Miracle-dz/UniFAR-FTUs huggingface dataset:
Association between gene polymorphisms of TGF-β and Smad3 and susceptibility to arthritis: a meta-analysis

ABSTRACT Objectives This meta-analysis was performed to investigate the associations between single-nucleotide polymorphisms (SNPs) in the TGF- β and Smad3 genes and arthritis. Methods A meta-analysis was performed in STATA 14.0, with publication bias and meta-regression analysis. All types of arthritis were included, and subgroup analyses were performed to interpret variations among different types of arthritis. Results Twenty-two qualified studieswere selected to analyze the pooled accuracy, and 4 SNP sites were involved. The analysis of the TGFB1 SNP rs1800470 showed an association with arthritis in allelic (P = 0.011), homozygous (P = 0.034) and recessive (P = 0.021) genetic models. The analysis of the TGFB1 SNP rs1800471 demonstrated a close association with rheumatoid arthritis (RA) in homozygous (P = 0.000, 95%) and recessive (P = 0.008) models. The analysis of the SMAD3 SNP rs12901499 revealed a close association with osteoarthritis (OA) in the allelic (P = 0.001) model. Conclusion This research showed that genetic variants of the TGF-β pathway impact arthritis. The polymorphisms rs1800470, rs1800471 and rs12901499 were correlated with a higher prevalence of arthritis.
Aging-Related Disorders and Mitochondrial Dysfunction: A Critical Review for Prospect Mitoprotective Strategies Based on Mitochondrial Nutrient Mixtures

A number of aging-related disorders (ARD) have been related to oxidative stress (OS) and mitochondrial dysfunction (MDF) in a well-established body of literature. Most studies focused on cardiovascular disorders (CVD), type 2 diabetes (T2D), and neurodegenerative disorders. Counteracting OS and MDF has been envisaged to improve the clinical management of ARD, and major roles have been assigned to three mitochondrial cofactors, also termed mitochondrial nutrients (MNs), i.e., α-lipoic acid (ALA), Coenzyme Q10 (CoQ10), and carnitine (CARN). These cofactors exert essential–and distinct—roles in mitochondrial machineries, along with strong antioxidant properties. Clinical trials have mostly relied on the use of only one MN to ARD-affected patients as, e.g., in the case of CoQ10 in CVD, or of ALA in T2D, possibly with the addition of other antioxidants. Only a few clinical and pre-clinical studies reported on the administration of two MNs, with beneficial outcomes, while no available studies reported on the combined administration of three MNs. Based on the literature also from pre-clinical studies, the present review is to recommend the design of clinical trials based on combinations of the three MNs.
Endothelial Cell Cystathionine γ‐Lyase Expression Level Modulates Exercise Capacity, Vascular Function, and Myocardial Ischemia Reperfusion Injury

Background Hydrogen sulfide (H2S) is an important endogenous physiological signaling molecule and exerts protective properties in the cardiovascular system. Cystathionine γ‐lyase (CSE), 1 of 3 H2S producing enzyme, is predominantly localized in the vascular endothelium. However, the regulation of CSE in vascular endothelium remains incompletely understood. Methods and Results We generated inducible endothelial cell‐specific CSE overexpressed transgenic mice (EC‐CSE Tg) and endothelial cell‐specific CSE knockout mice (EC‐CSE KO), and investigated vascular function in isolated thoracic aorta, treadmill exercise capacity, and myocardial injury following ischemia‐reperfusion in these mice. Overexpression of CSE in endothelial cells resulted in increased circulating and myocardial H2S and NO, augmented endothelial‐dependent vasorelaxation response in thoracic aorta, improved exercise capacity, and reduced myocardial‐reperfusion injury. In contrast, genetic deletion of CSE in endothelial cells led to decreased circulating H2S and cardiac NO production, impaired endothelial dependent vasorelaxation response and reduced exercise capacity. However, myocardial‐reperfusion injury was not affected by genetic deletion of endothelial cell CSE. Conclusions CSE‐derived H2S production in endothelial cells is critical in maintaining endothelial function, exercise capacity, and protecting against myocardial ischemia/reperfusion injury. Our data suggest that the endothelial NO synthase—NO pathway is likely involved in the beneficial effects of overexpression of CSE in the endothelium.
Dynamics of Neutralizing Antibody Titers in the Months After Severe Acute Respiratory Syndrome Coronavirus 2 Infection

