Miracle-dz/UniFAR-FTUs huggingface dataset:
Physical heaviness of work and sitting at work as predictors of mortality: a 26-year follow-up of the Helsinki Birth Cohort Study

Objectives To examine the relationships of late-career physical heaviness of work and sitting at work with mortality. A national-level job exposure matrix was used to determine the occupation-specific level of physical heaviness and sitting. Design Prospective cohort study between years 1990 and 2015. Setting Community. Participants 5210 men and 4725 women from the Helsinki Birth Cohort Study with an occupational code at baseline (ages 45–57 years). Primary and secondary outcome measures Total, cardiovascular (International Classification of Diseases 10th Revision I00–I99), cancer (C00–C97) and external (S00–Y84) mortality. Results The exposures, physical heaviness and sitting had a non-linear, inverse relationship. During the 26-year follow-up, 1536 men and 759 women died. Among men, physical heaviness of work was positively associated and sitting at work was negatively associated with all-cause, cardiovascular and external cause mortality but they were not associated with cancer mortality. The HRs for men in the highest quartile of physical heaviness of work compared with men in the lowest quartile were 1.54 (1.31–1.80) for all-cause mortality, 1.70 (1.30–2.23) for cardiovascular mortality and 3.18 (1.75–5.78) for external cause mortality (adjusted for age and years of education). Compared with the lowest quartile, the HRs for the highest quartile of sitting at work among men were 0.71 (0.61–0.82) for all-cause mortality, 0.59 (0.45–0.77) for cardiovascular mortality and 0.38 (0.22–0.66) for external cause mortality. In women, neither physical heaviness of work nor sitting at work was associated with mortality. Conclusions Men in physically heavy work at their late-work career are at higher risk of death than men in physically light work.
Humidity Sensor Based on a Long-Period Fiber Grating Coated with Polymer Composite Film

We demonstrate a simple and highly sensitive optical fiber relative humidity (RH) sensor based on a long-period fiber grating (LPFG) coated with polyethylene glycol (PEG)/polyvinyl alcohol (PVA) composite films. The resonance wavelength of the LPFG is sensitive to environmental humidity due to the change in effective refractive index caused by the strong surface absorption and desorption of the porous PEG/PVA coatings. The sensor is sensitive in a wide range from 50% to 95% RH, with a highest sensitivity of 2.485 nm/%RH in the range 50–75% RH. The proposed RH sensor has the advantages of compact size, good reversibility, and stability, which makes it attractive for high-humidity environments.
BMP‐7 attenuates TGF‐β1–induced fibroblast‐like differentiation of rat dermal papilla cells

Dermal papilla cells (DPCs) show phenotypic plasticity during wound healing. The multipotency of DPCs is well recognized, but the signaling pathways that regulate the differentiation of these cells into fibroblasts are poorly understood. A preliminary experiment showed that transforming growth factor beta1 (TGF‐β1) can induce DPCs to differentiate into fibroblast‐like cells, which suggests that DPCs may be a source of wound‐healing fibroblasts. Bone morphogenetic protein‐7 (BMP‐7), a member of the TGF‐β superfamily, can prevent and reverse fibrosis by counteracting the TGF‐β1–mediated profibrotic effect. To determine whether BMP‐7 attenuates the TGF‐β1–induced differentiation of DPCs into fibroblasts, we established an in vitro system for DPC differentiation and recorded the gene expression patterns that distinguished DPCs from fibroblasts. The proportion of fibroblast‐like cells was significantly enhanced in DPCs treated with TGF‐β1, as evidenced by immunocytochemistry, flow cytometry, quantitative real‐time reverse transcriptase polymerase chain reaction, and Western blot analysis. BMP‐7 and TGF‐β1 administration substantially decreased fibroblast‐like differentiation, indicating inhibition of TGF‐β1–induced differentiation. The antagonistic BMP‐7– and TGF‐β1–activated signaling pathways can be used to promote wound healing or suppress hypertrophic scarring.
Madelung-like deformity in pseudohypoparathyroidism type 1b.

