PH mice were treated with SB‐431542, an inhibitor of TGF‐β Type I receptor, aiming to address the role of TGF‐β signaling on the fate determination of HSCs during liver regeneration. After PH, control mice exhibited HSCs activation, progenitor cells accumulation, and a fraction of HSCs acquired the phenotype of hepatocyte or cholangiocyte. Blocking TGF‐β signaling delayed proliferation, impaired progenitor response, and scarring repair. In SB‐431542 group, merely no HSCs were found coexpressed progenitor makers, such as SOX9 and AFP. Inhibition of TGF‐β pathway disturbed the epithelial‐mesenchymal transitions and diminished the nuclear accumulation of β‐catenin as well as the expression of cytochrome P450 2E1 in HSC during liver regeneration. We identify a key role of TGF‐β signaling on promoting HSC transition, which subsequently becomes progenitor for generating liver epithelial cells after PH. This process might interact with an acknowledged stem cell function signaling, Wnt/β‐catenin.
Click-encoded rolling FISH for visualizing single-cell RNA polyadenylation and structures

Abstract Spatially resolved visualization of RNA processing and structures is important for better studying single-cell RNA function and landscape. However, currently available RNA imaging methods are limited to sequence analysis, and not capable of identifying RNA processing events and structures. Here, we developed click-encoded rolling FISH (ClickerFISH) for visualizing RNA polyadenylation and structures in single cells. In ClickerFISH, RNA 3′ polyadenylation tails, single-stranded and duplex regions are chemically labeled with different clickable DNA barcodes. These barcodes then initiate DNA rolling amplification, generating repetitive templates for FISH to image their subcellular distributions. Combined with single-molecule FISH, the proposed strategy can also obtain quantitative information of RNA of interest. Finally, we found that RNA poly(A) tailing and higher-order structures are spatially organized in a cell type-specific style with cell-to-cell heterogeneity. We also explored their spatiotemporal patterns during cell cycle stages, and revealed the highly dynamic organization especially in S phase. This method will help clarify the spatiotemporal architecture of RNA polyadenylation and structures.
Synonymous genome recoding: a tool to explore microbial biology and new therapeutic strategies

Abstract Synthetic genome recoding is a new means of generating designed organisms with altered phenotypes. Synonymous mutations introduced into the protein coding region tolerate modifications in DNA or mRNA without modifying the encoded proteins. Synonymous genome-wide recoding has allowed the synthetic generation of different small-genome viruses with modified phenotypes and biological properties. Recently, a decreased cost of chemically synthesizing DNA and improved methods for assembling DNA fragments (e.g. lambda red recombination and CRISPR-based editing) have enabled the construction of an Escherichia coli variant with a 4-Mb synthetic synonymously recoded genome with a reduced number of sense codons (n = 59) encoding the 20 canonical amino acids. Synonymous genome recoding is increasing our knowledge of microbial interactions with innate immune responses, identifying functional genome structures, and strategically ameliorating cis-inhibitory signaling sequences related to splicing, replication (in eukaryotes), and complex microbe functions, unraveling the relevance of codon usage for the temporal regulation of gene expression and the microbe mutant spectrum and adaptability. New biotechnological and therapeutic applications of this methodology can easily be envisaged. In this review, we discuss how synonymous genome recoding may impact our knowledge of microbial biology and the development of new and better therapeutic methodologies.
Chronic oral anticoagluation and risk of prostate cancer: Evidence of detection bias

Warfarin treatment has been associated with lower risks of prostate cancer, without a specified biological mechanism. Our study tested the hypothesis that reluctance to perform prostate biopsies in men who are anticoagulated results in lower rates of diagnosed prostate cancer, leading to an apparent protective effect. Rates of prostate biopsies have decreased from 2000 to 2015, allowing calendar time to be used as the intervention. In a national population‐based sample of elderly men, our study compared trends in prostate cancer incidence between 17,815 men treated with chronic oral anticoagulation for prosthetic heart valve thromboprophylaxis and a general population comparison group of 356,300 men. Cancer events were based on administrative claims. Among men enrolled in 2000–2001 and followed through 2015, prostate cancer incidence was substantially lower in the anticoagulation group (adjusted incidence rate ratio [IRR] 0.70; 95% confidence interval [CI] 0.62–0.80). Incidence decreased over time in the general population group to approach that of the anticoagulation group among men enrolled in 2008–2010 (IRR 0.86; 95% CI 0.71–1.04). Rates of prostate biopsies also decreased over time in the general population group to match the rate in the anticoagulation group. These results indicate that the apparent protective effect of warfarin treatment on the risk of prostate cancer is likely the result of detection bias from lower rates of biopsies among men who are anticoagulated.
Ibrutinib Potentiates Antihepatocarcinogenic Efficacy of Sorafenib by Targeting EGFR in Tumor Cells and BTK in Immune Cells in the Stroma