Abstract Most individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop neutralizing antibodies that target the viral spike protein. In this study, we quantified how levels of these antibodies change in the months after SARS-CoV-2 infection by examining longitudinal samples collected approximately 30–152 days after symptom onset from a prospective cohort of 32 recovered individuals with asymptomatic, mild, or moderate-severe disease. Neutralizing antibody titers declined an average of about 4-fold from 1 to 4 months after symptom onset. This decline in neutralizing antibody titers was accompanied by a decline in total antibodies capable of binding the viral spike protein or its receptor-binding domain. Importantly, our data are consistent with the expected early immune response to viral infection, where an initial peak in antibody levels is followed by a decline to a lower plateau. Additional studies of long-lived B cells and antibody titers over longer time frames are necessary to determine the durability of immunity to SARS-CoV-2.
Internal Oligoguanidinium Transporter: Mercury Free Scalable Synthesis, Improvement of Cellular Localization, Endosomal Escape, Mitochondrial Localization and Conjugation with Antisense Morpholino for NANOG Inhibition to Induce Chemosensitisation of Taxol in MCF-7 Cells.

A non toxic delivery vehicle is essential for the therapeutic applications of antisense phosphorodiamidate morpholino oligonucleotides (PMOs). Though guanidinium rich or arginine rich cellular transporter conjugated Vivo-PMO or PPMO has been developed for in vivo application, however, either their toxicity or stability has become an issue. Previously we reported non-peptidic internal guanidinium transporter (IGT) mediated delivery of PMO for gene silencing and got encouraging results. In this paper we report the synthesis of IGT using Hg-free method for scale up and N-terminal modification of IGT with a suitable hydrophobic or lipophilic group to improve the cell permeability, endosomal escape, mitochondrial localization and to reduce toxicity in MTT assay. For the delivery of PMO, IGT-PMO conjugate was synthesized to target NANOG in cells, a transcription factor required for cancer stem cell proliferation and embryonic development and is involved in many cancers. Our data shows IGT-PMO-facilitated NANOG inhibition and thereby the prevention of EpCAM-N-Cadherin-Vimentin axis mediated epithelial to mesenchymal transition (EMT) in MCF-7 cells. Moreover, unlike taxol, NANOG inhibition influences the expression of stemness factor c-Myc, Hh-Gli signaling proteins, other cancer related factors and their respective phenotypes in cancer cells. To the best of our knowledge, this is the first report to illustrate that the IGT-PMO-mediated NANOG inhibition increases the therapeutic potential of taxol and induces G0-G1 arrest in cancer cells to prevent the cancer progression. However, it warrants further investigations in other cancer cells and preclinical platforms.
Indole Derivative Interacts with Estrogen Receptor Beta and Inhibits Human Ovarian Cancer Cell Growth

Ovarian cancer remains the leading cause of mortality among gynecological tumors. Estrogen receptor beta (ERβ) expression has been suggested to act as a tumor suppressor in epithelial ovarian cancer by reducing both tumor growth and metastasis. ERβ expression abnormalities represent a critical step in the development and progression of ovarian cancer: for these reasons, its re-expression by genetic engineering, as well as the use of targeted ERβ therapies, still constitute an important therapeutic approach. 3-{[2-chloro-1-(4-chlorobenzyl)-5-methoxy-6-methyl-1H-indol-3-yl]methylene}-5-hydroxy-6-methyl-1,3-dihydro-2H-indol-2-one, referred to here as compound 3, has been shown to have cytostatic as well cytotoxic effects on various hormone-dependent cancer cell lines. However, the mechanism of its anti-carcinogenic activity is not well understood. Here, we offer a possible explanation of such an effect in the human ovarian cancer cell line IGROV1. Chromatin binding protein assay and liquid chromatography mass spectrometry were exploited to localize and quantify compound 3 in cells. Molecular docking was used to prove compound 3 binding to ERβ. Mass spectrometry-based approaches were used to analyze histone post-translational modifications. Finally, gene expression analyses revealed a set of genes regulated by the ERβ/3 complex, namely CCND1, MYC, CDKN2A, and ESR2, providing possible molecular mechanisms that underline the observed antiproliferative effects.
Direct and residual effects of integrated sulphur fertilization in maize (Zea mays)- chickpea (Cicer arietinum) cropping system on Typic Ustochrept

