Miracle-dz/UniFAR-FTUs huggingface dataset:
Into the Deep (Sequence) of the Foot-and-Mouth Disease Virus Gene Pool: Bottlenecks and Adaptation during Infection in Naïve and Vaccinated Cattle

Foot-and-mouth disease virus (FMDV), like many RNA viruses, infects hosts as a population of closely related viruses referred to as a quasispecies. The behavior of this quasispecies has not been described in detail over the full course of infection in a natural host species. In this study, virus samples taken from vaccinated and non-vaccinated cattle up to 35 days post experimental infection with FMDV A24-Cruzeiro were analyzed by deep-sequencing. Vaccination induced significant differences compared to viruses from non-vaccinated cattle. in virus substitution rates, entropy, and evidence for adaptation. Genomic variation detected during early infection was found to reflect the diversity inherited from the source virus (inoculum), whereas by 12 days post infection (dpi) dominant viruses were defined by newly acquired mutations. In most serially sampled cattle, mutations conferring recognized fitness gain occurred within numerous genetic backgrounds, often associated with selective sweeps. Persistent infections always included multiple FMDV subpopulations, suggesting independently maintained foci of infection within the nasopharyngeal mucosa. Although vaccination prevented disease, subclinical infection in this group was associated with very early bottlenecks which subsequently reduced the diversity within the virus population. This implies an added consequence of vaccination in the control of foot-and-mouth disease. Viruses sampled from both animal cohorts contained putative antigenic escape mutations. However, these mutations occurred during later stages of infection, at which time transmission between animals is less likely to occur. Importance Preparedness and control of foot-and-mouth disease virus have substantial, yet distinct implications in endemic and free regions. Viral evolution and emergence of novel strains are of critical concern in both settings. The factors that contribute to the asymptomatic carrier state, a common form of long-term FMDV infection in cattle and other species, are important but not well-understood. This experimental study of foot-and-mouth disease virus in cattle explored the evolution of the pathogen through detailed sampling and analytical methods in both vaccinated and non-vaccinated hosts. Significant differences were identified between the viruses subclinically infecting vaccinated animals and those causing clinical disease in the non-vaccinated cohort. These results can benefit vaccination programs and contribute to the understanding of persistent infection of cattle.
Role of CARD Region of MDA5 Gene in Canine Influenza Virus Infection

MDA5 belongs to the RIG-I-like receptor family, which is involved in innate immunity. During viral infection, MDA5 generates an antiviral response by recognizing the ligand to activate interferon. However, the role and mechanism of MDA5 in canine influenza virus (CIV) infection are unclear. To understand the mechanism of canine MDA5-mediated innate immunity during CIV infection, we detected the distribution of MDA5 in beagles, and the structural prediction showed that MDA5 was mainly composed of a CARD domain, RD domain, and DExD/H helix structure. Moreover, we found that MDA5 inhibits CIV replication. Furthermore, in the dual luciferase assay, we revealed that the CARD region of MDA5 strongly activated the IFN-β promoter and mainly transmitted signals through the CARD region. Overexpression of the CARD region of MDA5 revealed that the MDA5-mediated signaling pathway could transmit signals by activating the IRF3/NF-κB and IRF3 promoters, promoting the expression of antiviral proteins and cytokine release, thereby inhibiting CIV replication. Upon silencing of MDA5, cytokine production decreased, while the replication ability of CIV was increased. Thus, this study revealed a novel mechanism by which MDA5 mediated CIV infection and provided new avenues for the development of antiviral strategies.
Endocrine Disruptors in Water and Their Effects on the Reproductive System

