Miracle-dz/UniFAR-FTUs huggingface dataset:
Inhibitory Effects of Antiviral Drug Candidates on Canine Parvovirus in F81 cells

Canine parvovirus (CPV) is a common etiological agent of acute enteritis, which occurs globally in domestic and wild carnivores. Despite the widespread use of inactivated or live attenuated vaccines, the emergence of antigenic variants and the influence of maternal antibodies have raised some concerns regarding the efficacy of commercial vaccines. While no specific antiviral therapy for CPV infection exists, the only treatment option for the infection is supportive therapy based on symptoms. Thus, there is an urgent medical need to develop antiviral therapeutic options to reduce the burden of CPV-related disease. In this study, a cytopathic effect (CPE)-based high-throughput screening assay was used to screen CPV inhibitors from a Food and Drug Administration (FDA)-approved drug library. After two rounds of screening, seven out of 1430 screened drugs were found to have >50% CPE inhibition. Three drugs—Nitazoxanide, Closantel Sodium, and Closantel—with higher anti-CPV effects were further evaluated in F81 cells by absolute PCR quantification and indirect immunofluorescence assay (IFA). The inhibitory effects of all three drugs were dose-dependent. Time of addition assay indicated that the drugs inhibited the early processes of the CPV replication cycle, and the inhibition effects were relatively high within 2 h postinfection. Western blot assay also showed that the three drugs had broad-spectrum antiviral activity against different subspecies of three CPV variants. In addition, antiapoptotic effects were observed within 12 h in Nitazoxanide-treated F81 cells regardless of CPV infection, while Closantel Sodium- or Closantel-treated cells had no pro- or antiapoptotic effects. In conclusion, Nitazoxanide, Closantel Sodium, and Closantel can effectively inhibit different subspecies of CPV. Since the safety profiles of FDA-approved drugs have already been extensively studied, these three drugs can potentially become specific and effective anti-CPV drugs.
Application of Highly Immunocompromised Mice for the Establishment of Patient-Derived Xenograft (PDX) Models

Patient-derived xenograft (PDX) models are created by engraftment of patient tumor tissues into immunocompetent mice. Since a PDX model retains the characteristics of the primary patient tumor including gene expression profiles and drug responses, it has become the most reliable in vivo human cancer model. The engraftment rate increases with the introduction of Non-obese diabetic Severe combined immunodeficiency (NOD/SCID)-based immunocompromised mice, especially the NK-deficient NOD strains NOD/SCID/interleukin-2 receptor gamma chain(IL2Rγ)null (NOG/NSG) and NOD/SCID/Jak3(Janus kinase 3)null (NOJ). Success rates differ with tumor origin: gastrointestinal tumors acquire a higher engraftment rate, while the rate is lower for breast cancers. Subcutaneous transplantation is the most popular method to establish PDX, but some tumors require specific environments, e.g., orthotropic or renal capsule transplantation. Human hormone treatment is necessary to establish hormone-dependent cancers such as prostate and breast cancers. PDX mice with human hematopoietic and immune systems (humanized PDX) are powerful tools for the analysis of tumor–immune system interaction and evaluation of immunotherapy response. A PDX biobank equipped with patients’ clinical data, gene-expression patterns, mutational statuses, tumor tissue architects, and drug responsiveness will be an authoritative resource for developing specific tumor biomarkers for chemotherapeutic predictions, creating individualized therapy, and establishing precise cancer medicine.
Toxoplasma gondii effector TgIST blocks type I interferon signaling to promote infection

Significance Toxoplasma gondii infects a wide range of animals, including humans, where it can form chronic persistent infections for the life of the host. We demonstrate that the parasite T. gondii secretes an effector protein called TgIST that traffics to the host cell nucleus, binds to STAT1/STAT2 heterodimers, and blocks signaling through type I interferon (IFN). TgIST globally blocks induction of IFN-stimulated genes normally up-regulated by IFN-β, including those involved in innate defense pathways. Type I IFN is important for control of chronic infection by T. gondii in the central nervous system, and the ability of the parasite to modulate this pathway contributes to chronic persistence. In contrast to the importance of type II interferon-γ (IFN-γ) in control of toxoplasmosis, the role of type I IFN is less clear. We demonstrate here that TgIST, a secreted effector previously implicated in blocking type II IFN-γ signaling, also blocked IFN-β responses by inhibiting STAT1/STAT2-mediated transcription in infected cells. Consistent with a role for type I IFN in cell intrinsic control, ∆Tgist mutants were more susceptible to growth inhibition by murine and human macrophages activated with IFN-β. Additionally, type I IFN was important for production of IFN-γ by natural killer (NK) cells and recruitment of inflammatory monocytes at the site of infection. Mice lacking type I IFN receptors (Ifnar1−/−) showed increased mortality following infection with wild-type parasites and decreased virulence of ∆Tgist parasites was restored in Ifnar1−/− mice. The findings highlight the importance of type I IFN in control of toxoplasmosis and illuminate a parasite mechanism to counteract the effects of both type I and II IFN-mediated host defenses.
mTOR Inhibitor Therapy Diminishes Circulating CD8+ CD28− Effector Memory T Cells and Improves Allograft Inflammation in Belatacept-refractory Renal Allograft Rejection