A field experiment was conducted during the kharif and rabi season of 2000-04 at Indian Institute of Pulses Re- search, Kanpur to find out the performance of maize ( Zea mays L.)-chickpea ( Cicer arietinum L.) cropping se- quence with sulphur fertilization along with farmyard manure (FYM). Inorganic S at 0 and 20 kg/ha was applied during kharif maize cultivation and in rabi season, three levels of S (0, 10 and 20 kg/ha) were applied with 2 levels of FYM (0 and 4 t/ha). Maize grain yield increased by 0.59 t with the application of 20 kg S/ha over control (1.99 t/ ha). Significant positive effects of 20 kg/ha of S as manifested on growth, yield attributes, yield, S uptake, S utiliza- tion and economics of maize were not further carried over to following chickpea crop. However, in chickpea nodu- lation, grain and straw yield, protein content, and S uptake significantly increased due to application of sulphur along with FYM application. Higher mean nodule number (19.38), nodule dry weight (0.213 g/plant), grain yield (1.69 t/ha), straw yield (1.78 t/ha), and S uptake (15.6 kg/ha) was found with the 20 kg/ha of S fertilization. But utili- zation of added S decreased with increased S supply. Net return and return per rupee investment of the system also increased due to application of S and FYM to chickpea.
Exploring metal availability in the natural niche of Streptococcus pneumoniae to discover potential vaccine antigens

ABSTRACT Nasopharyngeal colonization by Streptococcus pneumoniae is a prerequisite for pneumococcal transmission and disease. Current vaccines protect only against disease and colonization caused by a limited number of serotypes, consequently allowing serotype replacement and transmission. Therefore, the development of a broadly protective vaccine against colonization, transmission and disease is desired but requires a better understanding of pneumococcal adaptation to its natural niche. Hence, we measured the levels of free and protein-bound transition metals in human nasal fluid, to determine the effect of metal concentrations on the growth and proteome of S. pneumoniae. Pneumococci cultured in medium containing metal levels comparable to nasal fluid showed a highly distinct proteomic profile compared to standard culture conditions, including the increased abundance of nine conserved, putative surface-exposed proteins. AliA, an oligopeptide binding protein, was identified as the strongest protective antigen, demonstrated by the significantly reduced bacterial load in a murine colonization and a lethal mouse pneumonia model, highlighting its potential as vaccine antigen.
Genome and Transcriptome Biomarkers of Response to Immune Checkpoint Inhibitors in Advanced Solid Tumors

Purpose: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of solid tumors with dramatic and durable responses seen across multiple tumor types. However, identifying patients who will respond to these drugs remains challenging, particularly in the context of advanced and previously treated cancers. Experimental Design: We characterized fresh tumor biopsies from a heterogeneous pan-cancer cohort of 98 patients with metastatic predominantly pretreated disease through the Personalized OncoGenomics program at BC Cancer (Vancouver, Canada) using whole genome and transcriptome analysis (WGTA). Baseline characteristics and follow-up data were collected retrospectively. Results: We found that tumor mutation burden, independent of mismatch repair status, was the most predictive marker of time to progression (P = 0.007), but immune-related CD8+ T-cell and M1-M2 macrophage ratio scores were more predictive for overall survival (OS; P = 0.0014 and 0.0012, respectively). While CD274 [programmed death-ligand 1 (PD-L1)] gene expression is comparable with protein levels detected by IHC, we did not observe a clinical benefit for patients with this marker. We demonstrate that a combination of markers based on WGTA provides the best stratification of patients (P = 0.00071, OS), and also present a case study of possible acquired resistance to pembrolizumab in a patient with non–small cell lung cancer. Conclusions: Interpreting the tumor-immune interface to predict ICI efficacy remains challenging. WGTA allows for identification of multiple biomarkers simultaneously that in combination may help to identify responders, particularly in the context of a heterogeneous population of advanced and previously treated cancers, thus precluding tumor type–specific testing.
Effects of childhood trauma experience and COMT Val158Met polymorphism on brain connectivity in a multimodal MRI study

