Miracle-dz/UniFAR-FTUs huggingface dataset:
Protein tyrosine phosphatase 1B regulates miR-208b-argonaute 2 association and thyroid hormone responsiveness in cardiac hypertrophy

Increased production of reactive oxygen species plays an essential role in the pathogenesis of several diseases, including cardiac hypertrophy. In our search to identify redox-sensitive targets that contribute to redox signaling, we found that protein tyrosine phosphatase 1B (PTP1B) was reversibly oxidized and inactivated in hearts undergoing hypertrophy. Cardiomyocyte-specific deletion of PTP1B in mice (PTP1B cKO mice) caused a hypertrophic phenotype that was exacerbated by pressure overload. Furthermore, we showed that argonaute 2 (AGO2), a key component of the RNA-induced silencing complex, was a substrate of PTP1B in cardiomyocytes and in the heart. Our results revealed that phosphorylation at Tyr393 and inactivation of AGO2 in PTP1B cKO mice prevented miR-208b–mediated repression of thyroid hormone receptor–associated protein 1 (THRAP1; also known as MED13) and contributed to thyroid hormone–mediated cardiac hypertrophy. In support of this conclusion, inhibiting the synthesis of triiodothyronine (T3) with propylthiouracil rescued pressure overload–induced hypertrophy and improved myocardial contractility and systolic function in PTP1B cKO mice. Together, our data illustrate that PTP1B activity is cardioprotective and that redox signaling is linked to thyroid hormone responsiveness and microRNA-mediated gene silencing in pathological hypertrophy. Description Oxidation of PTP1B alters microRNA processing to promote thyroid hormone–induced cardiac hypertrophy. Protecting the heart with PTP1B Pressure overload induced by aortic banding causes oxidative stress. Coulis et al. uncovered a pathway by which oxidative stress exacerbates cardiac hypertrophy after aortic banding. In mice subjected to pressure overload, the tyrosine phosphatase PTP1B was inactivated by oxidation, resulting in greater phosphorylation and decreased microRNA loading of Ago2, a component of the RNA-induced silencing complex. This ultimately led to enhanced sensitivity to thyroid hormone and increased cardiac hypertrophy. Mice with a cardiomyocyte-specific deletion of PTP1B had greater cardiac hypertrophy after pressure overload, an effect blunted by blocking thyroid hormone synthesis. Thus, oxidative stress during pressure overload promotes hypertrophy by inactivating PTP1B, altering microRNA processing, and increasing sensitivity to thyroid hormone.
Relationship between NAFLD and coronary artery disease: A Mendelian randomization study

Background and Aims: There is an ongoing debate on whether NAFLD is an active contributor or an innocent bystander in the pathogenesis of coronary artery disease (CAD). The aim of the present study was to assess the causal relationship between NAFLD and CAD. Approach and Results: We performed two‐sample Mendelian randomization (MR) analyses using summary‐level data to assess the association between genetically predicted NAFLD (i.e., chronically elevated serum alanine aminotransferase levels [cALT], imaging‐based and biopsy‐confirmed NAFLD) and risk of CAD. Analyses were repeated after exclusion of NAFLD susceptibility genes that are associated with impaired VLDL secretion. Inverse‐variance weighted MR analyses showed a statistically significant association between genetically predicted cALT and risk of CAD (OR: 1.116, 95% CI: 1.039, 1.199), but not for the other NAFLD‐related traits (OR: 1.046, 95% CI: 0.764, 1.433 and OR: 1.014, 95% CI: 0.968, 1.062 for imaging‐based and biopsy‐confirmed NAFLD, respectively). MR‐Egger regression revealed a statistically significant intercept, indicative of directional pleiotropy, for all traits. Repeat analyses after exclusion of genes associated with impaired VLDL secretion showed consistent associations between genetically predicted NAFLD and CAD for all traits (i.e., cALT [OR: 1.203, 95% CI: 1.113, 1.300]), imaging‐based (OR: 2.149, 95% CI: 1.276, 3.620) and biopsy‐confirmed NAFLD (OR: 1.113, 95% CI: 1.041, 1.189), which persisted when more stringent biopsy‐confirmed NAFLD criteria were used (OR: 1.154, 95% CI: 1.043, 1.278) or when more stringent MR methods were applied. MR‐Egger regression did not show a statistically significant intercept. Conclusion: The two‐sample MR analyses showed a robust association between genetically predicted NAFLD and CAD after exclusion of genetic variants that are implicated in impaired VLDL secretion.
A Randomized Controlled Trial of Dietary Rice Bran Intake on Microbiota Diversity, Enteric Dysfunction, and Fecal Secretory IgA in Malian and Nicaraguan Infants