CONTEXT Pseudohypoparathyroidism (PHP) types 1a and 1b are distinguished by clinical, biochemical, and molecular features. We report extended kindred with PHP 1b in which many affected members also had growth plate defects, including brachydactyly and a Madelung-like deformity. DESIGN Analyses included clinical examination, assessment of mineral metabolism, thyroid function, skeletal radiography, and analysis of the GNAS and STX16 genes. SETTING Patients were studied in an academic medical center. RESULTS We studied 37 members of a family in which PHP 1b occurred in 23 individuals. Ten of 17 affected patients who were examined had brachydactyly E, including two subjects with Madelung-like defects. Five of 16 subjects had subclinical hypothyroidism; no subject showed sc ossification or short stature. None of the unaffected members had brachydactyly or an elevated serum level of PTH or TSH. Levels of immunoactive erythrocyte Gα(s) were normal in two affected subjects tested. Linkage analysis indicated linkage between PTH resistance and the GNAS gene locus; however, no mutations were identified in GNAS exons 1-13. Methylation analysis of genomic DNA from affected subjects showed loss of maternal epigenotype in exon 1A with normal methylation of the differentially methylated regions for XLGαs and NESP55, and PCR demonstrated heterozygosity for a 3.0-kb deletion in the STX16 gene. CONCLUSION The segregation of brachydactyly with PHP 1b in this family indicates that an imprinting defect in GNAS can lead to growth plate defects, including brachydactyly and Madelung deformity. These features suggest that GNAS signaling plays a more extensive role in chondrocyte maturation than previously thought.
Evaluation of a modified thromboelastography assay for the screening of von Willebrand disease

Summary Thromboelastography (TEG) has been shown to be a valuable point-of-care device for the rapid diagnosis of various bleeding disorders. However, TEG has thus far not been used for the screening for von Willebrand disease (VWD). We evaluated the performance of a modified TEG assay for the laboratory screening of VWD. Three hundred twenty-eight patients (148 male, 180 female, median age 8.4 years, range 0.1 – 72.7 years) were included in the study. The diagnosis and classification of patients was based on personal and familial case history, von Willebrand factor antigen, ristocetin cofactor levels, collagen binding assay, factor VIII coagulant activity and multimer analysis. The ratio of clot strength after preincubation with ristocetin, and without ristocetin, represents the component of clot strength that is formed by cross-linked fibrin fibres and is dependent on the agglutinated platelet fraction. The decrease of the maximum amplitude is a function of the ristocetin concentration and provides a diagnostic parameter able to differentiate between healthy individuals and patients having VWD. Based on a preliminary cut-off value of 25% for the area under the curve (AUC) ratio, the sensitivity varied from 53% to 100% for the different VWD patient groups. The test is suitable for use as a screening test using whole blood and has the additional benefit of being suitable as a point of care test. It appears also useful for monitoring responses to desmopressin (DDAVP) and infusion therapy.
Structure and Hierarchy of Influenza Virus Models Revealed by Reaction Network Analysis

Influenza A virus is recognized today as one of the most challenging viruses that threatens both human and animal health worldwide. Understanding the control mechanisms of influenza infection and dynamics is crucial and could result in effective future treatment strategies. Many kinetic models based on differential equations have been developed in recent decades to capture viral dynamics within a host. These models differ in their complexity in terms of number of species elements and number of reactions. Here, we present a new approach to understanding the overall structure of twelve influenza A virus infection models and their relationship to each other. To this end, we apply chemical organization theory to obtain a hierarchical decomposition of the models into chemical organizations. The decomposition is based on the model structure (reaction rules) but is independent of kinetic details such as rate constants. We found different types of model structures ranging from two to eight organizations. Furthermore, the model’s organizations imply a partial order among models entailing a hierarchy of model, revealing a high model diversity with respect to their long-term behavior. Our methods and results can be helpful in model development and model integration, also beyond the influenza area.
Differences in profiles of emotional behavioral problems across instruments in verbal versus minimally verbal children with autism spectrum disorder