Anthropogenic contaminants in water can impose risks to reproductive health. Most of these compounds are known to be endocrine disrupting chemicals (EDCs). EDCs can impact the endocrine system and subsequently impair the development and fertility of non-human animals and humans. The source of chemical contamination in water is diverse, originating from byproducts formed during water disinfection processes, release from industry and livestock activity, or therapeutic drugs released into sewage. This review discusses the occurrence of EDCs in water such as disinfection byproducts, fluorinated compounds, bisphenol A, phthalates, pesticides, and estrogens, and it outlines their adverse reproductive effects in non-human animals and humans.
Zinc Binding to Fulvic acids: Assessing the Impact of pH, Metal Concentrations and Chemical Properties of Fulvic Acids on the Mechanism and Stability of Formed Soluble Complexes

The aim of the study was defined as a complementary analysis of molecular interactions between zinc (Zn) and fulvic acids (FAs) at a broad pH range (3–7), different metal concentrations (0–50 mg dm−3) and chemical properties of FAs and their impact on the Zn binding mechanism, stability, and efficiency. The results showed that the complexation reaction prevailed at pH 6 and 7, whereas protons exchange dominated interactions at pH 3. Stability constant of the complexes increased along with pH (logK increased from ~3.8 to 4.2). Complexation was preferred by less-humidified structures of lower molecular mass containing more oxygen groups. The number of fluorophores available for Zn(II) increased from pH 3 to 7 by ~44%. Depending on the pH, complexation involved a bidentate chelate, monodentate and bidentate bridging mode. Zn(II) binding was insufficiently modeled by the classic Stern–Volmer equation and well described by the double logarithmic equation (R > 0.94) as well as by a modified Stern–Volmer formula assuming the existence of available and unavailable fluorophore populations (R > 0.98). The fluorescence ratio of different fluorophores was proposed as an indicator of the binding affinity of various structures. A positive relationship was found between the fraction of accessible fluorophores and Zn(II) binding at pH 7 determined based on proton release (R = 0.91–0.97). The obtained results can find application in controlling the mobility and bioavailability of Zn in different conditions.
Essential role of laboratory physicians in transformation of laboratory practice and management to a value-based patient-centric model

Abstract The laboratory is a vital part of the continuum of patient care. In fact, there are few programs in the healthcare system that do not rely on ready access and availability of complex diagnostic laboratory services. The existing transactional model of laboratory “medical practice” will not be able to meet the needs of the healthcare system as it rapidly shifts toward value-based care and precision medicine, which demands that practice be based on total system indicators, clinical effectiveness, and patient outcomes. Laboratory “value” will no longer be focused primarily on internal testing quality and efficiencies but rather on the relative cost of diagnostic testing compared to direct improvement in clinical and system outcomes. The medical laboratory as a “business” focused on operational efficiency and cost-controls must transform to become an essential clinical service that is a tightly integrated equal partner in direct patient care. We would argue that this paradigm shift would not be necessary if laboratory services had remained a “patient-centric” medical practice throughout the last few decades. This review is focused on the essential role of laboratory physicians in transforming laboratory practice and management to a value-based patient-centric model. Value-based practice is necessary not only to meet the challenges of the new precision medicine world order but also to bring about sustainable healthcare service delivery.
A 55-Day-Old Female Infant Infected With 2019 Novel Coronavirus Disease: Presenting With Pneumonia, Liver Injury, and Heart Damage

Abstract Background Previous studies on the pneumonia outbreak caused by the 2019 novel coronavirus disease (COVID-19) were mainly based on information from adult populations. Limited data are available for children with COVID-19, especially for infected infants. Methods We report a 55-day-old case with COVID-19 confirmed in China and describe the identification, diagnosis, clinical course, and treatment of the patient, including the disease progression from day 7 to day 11 of illness. Results This case highlights that children with COVID-19 can also present with multiple organ damage and rapid disease changes. Conclusions When managing such infant patients with COVID-19, frequent and careful clinical monitoring is essential.
Comparison of calcium metabolism in different subgroups of nephrotic syndrome in children