Hepatocellular carcinoma (HCC), the most prevalent primary liver cancer, is a leading cause of cancer-related death worldwide because of rising incidence and limited therapy. Although treatment with sorafenib or lenvatinib is the standard of care in patients with advanced-stage HCC, the survival benefit from sorafenib is limited due to low response rate and drug resistance. Ibrutinib, an irreversible tyrosine kinase inhibitor (TKI) of the TEC (e.g., BTK) and ErbB (e.g., EGFR) families, is an approved treatment for B-cell malignancies. Here, we demonstrate that ibrutinib inhibits proliferation, spheroid formation, and clonogenic survival of HCC cells, including sorafenib-resistant cells. Mechanistically, ibrutinib inactivated EGFR and its downstream Akt and ERK signaling in HCC cells, and downregulated a set of critical genes involved in cell proliferation, migration, survival, and stemness, and upregulated genes promoting differentiation. Moreover, ibrutinib showed synergy with sorafenib or regorafenib, a sorafenib congener, by inducing apoptosis of HCC cells. In vivo, this TKI combination significantly inhibited HCC growth and prolonged survival of immune-deficient mice bearing human HCCLM3 xenograft tumors and immune-competent mice bearing orthotopic mouse Hepa tumors at a dose that did not exhibit systemic toxicity. In immune-competent mice, the ibrutinib–sorafenib combination reduced the numbers of BTK+ immune cells in the tumor microenvironment. Importantly, we found that the BTK+ immune cells were also enriched in the tumor microenvironment in a subset of primary human HCCs. Collectively, our findings implicate BTK signaling in hepatocarcinogenesis and support clinical trials of the sorafenib–ibrutinib combination for this deadly disease.
Effectiveness of the Diabetes Prevention Program for Obesity Treatment in Real World Clinical Practice in a Middle-Income Country in Latin America

The Diabetes Prevention Program (DPP) is effective for the prevention of type 2 diabetes by weight loss with diet and physical activity. However, there is little evidence as to whether this program could be translated into real-world clinical practice in Latin American countries. The objective of this work was to evaluate the effectiveness of the DPP for the management of overweightness and obesity at 6 and 12 months in clinical practice in Mexico. This was a non-controlled intervention study implemented in five public clinics in northern Mexico. Two hundred and thirty-seven adults aged 45.7 ± 9.9 years with a Body Mass Index (BMI) of 34.4 ± 5.4 kg/m2 received group sessions with an adaptation of the DPP, in addition to nutrition counseling. One hundred and thirty-three (56%) participants concluded the 6 month phase. They showed a significant weight loss, ranging from 2.76 ± 4.76 to 7.92 ± 6.85 kg (p ≤ 0.01) in the clinics. The intention-to-treat analysis showed a more conservative weight loss. Participant retention at the end of 12 months was low (40%). The implementation of the DPP in different public clinics in Mexico was effective in the management of obesity in the short term, but better strategies are required to improve participant retention in the long term.
DORMAN: Database of Reconstructed MetAbolic Networks

Genome-scale reconstructed metabolic networks have provided an organism specific understanding of cellular processes and their relations to phenotype. As they are deemed essential to study metabolism, the number of organisms with reconstructed metabolic networks continues to increase. This everlasting research interest lead to the development of online systems/repositories that store existing reconstructions and enable new model generation, integration, and constraint-based analyses. While features that support model reconstruction are widely available, current systems lack the means to help users who are interested in analyzing the topology of the reconstructed networks. Here, we present the Database of Reconstructed Metabolic Networks - DORMAN. DORMAN is a centralized online database that stores SBML-based reconstructed metabolic networks published in the literature, and provides web-based computational tools for visualizing and analyzing the model topology. Novel features of DORMAN are (i) interactive visualization interface that allows rendering of the complete network as well as editing and exporting the model, (ii) hierarchical navigation that provides efficient access to connected entities in the model, (iii) built-in query interface that allow posing topological queries, and finally, and (iv) model comparison tool that enables comparing models with different nomenclatures, using approximate string matching. DORMAN is online and freely accessible at http://ciceklab.cs. bilkent.edu. tr/dorman.
Organic Anion-Transporting Polypeptide Genes Are Not Induced by the Pregnane X Receptor Activator Rifampin: Studies in Hepatocytes In Vitro and in Monkeys In Vivo