ABSTRACT Background Malnutrition and diarrhea are leading causes of death in children aged <5 y. Rice bran is a nutrient-dense prebiotic available globally. Objectives The objective of this secondary analysis was to evaluate the effects of daily rice bran supplementation on environmental enteric dysfunction (EED) markers, total fecal secretory IgA (sIgA), and microbiota in infants at high risk of malnutrition. Methods Six-month-old Malian and Nicaraguan infants were randomly assigned to control or daily rice bran supplementation cohorts (1 to 5 g/d). Feces were collected monthly for 6 mo to evaluate fecal sIgA, markers of EED, and microbiota diversity. Statistical methods included linear mixed models, generalized mixed models, Spearman correlation, and Wilcoxon rank-sum tests. Results Six-month-old Malian infants had significantly elevated sIgA (4.0× higher, P < 0.001), fecal myeloperoxidase (31.6× higher, P < 0.001), fecal α1-antitrypsin (1.8× higher, P = 0.006), and lower fecal neopterin (0.13× higher, P < 0.001) than the age-matched Nicaraguan infants. In the Nicaraguan rice bran cohort from 6 to 12 mo of age, there was a significant decrease in sIgA concentrations (0.4×, P < 0.05) and a correlation between sIgA and the EED marker α1-antitrypsin (0.523, P < 0.0001) at 12 mo of age. In Malian infants, daily rice bran ingestion resulted in decreased EED scores (0.71×, P = 0.02) and a stable sIgA concentration over time. The rice bran group of Malian infants also had correlation between sIgA and the EED marker neopterin (0.544, P < 0.001) at 12 mo of age and a significant (P < 0.05) increase in microbiota α-diversity at a younger age (9 mo with rice bran compared with 10 mo in control group), which supports earlier microbiota maturation. Conclusions These results support rice bran as a functional food ingredient targeting gut mucosa in children at high-risk of malnutrition.
Review of the structures and functions of algal photoreceptors to optimize bioproduct production with novel bioreactor designs for strain improvement

Microalgae are important renewable feedstock to produce biodiesel and high‐value chemicals. Different wavelengths of light influence the growth and metabolic activities of algae. Recent research has identified the light‐sensing proteins called photoreceptors that respond to blue or red light. Structural elucidations of algal photoreceptors have gained momentum over recent years. These include channelrhodopsins, PHOT proteins, animal‐like cryptochromes, and blue‐light sensors utilizing flavin‐adenine dinucleotide proteins. Pulsing light has also been investigated as a means to optimize energy inputs into bioreactors. This study summarizes the current structural and functional basis of photoreceptor modulation to optimize the growth, production of carotenoids and other high‐value metabolites from microalgae. The review also encompasses novel photobioreactor designs that implement different light regimes including light wavelengths and time to optimize algal growth and desired metabolite profiles for high‐value products.
Development of synaptic fidelity and action potential robustness at an inhibitory sound localization circuit: effects of otoferlin‐related deafness