There has been increasing attention to the assessment of minimally verbal (MV) children with autism spectrum disorder (ASD). Previous research has begun to examine the relationship between verbal abilities and emotional and behavioral problems (EBP). The current study compared parent‐reported EBP in children of differing language levels on two instruments commonly used in ASD research and clinical practice, the Child Behavior Checklist (CBCL) and Aberrant Behavior Checklist (ABC). The study consisted of 1,937 6–18 years old children with ASD from the Simons Simplex Collection. Children were divided into three language groups, by ADOS module (Module 1 = MV, 2 = phrase speech (PS), and 3 = verbally fluent (VF)) and then compared on CBCL and ABC subscales. The ABC and CBCL showed different patterns of elevations across the language groups. MV children were reported to have more impairment than VF children on the ABC irritability, lethargy, and hyperactivity scales. Children with less language (MV and PS) exhibited less impairment on the CBCL internalizing domain than VF children, but did not differ on the externalizing domain. Post hoc comparisons showed that internalizing differences were driven by fewer children with less language exhibiting clinically elevated anxious/depressed scores compared to VF children. The present study underscores the significance of considering language when assessing EBP. Results have implications for the psychiatric screening of children with ASD, particularly those with language impairments. Researchers should exercise caution when applying EBP instruments designed for use with different populations and purposes to broad samples of children. Autism Res 2019, 12: 1367–1375. © 2019 International Society for Autism Research, Wiley Periodicals, Inc.
Gender differences among medical students, house staff, and faculty physicians at high risk for suicide: A HEAR report

In comparison with the general population, physicians, and physicians‐in‐training are at greater risk for suicide. Although key gender differences in suicide risk factors and behaviors have been identified in the general population, the extent to which these differences apply to physicians and physicians‐in‐training is unclear. Here, we aimed to identify gender differences in risk factors, clinical presentation, and help‐seeking behaviors of medical students, house staff, and physician faculty at high risk for suicide.
Effects of pioglitazone and/or simvastatin on circulating TNFα and adiponectin levels in insulin resistance

The current study investigated the effects of 14-day pioglitazone (PIO) and/or simvastatin (SIM) treatments on serum adiponectin (Adp) and TNFα levels (markers of adipocyte dysfunction), as well as on metabolic perturbations that arise from prolonged (8 week) consumption of a high fructose (HFD; 60%) diet in a rat model of pre-diabetic insulin resistance. The HFD induced a deranged lipid profile that was associated with adipose tissue hypertrophy, increased ratios of visceral and epididymal fats to body weight, and fatty liver. These perturbations were associated with hypo-adiponectinemia (50.8%) and increased serum TNFα (6.5-fold) levels. Treatment with PIO ameliorated the altered blood and hepatic glucose metabolism via an Adp-dependent mechanism; PIO also mitigated the changes in blood TNFα and led to a hyperelevation of Adp levels. SIM amended hepatic and overall lipid metabolism, regulated TNFα, but failed to alter the glucose intolerance or significantly impact on the HFD-altered Adp levels. Coadministration of SIM + PIO was superior in improving overall metabolic parameters compared to each monotherapy. Cotreatment was optimal in reestablishing insulin resistance, most efficacious in improving serum lipid profiles, normalizing percentage ratios of epididymal and visceral fats to body weight, and augmenting Adp/reducing TNFα levels relative to that in the HFD group or with HFD + each drug alone. The results here show that use of either monotherapy or a combined SIM + PIO approach might, from a clinical perspective, provide an ability to delay progression to Type 2 diabetes and its associated inflammatory/cardiovascular effects.
Tuberculosis household accompaniment to improve the contact management cascade: A prospective cohort study

Background Appropriate management of people exposed in the home to tuberculosis is essential to prevent morbidity. These household contacts, particularly children, should receive preventive therapy to prevent them from falling ill. However, few people receive preventive therapy worldwide. We sought to determine whether a community-based accompaniment intervention could improve tuberculosis contact management. Methods We conducted a prospective cohort study of household contacts of tuberculosis patients who initiated treatment during September 2015-June 2016 in Lima, Peru. Enrolled households received an intervention comprising home visits, transport vouchers, assistance coordinating evaluation procedures, and adherence support during preventive therapy. To evaluate the impact of the intervention, we conducted retrospective chart reviews of all patients initiating treatment during 6-month baseline and intervention periods. Results We enrolled 314 household contacts of 109 index patients. Of these, 283 (90%) completed evaluation, and 4 (1%) were diagnosed with tuberculosis. Preventive therapy was prescribed for 35/38 (92%) contacts 0–19 years old who were eligible under Peruvian guidelines. Preventive therapy was also prescribed for 6/26 (23%) contacts with unknown eligibility due to lack of a tuberculin skin test (TST), and 20/69 (29%) who were ineligible either because of a negative TST result or exposure to a drug-resistant or extrapulmonary case. Of the 61 contacts who were prescribed preventive therapy, 57 (93%) initiated treatment, and 51 (91%) completed treatment. The proportion of contacts who completed evaluation increased from 42% during the baseline period to 71% during the evaluation period (risk ratio [RR] = 1.73, 95% confidence interval [95% CI]: 1.41–2.13). The proportion of contacts who initiated preventive therapy increased from 15% to 40% (RR = 2.45, 95% CI: 1.42–4.22). Conclusion Accompaniment of TB patient households greatly improved the evaluation of household contacts for TB and increased the use of preventive therapy.
Expression of Glypican 3 Is an Independent Prognostic Biomarker in Primary Gastro-Esophageal Adenocarcinoma and Corresponding Serum Exosomes