Induction potentials of the pregnane X receptor (PXR) activator rifampin (RIF) on transporter genes [e.g., organic anion-transporting polypeptides (OATPs)] are still in its infancy or remain controversial in the field. The present investigations characterized changes in transporter gene expression by RIF in sandwich-cultured hepatocytes from multiple donors of human and cynomolgus monkey using real-time quantitative reverse transcription polymerase chain reaction method. Three-day treatment of RIF significantly induced CYP3A4 (∼60-fold induction), but not CYP1A2 and CYP2D6 genes. SLC51B was the most highly induced uptake transporter gene (>10-fold) in both human and monkey hepatocytes. A greater induction of CYP2C9 was observed in monkey hepatocytes than that in humans. ATP-binding cassette (ABC)B1 and ABCC2 were induced slightly above 2-fold in human and monkey hepatocytes and appeared to be dose-dependent. The induction of OATP and other transporter genes was generally less than 2-fold and considered not clinically relevant. SLCO2B1 was not detectable in monkey hepatocytes. To investigate in vivo OATP induction, RIF (18 mg/kg per day) was orally dosed to cynomolgus monkeys for 7 days. Pitavastatin and antipyrine were intravenously dosed before and after RIF treatment as exogenous probes of OATP and CYP activities, respectively. Plasma coproporphyrin-I (CP-I) and coproporphyrin-III (CP-III) were measured as OATP endogenous biomarkers. Although a significant increase of antipyrine clearance (CL) was observed after RIF treatment, the plasma exposures of pitavastatin, CP-I, and CP-III remained unchanged, suggesting that OATP function was not significantly altered. The results suggested that OATP transporters were not significantly induced by PXR ligand RIF. The data are consistent with current regulatory guidances that the in vitro characterization of transporter induction during drug development is not required. SIGNIFICANCE STATEMENT Organic anion-transporting polypeptide (OATP) genes were not induced by rifampin in sandwich-cultured human and monkey hepatocytes OATP functions measured by OATP probe pitavastatin and endogenous marker coproporphyrins were not altered in monkeys in vivo by 7-day rifampin treatment. The data suggested that OATP transporters are unlikely induced by the pregnane X receptor ligand rifampin, which are consistent with current regulatory guidances that the in vitro characterization of OATP1B induction during drug development is not required.
Test-retest stability of self-reported violence against women measures: results from the stepping stones and creating futures pilot

ABSTRACT Background: Stability of measures in quantitative social science research is crucial to understand. There is very little evidence on the stability of violence against women and girls measures in the global South. Objective: To assess the test-retest stability of violence against women and girls measures, amongst young (18–30) people in South Africa. Methods: Data were collected from 124 women and 112 men at zero weeks (time 1) and two weeks (time 2), who resided in urban informal settlements in South Africa. Prevalence of each construct was assessed using chi-square contingency tables. Stability of self-report over time was assessed using Cohen’s Kappa. Bivariate logistic regression assessed factors associated with changing responses between time 1 and time 2. Results: At group level prevalence of all measures showed no significant differences. Stability of self-report: kappas for past year physical IPV were both k0.20, for ever physical IPV (women k0.58; men k0.50). Sexual IPV in past 12m (women k0.44; men k0.18), and for ever sexual IPV (women k0.56; men k0.46). Kappas for men’s perpetration of non-partner sexual violence was k0.29 for past 12m and k0.38 ever. In bivariate regression, completion of secondary education was associated with a reduced odds of changing responses over the time-period for sexual IPV ever women (OR0.16, 0.02–1.04), sexual IPV past 12 months men (OR 0.09, 0.01–0.56), past 12 month non-partner sexual violence men (OR0.19, 0.02–1.41) and lifetime non-partner sexual violence (OR0.23, 0.04–1.19). Being male, compared to being female, was associated with an increased likelihood of changing responses for past 12 month sexual IPV (OR2.10, 1.08–4.09). Conclusions: Prevalence estimates of violence against women measures are stable at group level, but stability of self-reported measures remains a concern. Individual statistical analyses must be treated with caution. Future studies are required to develop further understandings of stability of measures over time.
MALDI-TOF Mass Spectrometry-Based High-Throughput Screening for Inhibitors of the Cytosolic DNA Sensor cGAS

Comprehensive and unbiased detection methods are a prerequisite for high-throughput screening (HTS) campaigns within drug discovery research. Label-free matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) has been introduced as an HTS-compatible readout for biochemical test systems to support the drug discovery process. So far, reported HTS applications were based on surface-modified systems or proof-of-concept studies. We present the utilization of a MALDI-TOF-based screening platform to identify inhibitors of human cyclic GMP-AMP synthase (cGAS), a mediator of innate immune response whose aberration has been causally correlated to a number of inflammatory disorders. In this context, the development and validation of a MALDI-TOF-based activity assay is reported to demonstrate fast, robust, and accurate detection of chemical cGAS inhibition by direct quantification of the physiological reaction product cyclic GMP-ATP (cGAMP). Results from a screen of a diverse library of more than 1 million small molecules in 1536-well format against the catalytic cGAS activity are presented with excellent assay performance and data quality. Identified hits were qualified in dose–response experiments and confirmed by RapidFire-MS measurements. Conclusively, the presented data provide the first proof of applicability of direct automated MALDI-TOF MS as a readout strategy for large-scale drug discovery HTS campaigns.
The Association between Early Childhood and Later Childhood Sugar-Containing Beverage Intake: A Prospective Cohort Study