Sound localization involves information analysis in the lateral superior olive (LSO), a conspicuous nucleus in the mammalian auditory brainstem. LSO neurons weigh interaural level differences (ILDs) through precise integration of glutamatergic excitation from the cochlear nucleus (CN) and glycinergic inhibition from the medial nucleus of the trapezoid body (MNTB). Sound sources can be localized even during sustained perception, an accomplishment that requires robust neurotransmission. Virtually nothing is known about the sustained performance and the temporal precision of MNTB–LSO inputs after postnatal day (P)12 (time of hearing onset) and whether acoustic experience guides development. Here we performed whole‐cell patch‐clamp recordings to investigate neurotransmission of single MNTB‐LSO fibres upon sustained electrical stimulation (1–200 Hz/60 s) at P11 and P38 in wild‐type (WT) and deaf otoferlin (Otof) knock‐out (KO) mice. At P11, WT and KO inputs performed remarkably similarly. In WTs, the performance increased drastically between P11 and P38, e.g. manifested by an 8 to 11‐fold higher replenishment rate (RR) of synaptic vesicles and action potential robustness. Together, these changes resulted in reliable and highly precise neurotransmission at frequencies ≤100 Hz. In contrast, KO inputs performed similarly at both ages, implying impaired synaptic maturation. Computational modelling confirmed the empirical observations and established a reduced RR per release site for P38 KOs. In conclusion, acoustic experience appears to contribute massively to the development of reliable neurotransmission, thereby forming the basis for effective ILD detection. Collectively, our results provide novel insights into experience‐dependent maturation of inhibitory neurotransmission and auditory circuits at the synaptic level.
A Real World Perspective of PARP Inhibitor Use in Gynecological Cancer Patients

Introduction: Over the last few years, targeted therapy has become the mainstay maintenance treatment of patients with ovarian cancer including patients with BRCA1/BRCA2 mutations. Poly ADP ribose polymerase inhibitors (PARPi) are effective in the treatment of patients who are in complete or partial remission. PARPi are known to cause hematological adverse events (AEs), but have not been compared directly to each other. Objective: Primary objective was to compare the incidence of hematological and non-hematological AEs associated with the use of PARPi. Methods: This was a single institution, retrospective study evaluating patients who were treated with PARPi for ovarian cancer from January 2017 to October 2020. Patients were stratified according to which PARP inhibitor they received. Results: Ninety-two patients were included in final analysis. Thirty-one (33.7%) patients received niraparib and 61 (66.3%) patients received olaparib. Median age of patients were 64.3 (range, 33.8 to 92.3) years, 66 (71.7%) were white, and 84 (91.3%) had an ECOG PS of 0/1. Patients in the niraparib group experienced a higher rate of hematologic AEs, with 11 (35.5%), 20 (64.5%), and 18 (58.1%) experiencing neutropenia, anemia, and thrombocytopenia, respectively. Eight (13.1%), 24 (39.3%), and 16 (26.2%) patients in the olaparib group experienced neutropenia, anemia, and thrombocytopenia, respectively. Conclusion: This single institution retrospective study outlines the hematological toxicities observed between two PARPi. Our results suggested that niraparib tended to be associated with a higher risk for hematologic toxicities than olaparib. Anemia was the most common hematologic toxicity which was consistent with what has been widely documented in the literature.
Portuguese Version of the Stigma Scale: Preliminary Psychometric Characteristics.

INTRODUCTION Stigma is associated with poor prognosis of illness and reduced help-seeking behavior, self-esteem and treatment compliance. The aims of this study were to study the reliability and construct validity of the King's et al Stigma Scale, and its association with Illness and Help-Seeking Behaviors scale (IHSBS) scores. MATERIAL AND METHODS One hundred and forty mental health patients filled out the Stigma scale and the Illness and Help-Seeking Behaviors scale. The exploratory factor analysis of the stigma scale was performed, and its reliability studied. The correlation analysis was used and mean differences in Stigma Scale scores among IHSBS groups were explored. RESULTS The exploratory factor analysis indicated four factors (F): F1-Disclosure, F2-Discrimination, F3-Acceptance and F4-Personal Growth, which showed acceptable/good internal consistency (α from 0.70 to 0.91). Help-seeking behaviors were not associated with stigma. The levels of Discrimination were high in the group with global high-IHSB and in patients with medium/high illness behavior (IB) and health-related worries (HW). Additionally, Disclosure and overall stigma levels were higher in groups with high-HW and with medium-IB scores (when compared with the group with low-IB). The group with low-IB also had lower levels of Acceptance and Personal Growth when compared with the groups with medium-IB and high-IB, respectively. CONCLUSION The Stigma Scale (27 items) is a valid, reliable instrument and useful tool to assess stigma in mental health patients.
Predicting Archaic Hominin Phenotypes from Genomic Data