Background: Children with nephrotic syndrome are at risk of altered calcium metabolism because of the disease per se as well as steroid therapy even before fall in glomerular filtration rate (GFR). Objective: To compare the pattern of alteration in calcium metabolism in different subgroups (infrequent relapser [IFR], frequent relapser or steroid-dependent nephrotic syndrome [FR/ SDNS], and patients in remission) of nephrotic syndrome in children. Methods: We conducted a cross-sectional study in the Department of Pediatrics, PGIMS, Rohtak. Children between 1 and 8 years of age were divided into three groups, viz., IFR (Group I), FR/SDNS (Group II), and patients in remission (Group III). Serum total calcium, ionized calcium, phosphate, parathormone (PTH), albumin levels, and urinary calcium and phosphate were measured, and X-rays of both lower limbs were done. Results: 10 patients in each group were compared. Serum total calcium, ionic calcium, and urinary calcium levels were decreased in patient with nephrotic syndrome during active disease. No difference was noted in serum phosphate, urinary phosphate, and GFR in all the three groups (p>0.05). Serum calcium and urinary calcium were significantly lower in Group II as compared to Group I (p<0.05), whereas serum PTH levels were significantly higher in Group II as compared to Group I (p<0.05). None of the patients with IFR and in remission had changes of osteopenia while 50% patients with FR/SDNS had features of osteopenia in their X-rays. Conclusion: Hypocalcemia is a common finding in children with nephritic syndrome. These children especially those with FR or SDNS should undergo careful monitoring of calcium, phosphorus, and PTH to prevent bone mineral disease.
Alcelaphine herpesvirus 1 genes A7 and A8 regulate viral spread and are essential for malignant catarrhal fever

Alcelaphine herpesvirus 1 (AlHV-1) is a gammaherpesvirus that is carried asymptomatically by wildebeest. Upon cross-species transmission to other ruminants, including domestic cattle, AlHV-1 induces malignant catarrhal fever (MCF), which is a fatal lymphoproliferative disease resulting from proliferation and uncontrolled activation of latently infected CD8+ T cells. Two laboratory strains of AlHV-1 are used commonly in research: C500, which is pathogenic, and WC11, which has been attenuated by long-term maintenance in cell culture. The published genome sequence of a WC11 seed stock from a German laboratory revealed the deletion of two major regions. The sequence of a WC11 seed stock used in our laboratory also bears these deletions and, in addition, the duplication of an internal sequence in the terminal region. The larger of the two deletions has resulted in the absence of gene A7 and a large portion of gene A8. These genes are positional orthologs of the Epstein-Barr virus genes encoding envelope glycoproteins gp42 and gp350, respectively, which are involved in viral propagation and switching of cell tropism. To investigate the degree to which the absence of A7 and A8 participates in WC11 attenuation, recombinant viruses lacking these individual functions were generated in C500. Using bovine nasal turbinate and embryonic lung cell lines, increased cell-free viral propagation and impaired syncytia formation were observed in the absence of A7, whereas cell-free viral spread was inhibited in the absence of A8. Therefore, A7 appears to be involved in cell-to-cell viral spread, and A8 in viral cell-free propagation. Finally, infection of rabbits with either mutant did not induce the signs of MCF or the expansion of infected CD8+ T cells. These results demonstrate that A7 and A8 are both essential for regulating viral spread and suggest that AlHV-1 requires both genes to efficiently spread in vivo and reach CD8+ T lymphocytes and induce MCF.
Reorganizing and integrating public health, health care, social care and wider public services: a theory-based framework for collaborative adaptive health networks to achieve the triple aim