Exosomes are nano-sized membranous vesicles of endosomal origin that carry nucleic acids, lipids and proteins. The cargo of exosomes is cell origin specific and the release of these exosomes and uptake by an acceptor cell is seen as a vital element of cell-cell communication. Here, we sought to investigate the diagnostic and prognostic value of the expression of glypican 3 (GPC3) on primary gastro-esophageal adenocarcinoma (GEA) tissue (tGPC3) and corresponding serum exosomes (eGPC3). Circulating exosomes were extracted from serum samples of 49 patients with GEA and 56 controls. Extracted exosomes were subjected to flow cytometry for the expression of eGPC3 and GPC3 expression on primary GEA tissue samples was determined by immunohistochemistry and correlated to clinicopathological parameters. We found decreased eGPC3 levels in GEA patients compared to healthy controls (p < 0.0001) and high tGPC3 expression. This was significantly associated with poor overall survival (high vs. low eGPC3: 87.40 vs. 60.93 months, p = 0.041, high vs. low tGPC3: 58.03 vs. 84.70 months, p = 0.044). Cox regressional analysis confirmed tGPC3 as an independent prognostic biomarker for GEA (p = 0.02) and tGPC3 expression was validated in two independent cohorts. Our findings demonstrate that eGPC3 and tGPC3 can be used as potential diagnostic and prognostic biomarkers for GEA.
Cellular Automata Modeling of Stem‐Cell‐Driven Development of Tissue in the Nervous System

Mathematical and computational modeling enables biologists to integrate data from observations and experiments into a theoretical framework. In this review, we describe how developmental processes associated with stem‐cell‐driven growth of tissue in both the embryonic and adult nervous system can be modeled using cellular automata (CA). A cellular automaton is defined by its discrete nature in time, space, and state. The discrete space is represented by a uniform grid or lattice containing agents that interact with other agents within their local neighborhood. This possibility of local interactions of agents makes the cellular automata approach particularly well suited for studying through modeling how complex patterns at the tissue level emerge from fundamental developmental processes (such as proliferation, migration, differentiation, and death) at the single‐cell level. As part of this review, we provide a primer for how to define biologically inspired rules governing these processes so that they can be implemented into a CA model. We then demonstrate the power of the CA approach by presenting simulations (in the form of figures and movies) based on building models of three developmental systems: the formation of the enteric nervous system through invasion by neural crest cells; the growth of normal and tumorous neurospheres induced by proliferation of adult neural stem/progenitor cells; and the neural fate specification through lateral inhibition of embryonic stem cells in the neurogenic region of Drosophila.
Interest of a new biodegradable stent coated with paclitaxel on anastomotic wound healing after biliary reconstruction