Ancient DNA provides a powerful window into the biology of extant and extinct species, including humans’ closest relatives: Denisovans and Neanderthals. Here, we review what is known about archaic hominin phenotypes from genomic data and how those inferences have been made. We contend that understanding the influence of variants on lower-level molecular phenotypes—such as gene expression and protein function—is a promising approach to using ancient DNA to learn about archaic hominin traits. Molecular phenotypes have simpler genetic architectures than organism-level complex phenotypes, and this approach enables moving beyond association studies by proposing hypotheses about the effects of archaic variants that are testable in model systems. The major challenge to understanding archaic hominin phenotypes is broadening our ability to accurately map genotypes to phenotypes, but ongoing advances ensure that there will be much more to learn about archaic hominin phenotypes from their genomes.
Average semivariance directly yields accurate estimates of the genomic variance in complex trait analyses

Abstract Many important traits in plants, animals, and microbes are polygenic and challenging to improve through traditional marker-assisted selection. Genomic prediction addresses this by incorporating all genetic data in a mixed model framework. The primary method for predicting breeding values is genomic best linear unbiased prediction, which uses the realized genomic relationship or kinship matrix (K) to connect genotype to phenotype. Genomic relationship matrices share information among entries to estimate the observed entries’ genetic values and predict unobserved entries’ genetic values. One of the main parameters of such models is genomic variance (σg2), or the variance of a trait associated with a genome-wide sample of DNA polymorphisms, and genomic heritability (hg2); however, the seminal papers introducing different forms of K often do not discuss their effects on the model estimated variance components despite their importance in genetic research and breeding. Here, we discuss the effect of several standard methods for calculating the genomic relationship matrix on estimates of σg2 and hg2. With current approaches, we found that the genomic variance tends to be either overestimated or underestimated depending on the scaling and centering applied to the marker matrix (Z), the value of the average diagonal element of K, and the assortment of alleles and heterozygosity (H) in the observed population. Using the average semivariance, we propose a new matrix, KASV, that directly yields accurate estimates of σg2 and hg2 in the observed population and produces best linear unbiased predictors equivalent to routine methods in plants and animals.
PDF) Scoperte Scientifiche Non Autorizzate Oltre La Verita Ufficiale Brossura Marco Pizzuti (PDF) Application Engine Peoplesoft Interview Questions (PDF) Key Performance Indicators Kpi The 75 Measures Every Manager Needs To Know

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Longitudinal Predictors of Informant-Rated Everyday Function in Mild Cognitive Impairment

Objective To examine predictors of informant-reported everyday functioning in mild cognitive impairment (MCI) and relations between everyday function and conversion to dementia. Methods Informants of participants (n = 2614) with mild cognitive impairment (MCI) were administered the Functional Activities Questionnaire (FAQ). Changes in dimensions of functional ability as determined by an exploratory factor analysis (EFA) were examined over 3 years and participant predictors of change were examined using multilevel modeling (MLM). Results The FAQ consisted of 3 factors, multistep, finance, and memory/orientation daily tasks. Impairment in memory/orientation tasks was significantly higher than impairment in multistep tasks. Worse functioning was associated with greater depression, worse memory, worse speed/EF, higher years of education and identifying as White. There was variability in some of these associations with different FAQ factors. Impairments in financial and memory/orientation daily tasks predicted follow-up conversion to dementia. Conclusions Depression, speed/EF, and memory are consistently associated with domains of everyday functioning. Race, education, and age may be more variability associated with everyday functioning. Specific attention should be paid to subtle declines in the financial and memory/orientation domains as they may uniquely predict future dementia development. Depression may be a modifiable risk factor associated with functional impairment over time.
Extracellular ATP promotes angiogenesis and adhesion of TNBC cells to endothelial cells via upregulation of CTGF