Objective Population health management (PHM) refers to large-scale transformation efforts by collaborative adaptive health networks that reorganize and integrate services across public health, health care, social care and wider public services in order to improve population health and quality of care while at the same time reducing cost growth. However, a theory-based framework that can guide place-based approaches towards a comprehensive understanding of how and why strategies contribute to the development of PHM is lacking, and this review aims to contribute to closing this gap by identifying the key components considered to be key to successful PHM development. Methods We carried out a scoping realist review to identify configurations of strategies (S), their outcomes (O), and the contextual factors (C) and mechanisms (M) that explain how and why these outcomes were achieved. We extracted theories put forward in included studies and that underpinned the formulated strategy-context-mechanism-outcome (SCMO) configurations. Iterative axial coding of the SCMOs and the theories that underpin these configurations revealed PHM themes. Results Forty-one studies were included. Eight components were identified: social forces, resources, finance, relations, regulations, market, leadership, and accountability. Each component consists of three or more subcomponents, providing insight into (1) the (sub)component-specific strategies that accelerate PHM development, (2) the necessary contextual factors and mechanisms for these strategies to be successful and (3) the extracted theories that underlie the (sub)component-specific SCMO configurations. These theories originate from a wide variety of scientific disciplines. We bring these (sub)components together into what we call the Collabroative Adaptive Health Network (CAHN) framework. Conclusions This review presents the strategies that are required for the successful development of PHM. Future research should study the applicability of the CAHN framework in practice to refine and enrich identified relationships and identify PHM guiding principles.
Monocyte count in schizophrenia and related disorders: a systematic review and meta-analysis

Abstract Objective: Increasing evidence suggests that immunological and inflammatory dysfunctions may play an important role in predisposition, onset, and progression of schizophrenia and related psychosis. The activation of cells of the mononuclear phagocyte system, especially microglia and monocytes, has been reported in schizophrenia. We carried out this systematic review and meta-analysis to investigate if there are significant differences in monocyte count comparing healthy controls with people suffering from schizophrenia and related disorders. Methods: We searched main electronic databases; nine records met all our criteria and were included in the meta-analysis. Meta-analyses based on random effects models have been carried out generating pooled standardised mean differences (SMDs) of monocyte count in peripheral blood between schizophrenia and related psychosis and healthy controls. Heterogeneity was estimated. Relevant sensitivity and subgroup analyses were conducted. Results: Patients showed higher monocyte count as compared with healthy control (SMD = 0.393; p = 0.001). Heterogeneity across studies was from moderate to high (I2 = 65.952%); sensitivity analysis leaving out two studies responsible for most of the heterogeneity showed a slightly higher SMD. Subgroup analyses confirmed this result, showing no significant differences in the effect size across different study characteristics. Conclusions: Monocyte count can be considered an indirect marker of microglia activation in the central nervous system. Thus, the observed higher monocyte count in patients could be considered as a possible peripheral marker of microgliaʼs activation in schizophrenia disorder.
Identity, civic engagement, and altruism: a phenomenological exploration of activity engagement in older adults

Abstract Background Older adults’ health and quality of life, proxies for aging well, are tied to activity engagement. Recent research indicates studying the perspective of older adults through their personal stories is key to understanding the phenomenon of occupational engagement as experienced day-to-day. Aim To uncover the lived experience of older adults within their natural settings to better understand the phenomenon of activity engagement. This new knowledge informs programming options suited to older adults’ wants and needs. Materials/methods Ten community-dwelling older adults (5 female, 5 male mean 79 years) were studied. Researchers performed phenomenological interpretive analysis (IPA) with multiple coders and member cheques to triangulate findings. Results Daily activities revolved around three themes: 1) Perspectives of self-identity are viewed as consistent throughout the lifespan; 2) Civic engagement is beneficial for social support and self-efficacy; and 3) Philosophical outlook influences activity choices and outlooks centred on altruism are critical to continued activity engagement. Seven of the ten participants expressed an overall positive outlook on aging. Three participants described a negative outlook on aging, expressed more difficulty with activity engagement, but reported desire to help others. Conclusions and significance These themes provide a basis for programming to increase activity engagement with older adults in the community.
Pemetrexed Enhances Membrane PD-L1 Expression and Potentiates T Cell-Mediated Cytotoxicity by Anti-PD-L1 Antibody Therapy in Non-Small-Cell Lung Cancer