Childhood adversity may act as a stressor to produce a cascade of neurobiological effects that irreversibly alter neural development, setting the stage for developing psychopathology in adulthood. The catechol‐O‐methyltransferase (COMT) Val158Met polymorphism has received much attention as a candidate gene associated with environmental adversity, modifying risk for psychopathology. In this study, we aim to see how gene × brain × environment models give a more integrative understanding of brain modifications that contribute to predicting psychopathology related to childhood adversity. A large nonclinical sample of young adults completed Childhood Trauma Questionnaire (CTQ), behavioral scores, multimodal magnetic resonance imaging (MRI) scans, and genotyping. We utilized graph‐based connectivity analysis in morphometric similarity mapping and resting‐state functional MRI to investigate brain alterations. Relationships among COMT genotypes, CTQ score, imaging phenotypes, and behavioral scores were identified by multiple regression and mediation effect analysis. Significant main effect of CTQ score was found in anatomic connectivity of orbitofrontal cortex that was an outstanding mediator supporting the relationship between CTQ score and anxiety/harm‐avoiding personality. We also noted the main effect of childhood trauma on reorganization of functional connectivity within the language network. Additionally, we found genotype × CTQ score interactions on functional connectivity of the right frontoparietal network as well as anatomic connectivity of motor and limbic regions. Our data demonstrate childhood adversity and COMT genotypes are associated with abnormal brain connectivity, structurally and functionally. Early identification of individuals at risk, assessment of brain abnormality, and cognitive interventions may help to prevent or limit negative outcomes.
Fugitive Dust During Planting of Canola with an Air Seeder as a Source of Environmental Contamination for Pesticides Applied on Seed: A Case Study

The dispersion of clothianidin from treated seeds was studied in a commercial winter canola field. During planting, using a John Deere 1890 single disk air seeder, a proportion, an estimated 14.2 ± 2.9% (mean ± standard error), of the clothianidin that was applied to the seed escaped into the atmosphere from the seeder's exhaust. We suggest that this source of environmental contamination may be the main contributor that explains the off‐target detection of neonicotinoid residues in soils and water near canola plantings better than movement from seed after it is placed in the soil, which is often proposed in the literature. Environ Toxicol Chem 2020;39:2420–2423. © 2020 SETAC
Patterns of organizing pneumonia and microinfarcts as surrogate for endothelial disruption and microangiopathic thromboembolic events in patients with coronavirus disease 2019

Background To evaluate chest-computed-tomography (CT) scans in coronavirus-disease-2019 (COVID-19) patients for signs of organizing pneumonia (OP) and microinfarction as surrogate for microscopic thromboembolic events. Methods Real-time polymerase-chain-reaction (RT-PCR)-confirmed COVID-19 patients undergoing chest-CT (non-enhanced, enhanced, pulmonary-angiography [CT-PA]) from March-April 2020 were retrospectively included (COVID-19-cohort). As control-groups served 175 patients from 2020 (cohort-2020) and 157 patients from 2019 (cohort-2019) undergoing CT-PA for pulmonary embolism (PE) during the respective time frame at our institution. Two independent readers assessed for presence and location of PE in all three cohorts. In COVID-19 patients additionally parenchymal changes typical of COVID-19 pneumonia, infarct pneumonia and OP were assessed. Inter-reader agreement and prevalence of PE in different cohorts were calculated. Results From 68 COVID-19 patients (42 female [61.8%], median age 59 years [range 32–89]) undergoing chest-CT 38 obtained CT-PA. Inter-reader-agreement was good (k = 0.781). On CT-PA, 13.2% of COVID-19 patients presented with PE whereas in the control-groups prevalence of PE was 9.1% and 8.9%, respectively (p = 0.452). Up to 50% of COVID-19 patients showed changes typical for OP. 21.1% of COVID-19 patients suspected with PE showed subpleural wedge-shaped consolidation resembling infarct pneumonia, while only 13.2% showed visible filling defects of the pulmonary artery branches on CT-PA. Conclusion Despite the reported hypercoagulability in critically ill patients with COVID-19, we did not encounter higher prevalence of PE in our patient cohort compared to the control cohorts. However, patients with suspected PE showed a higher prevalence of lung changes, resembling patterns of infarct pneumonia or OP and CT-signs of pulmonary-artery hypertension.
Observing maternal sensitivity in a South African township: an exploratory study into behavioral features using different measures