Our previous works have indicated that extracellular ATP is an important prometastasis factor. However, the molecular mechanism involved needs to be further studied. We demonstrated that extracellular ATP treatment could upregulate the expression of connective tissue growth factor (CTGF) in both triple‐negative breast cancer (TNBC) cells and endothelial cells (ECs). Extracellular ATP stimulated the migration of TNBC cells and ECs, and angiogenesis of ECs via the P2Y2––YAP‐CTGF axis. Furthermore, we demonstrated that adenosine triphosphate (ATP) stimulated TNBC cell adhesion to ECs and transmigration through the EC layer via CTGF by upregulation of integrin β1 on TNBC cells and VCAM‐1 on ECs. Both apyrase (ATP‐diphosphohydrolase) and CTGF shRNA treatments could inhibit the metastasis of inoculated tumors to lung and liver in a mouse model, and these treated tumors had fewer blood vessels. Collectively, our data indicated that extracellular ATP promotes tumor angiogenesis and the interactions between TNBC cells and ECs through upregulation of CTGF, thereby stimulating TNBC metastasis. The pleiotropic effects of ATP in angiogenesis and cell adhesion suggest that extracellular ATP or CTGF could be an effective target for TNBC therapy.
Modeling the consequences of the dikaryotic life cycle of mushroom-forming fungi on genomic conflict

Generally, sexual organisms contain two haploid genomes, one from each parent, united in a single diploid nucleus of the zygote which links their fate during growth. A fascinating exception to this is Basidiomycete fungi, where the two haploid genomes remain separate in a dikaryon, retaining the option to fertilize subsequent monokaryons encountered. How the ensuing nuclear competition influences the balance of selection within and between individuals is largely unexplored. We test the consequences of the dikaryotic life cycle for mating success and mycelium-level fitness components. We assume a trade-off between mating fitness at the level of the haploid nucleus and fitness of the fungal mycelium. We show that the maintenance of fertilization potential by dikaryons leads to a higher proportion of fertilized monokaryons, but that the ensuing intradikaryon selection for increased nuclear mating fitness leads to reduced mycelium fitness relative to a diploid life cycle. However, this fitness reduction is lower compared to a hypothetical life cycle where dikaryons can also exchange nuclei. Prohibition of fusion between dikaryons therefore reduces the level of nuclear parasitism. The number of loci influencing fitness is an important determinant of the degree to which average mycelium-level fitness is reduced. The results of this study crucially hinge upon a trade-off between nucleus and mycelium-level fitness. We discuss the evidence for this assumption and the implications of an alternative that there is a positive relationship between nucleus and mycelium-level fitness.
Publicly Available, Interactive Web-Based Tools to Support Advance Care Planning: Systematic Review

Background There is an increasing number of interactive web-based advance care planning (ACP) support tools, which are web-based aids in any format encouraging reflection, communication, and processing of publicly available information, most of which cannot be found in the peer-reviewed literature. Objective This study aims to conduct a systematic review of web-based ACP support tools to describe the characteristics, readability, and quality of content and investigate whether and how they are evaluated. Methods We systematically searched the web-based gray literature databases OpenGrey, ClinicalTrials.gov, ProQuest, British Library, Grey Literature in the Netherlands, and Health Services Research Projects in Progress, as well as Google and app stores, and consulted experts using the following eligibility criteria: web-based, designed for the general population, accessible to everyone, interactive (encouraging reflection, communication, and processing of information), and in English or Dutch. The quality of content was evaluated using the Quality Evaluation Scoring Tool (score 0-28—a higher score indicates better quality). To synthesize the characteristics of the ACP tools, readability and quality of content, and whether and how they were evaluated, we used 4 data extraction tables. Results A total of 30 tools met the eligibility criteria, including 15 (50%) websites, 10 (33%) web-based portals, 3 (10%) apps, and 2 (7%) with a combination of formats. Of the 30 tools, 24 (80%) mentioned a clear aim, including 7 (23%) that supported reflection or communication, 8 (27%) that supported people in making decisions, 7 (23%) that provided support to document decisions, and 2 (7%) that aimed to achieve all these aims. Of the 30 tools, 7 (23%) provided information on the development, all of which were developed in collaboration with health care professionals, and 3 (10%) with end users. Quality scores ranged between 11 and 28, with most of the lower-scoring tools not referring to information sources. Conclusions A variety of ACP support tools are available on the web, varying in the quality of content. In the future, users should be involved in the development process of ACP support tools, and the content should be substantiated by scientific evidence. Trial Registration PROSPERO CRD42020184112; https://tinyurl.com/mruf8b43