Immunotherapy has significantly changed the treatment landscape for advanced non-small-cell lung cancer (NSCLC) with the introduction of drugs targeting programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1). In particular, the addition of the anti-PD-1 antibody pembrolizumab to platinum-pemetrexed chemotherapy resulted in a significantly improved overall survival in patients with non-squamous NSCLC, regardless of PD-L1 expression. In this preclinical study, we investigated whether chemotherapy can modulate PD-L1 expression in non-squamous NSCLC cell lines, thus potentially affecting immunotherapy efficacy. Among different chemotherapeutic agents tested, only pemetrexed increased PD-L1 levels by activating both mTOR/P70S6K and STAT3 pathways. Moreover, it also induced the secretion of cytokines, such as IFN-γ and IL-2, by activated peripheral blood mononuclear cells PBMCs that further stimulated the expression of PD-L1 on tumor cells, as demonstrated in a co-culture system. The anti-PD-1/PD-L1 therapy enhanced T cell-mediated cytotoxicity of NSCLC cells treated with pemetrexed and expressing high levels of PD-L1 in comparison with untreated cells. These data may explain the positive results obtained with pemetrexed-based chemotherapy combined with pembrolizumab in PD-L1-negative NSCLC and can support pemetrexed as one of the preferable chemotherapy partners for immunochemotherapy combination regimens.
Intracellular Metabolites in Marine Microorganisms during an Experiment Evaluating Microbial Mortality

Metabolomics is a tool with immense potential for providing insight into the impact of biological processes on the environment. Here, we used metabolomics methods to characterize intracellular metabolites within marine microorganisms during a manipulation experiment that was designed to test the impact of two sources of microbial mortality, protozoan grazing and viral lysis. Intracellular metabolites were analyzed with targeted and untargeted mass spectrometry methods. The treatment with reduced viral mortality showed the largest changes in metabolite concentrations, although there were organic compounds that shifted when the impact of protozoan grazers was reduced. Intracellular concentrations of guanine, phenylalanine, glutamic acid, and ectoine presented significant responses to changes in the source of mortality. Unexpectedly, variability in metabolite concentrations were not accompanied by increases in microbial abundance which indicates that marine microorganisms altered their internal organic carbon stores without changes in biomass or microbial growth. We used Weighted Correlation Network Analysis (WGCNA) to identify correlations between the targeted and untargeted mass spectrometry data. This analysis revealed multiple unknown organic compounds were correlated with compatible solutes, also called osmolytes or chemical chaperones, which emphasizes the dominant role of compatible solutes in marine microorganisms.
The Correlation of Burnout and Optimism among Medical Residents

Introduction Burnout is common among clinical specialties and has implications on the residents’ well-being and mental health. Evidence suggests that optimism and burnout are correlated, but research has not focused on the applicability to medical residents. The objective of the study was to define burnout in residents and correlate it with optimism. Methods The authors conducted a correlational, prospective cross-sectional study using self-reported single item burnout (1-10) and Life Oriented Test-Revised (LOT-R) (0-24) survey instruments among residents of neurosurgery, neurology, internal medicine, family medicine and emergency medicine at a community-based hospital. Residents were asked to fill out the survey once in the 2018 academic year and once again in the 2019 academic year. Burnout and optimism scores were correlated and compared across subgroups for each year. Results There was no statistical significance found amongst any subgroups in burnout in 2018 but significance was found for both internal medicine (t = 3.74, p = 0.001) and neurosurgery (t = -3.07, p = 0.01) in 2019. Mean burnout increased from 2018 to 2019 from 4.39 to 5.1. Optimism remained constant from 2018 to 2019 (16.7 and 16.76, respectively) and there was no difference across subgroups. There was a statistically significant negative correlation between burnout and optimism in both 2018 (r = -0.364, p = 0.006) and 2019 (r = -0.39, p = .001). Conclusion Burnout and optimism are negatively correlated. Although burnout increased over time, optimism remained constant indicating the stability of this trait and implication for future interventions.