Objective Benign biliary stricture of anastomotic stoma is frequent after biliary reconstruction. To prevent such a complication, a new paclitaxel-coated poly-L-lactide acid (PLLA) biodegradable biopolymer stent was designed. This original device was intended both to exert adequate mechanical support properties and to allow controlled drug delivery from the coating, with the goal of favoring wound healing after biliary reconstruction. Methods PLLA stents coated with three different paclitaxel concentrations were implanted in the biliary anastomosis of mongrel dogs (defining groups B, C, and D, respectively). Dogs without stent placement were included in control group A. Liver function tests and residual dosage of paclitaxel from each stent were measured. Histological data and &agr;-smooth muscle actin immunohistochemical staining of biliary–enteric anastomosis were examined. Results There were no significant differences in liver function among the four groups and no bile leakage was observed. The paclitaxel-coated stents could slowly release paclitaxel for 9 weeks. In groups C and D, histological examinations showed less granulation tissue and glandular hyperplasia in biliary–enteric anastomosis than in control groups A and B. Submucosal collagen deposition was reduced and &agr;-smooth muscle actin-positive cells decreased significantly, indicating the inhibition of myofibroblast proliferation in groups C and D. Conclusion PLLA–paclitaxel-coated stents reduced the proliferation of granulation tissue and glandular hyperplasia, and inhibited the myofibroblast proliferation and extracellular matrix overdeposition during the healing process of biliary–enteric anastomotic stoma. This original device may offer a new way for the prevention of benign biliary structure.
TDP-43 induces mitochondrial damage and activates the mitochondrial unfolded protein response

Mutations in or dys-regulation of the TDP-43 gene have been associated with TDP-43 proteinopathy, a spectrum of neurodegenerative diseases including Frontotemporal Lobar Degeneration (FTLD) and Amyotrophic Lateral Sclerosis (ALS). The underlying molecular and cellular defects, however, remain unclear. Here, we report a systematic study combining analyses of patient brain samples with cellular and animal models for TDP-43 proteinopathy. Electron microscopy (EM) analyses of patient samples revealed prominent mitochondrial impairment, including abnormal cristae and a loss of cristae; these ultrastructural changes were consistently observed in both cellular and animal models of TDP-43 proteinopathy. In these models, increased TDP-43 expression induced mitochondrial dysfunction, including decreased mitochondrial membrane potential and elevated production of reactive oxygen species (ROS). TDP-43 expression suppressed mitochondrial complex I activity and reduced mitochondrial ATP synthesis. Importantly, TDP-43 activated the mitochondrial unfolded protein response (UPRmt) in both cellular and animal models. Down-regulating mitochondrial protease LonP1 increased mitochondrial TDP-43 levels and exacerbated TDP-43-induced mitochondrial damage as well as neurodegeneration. Together, our results demonstrate that TDP-43 induced mitochondrial impairment is a critical aspect in TDP-43 proteinopathy. Our work has not only uncovered a previously unknown role of LonP1 in regulating mitochondrial TDP-43 levels, but also advanced our understanding of the pathogenic mechanisms for TDP-43 proteinopathy. Our study suggests that blocking or reversing mitochondrial damage may provide a potential therapeutic approach to these devastating diseases.
Topical modulation of interleukin-1 activity in corneal neovascularization.

PURPOSE To determine whether inflammatory corneal neovascularization (CNV) is associated with interleukin-1 (IL-1) activity and if so, to assess the efficacy of topical interleukin-1 receptor antagonist (IL-1ra) to suppress CNV. METHODS Inflammatory CNV was induced on day 0 by placement of paracentral intrastromal sutures in BALB/c murine eyes. Quantification of IL-1alpha and -beta cytokine levels was done by a sandwich enzyme-linked immunosorbent assay (ELISA) on the supernatants of incubated corneas excised at specified time points after induction of CNV (n = 6 per time point studied). To study suppression of CNV by IL-1ra, animals were divided into treatment subgroups that received topical 20 mg/ml of IL-1ra mixed in 0.2% sodium hyaluronate (n = 28) or placebo (vehicle) alone (n = 22) 3 times daily during days 0-35. Other groups of animals received placebo for 1 (n = 10) or 2 (n = 14) weeks before being switched and retained on IL-1ra. Neovascularization was assessed biomicroscopically and graded by using a standardized scheme. RESULTS Induction of CNV stimulus was associated with a significant surge in the expression of both IL-1alpha (p < 0.001) and IL-1beta (p < 0.001) as early as 2 h after the stimulus, which peaked at 24 h, before decreasing substantially in the case of IL-1beta and returning to basal levels by day 7. Topical application of IL-1ra led to a significant suppression of CNV for the duration of therapy only if initiated early after induction of the neovascular stimulus. Initiation of therapy 1 week after CNV induction was associated only with a transient suppression in the angiogenic response. CONCLUSION Our data strongly implicate IL-1 as a critical mediator in the early phase of CNV and suggest that IL-1ra can be an effective modality in suppressing CNV if initiated sufficiently early after the inflammatory neovascular stimulus.