Sugar-containing beverages (SCBs) are a major source of sugar intake in children. Early life intake of SCBs may be a strong predictor of SCB intake later in life. The primary objective of this study was to evaluate if SCB intake (defined as 100% fruit juice, soda, and sweetened drinks) in early childhood (≤2.5 years of age) was associated with SCB intake in later childhood (5–9 years of age). A prospective cohort study was conducted using data from the TARGet Kids! primary care practice network (n = 999). Typical daily SCB intake was measured by parent-completed questionnaires. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression. A total of 43% of children consumed ≥0.5 cups/day of SCBs at ≤2.5 years and this increased to 64% by 5–9 years. Daily SCB intake, compared to no daily intake, at ≤2.5 years was significantly associated with SCB intake at 5–9 years (adjusted OR: 4.03; 95% CI: 2.92–5.55) and this association was much stronger for soda/sweetened drinks (adjusted OR: 12.83; 95% CI: 4.98, 33.0) than 100% fruit juice (OR: 3.61; 95% CI: 2.63–4.95). Other early life risk factors for SCB intake at 5–9 years were presence of older siblings, low household income, and shorter breastfeeding duration. Daily intake of SCBs in early childhood was strongly associated with greater SCB intake in later childhood. Early life may be an important period to target for population prevention strategies.
An Integrated Bioinformatics Analysis Repurposes an Antihelminthic Drug Niclosamide for Treating HMGA2-Overexpressing Human Colorectal Cancer

Aberrant overexpression of high mobility group AT-hook 2 (HMGA2) is frequently found in cancers and HMGA2 has been considered an anticancer therapeutic target. In this study, a pan-cancer genomics survey based on Cancer Cell Line Encyclopedia (CCLE) and The Cancer Genome Atlas (TCGA) data indicated that HMGA2 was mainly overexpressed in gastrointestinal cancers including colorectal cancer. Intriguingly, HMGA2 overexpression had no prognostic impacts on cancer patients’ overall and disease-free survivals. In addition, HMGA2-overexpressing colorectal cancer cell lines did not display higher susceptibility to a previously identified HMGA2 inhibitor (netroposin). By microarray profiling of HMGA2-driven gene signature and subsequent Connectivity Map (CMap) database mining, we identified that S100 calcium-binding protein A4 (S100A4) may be a druggable vulnerability for HMGA2-overexpressing colorectal cancer. A repurposing S100A4 inhibitor, niclosamide, was found to reverse the HMGA2-driven gene signature both in colorectal cancer cell lines and patients’ tissues. In vitro and in vivo experiments validated that HMGA2-overexpressing colorectal cancer cells were more sensitive to niclosamide. However, inhibition of S100A4 by siRNAs and other inhibitors was not sufficient to exert effects like niclosamide. Further RNA sequencing analysis identified that niclosamide inhibited more cell-cycle-related gene expression in HMGA2-overexpressing colorectal cancer cells, which may explain its selective anticancer effect. Together, our study repurposes an anthelminthic drug niclosamide for treating HMGA2-overexpression colorectal cancer.
The effects of on-call work on mental health issues among wage workers in the Republic of Korea

ABSTRACT On-call workers are often on standby at night or on weekends and are called to perform work when unanticipated incidents occur. However, the effects of on-call duty on the mental health has received little attention. The objective of this study was to investigate the effects of on-call work on mental health problems among Korean wage workers. Korean wage workers (56,553) from the 2011–2014 Korean Working Condition Survey were enrolled. The outcome measures included insomnia or sleep disorder and depression or anxiety disorder. General characteristics, occupational and work environment characteristics were used to adjust for control variables. Among the Korean wage workers, 8.2% (N=4,653) performed on-call duties. On-call workers were more likely to experience insomnia or sleep disturbance (3.8%vs2.4%; p<.0001) and depression or anxiety disorder (2.2%vs1.2%; p<.0001) than those who did not have on-call duties. After adjusting for control variables, the odds ratio (OR) for insomnia or sleep disturbance was 1.56 (95% CI, 1.23–1.99), and the OR for depression or anxiety disorder was 2.23 (95% CI, 1.61–3.08). In conclusion, on-call work was associated with mental health problems in Korean wage workers. Therefore, we need to understand the problems of on-call workers, and try to improve their health care.