ABSTRACT There is evidence that sensitive responsiveness is manifested differently in varying cultural contexts. This exploratory study examines a sample of 50 South African mothers in the context of a socioeconomically deprived Township, and investigates differences between the Ainsworth sensitivity scale (that does not specify particular manifestations of sensitivity) and the Maternal Behavior Q-sort (MBQ) mini, that assesses a more specified array of behaviors. Results showed a significant but modest association between the two measures, and maternal education was related to the MBQ-mini but not the Ainsworth scores. This pattern of results appears to be due to the higher salience of social games and verbal teaching in the MBQ-mini than in the Ainsworth scale. Such behaviors are less common in South African parenting, where more physical forms of responsiveness seem more typical. A local “South African” sort was developed to capture culture-specific manifestations of sensitivity.
Evaluating the Extended Parallel Process Model’s Danger Control Predictions in the Context of Dense Breast Notification Laws

ABSTRACT This study evaluates predictions central to the extended parallel process model (EPPM) in the context of dense breast notifications. Many EPPM propositions have gone untested and competing predictions to the model have been evaluated to an even lesser extent. Also left as an open question is exactly how perceived threat and efficacy constructs should be treated in health communication research. Using experimental data collected from women likely to receive dense breast notification letters (i.e., aged 40 to 50 years) in states with and without dense breast notification legislation, this study explicitly tests EPPM predictions regarding danger control responses. These data were largely unsupportive of the EPPM’s predictions and instead finds that negative affect is more of a direct predictor of intention than expected. These data also provide evidence supporting the separate treatment of the perceived severity, susceptibility, self-efficacy, and response efficacy variables, contrary to convention in EPPM research. Implications for breast density research and EPPM theorizing are discussed in light of these findings.
Early-life exposure to bisphenol A and reproductive-related outcomes in rodent models: a systematic review and meta-analysis

We performed this meta-analysis to elucidate the associations between early-life BPA exposure and reproductive-related outcome indicators. The standardized mean differences (SMDs) and its 95% confidence intervals (CIs) were measured by fixed-effects or random-effects models. The results revealed that BPA exposure at extremely-high dose (>50mg/kg/day) was significantly associated with negative reproductive-related outcomes (Prostate weight: SMD: -4.21; 95% Cl: -5.97, -2.44; Testis weight: SMD: -1.92; 95% Cl: -2.61, -1.23; Epididymis weight: SMD: -2.16; 95% Cl: -3.47, -0.86; Daily sperm production; SMD: -1.90; 95% Cl: -3.27, -0.53; Epididymal sperm count; SMD: -3.42; 95% Cl: -3.87, -2.97). Meanwhile, regardless of the dose, early-life BPA exposure could result in an adverse effect on sperm parameters of F1 generation male rodents at any period. Also, we found the non-monotonic dose response curves of BPA in specific tissues or organs, which may challenge the traditional mindset of "safe dose". This study demonstrated that bisphenol A exposure was relevant to adverse reproductive-related outcomes at specially appointed dose and period of life. Yet the assumption that no adverse effects can occur below the "safe" dose is suspected.
Efeitos do incremento da fibra em detergente neutro na dieta de suínos sobre a morfologia dos órgãos digestivos e não digestivos

This work was targeted to evaluate the effects of including 0 or 8% of neutral detergent fiber from grass hay on the morphology of digestive and non-digestive organs of swine receiving starting or growing-finishing diets. It was employed cross-bred animals fed isoproteic and isoenergetic ad libitum rations in a completely randomized experimental design. At the end of each period, animals were slaughtered and eviscerated. It was detected that the fibrous ration increased the weight of empty stomach, large intestine and filled cecum (as a percentage of live weight) of starting animals. In the growing-finishing animals fibrous ration increased the weights of filled gastrointestinal tract and empty stomach. Higher weights of some digestive organs suggest a possible morphological adaptation to high fiber diets.