Supplemental Digital Content is available in the text. Background. Renal allograft rejection is more frequent under belatacept-based, compared with tacrolimus-based, immunosuppression. We studied kidney transplant recipients experiencing rejection under belatacept-based early corticosteroid withdrawal following T-cell–depleting induction in a recent randomized trial (Belatacept-based Early Steroid Withdrawal Trial, clinicaltrials.gov NCT01729494) to determine mechanisms of rejection and treatment. Methods. Peripheral mononuclear cells, serum creatinine levels, and renal biopsies were collected from 8 patients undergoing belatacept-refractory rejection (BRR). We used flow cytometry, histology, and immunofluorescence to characterize CD8+ effector memory T cell (TEM) populations in the periphery and graft before and after mammalian target of rapamycin (mTOR) inhibition. Results. Here, we found that patients with BRR did not respond to standard antirejection therapy and had a substantial increase in alloreactive CD8+ T cells with a CD28low/DRhi/CD38hi/CD45RO+ TEM. These cells had increased activation of the mTOR pathway, as assessed by phosphorylated ribosomal protein S6 expression. Notably, everolimus (an mTOR inhibitor) treatment of patients with BRR halted the in vivo proliferation of TEM cells and their ex vivo alloreactivity and resulted in their significant reduction in the peripheral blood. The frequency of circulating FoxP3+ regulatory T cells was not altered. Importantly, everolimus led to rapid resolution of rejection as confirmed by histology. Conclusions. Thus, while prior work has shown that concomitant belatacept + mTOR inhibitor therapy is effective for maintenance immunosuppression, our preliminary data suggest that everolimus may provide an available means for effecting “rescue” therapy for rejections occurring under belatacept that are refractory to traditional antirejection therapy with corticosteroids and polyclonal antilymphocyte globulin.
Model Free Localization with Deep Neural Architectures by Means of an Underwater WSN

In recent years, there has been a significant effort towards developing localization systems in the underwater medium, with current methods relying on anchor nodes, explicitly modeling the underwater channel or cooperation from the target. Lately, there has also been some work on using the approximation capabilities of Deep Neural Networks in order to address this problem. In this work, we study how the localization precision of using Deep Neural Networks is affected by the variability of the channel, the noise level at the receiver, the number of neurons of the neural network and the utilization of the power or the covariance of the received acoustic signals. Our study shows that using deep neural networks is a valid approach when the channel variability is low, which opens the door to further research in such localization methods for the underwater environment.
Lgl1 deficiency disrupts hippocampal development and impairs cognitive performance in mice

Cellular polarity is crucial for brain development and morphogenesis. Lethal giant larvae 1 (Lgl1) plays a crucial role in the establishment of cell polarity from Drosophila to mammalian cells. Previous studies have found the importance of Lgl1 in the development of cerebellar, olfactory bulb, and cerebral cortex. However, the role of Lgl1 in hippocampal development during the embryonic stage and function in adult mice is still unknown. In our study, we created Lgl1‐deficient hippocampus mice by using Emx1‐Cre mice. Histological analysis showed that the Emx1‐Lgl1−/− mice exhibited reduced size of the hippocampus with severe malformations of hippocampal cytoarchitecture. These defects mainly originated from the disrupted hippocampal neuroepithelium, including increased cell proliferation, abnormal interkinetic nuclear migration, reduced differentiation, increased apoptosis, gradual disruption of adherens junctions, and abnormal neuronal migration. The radial glial scaffold was disorganized in the Lgl1‐deficient hippocampus. Thus, Lgl1 plays a distinct role in hippocampal neurogenesis. In addition, the Emx1‐Lgl1−/− mice displayed impaired behavioral performance in the Morris water maze and fear conditioning test.
Joint Shock/Death Risk Prediction Model for Patients Considering Implantable Cardioverter-Defibrillators.

BACKGROUND The risk of death or appropriate therapy varies widely among recipients of implantable cardioverter-defibrillators (ICDs). The goals of this study were to develop a risk prediction tool that jointly considers future outcome probabilities of ICD shock and death. METHODS AND RESULTS We performed a secondary analysis of patients receiving ICDs as part of the SCD-HeFT trial (Sudden Cardiac Death in Heart Failure Trial). We applied an illness-death regression model to jointly model both ICD shocks and death under the semi-competing risks framework, which predicts for each patient their probability of having received ICD shocks, dying, or both at any given point in time. Among 803 ICD recipients (mean age, 60 years; 23% women) followed for a median of 41.1 months, 430 (53.5%) patients completed the study without dying or receiving an ICD shock, 206 (25.7%) received at least 1 shock but survived, 113 (14.1%) died before experiencing a shock, and 54 (6.7%) received at least 1 shock and subsequently died. Predicted outcome probabilities based on baseline demographic and clinical variables reveal substantial heterogeneity in joint shock and death risks, both between patients at each time point and for each single patient across time. Overall, predictive performance for ICD shock and death individually was adequate, based on area under the curve at 5 years of 0.65 for shocks and of 0.79 for death. CONCLUSIONS Our analysis of outcomes after ICD implantation provides an alternative predictive model for individual risk of death or ICD shocks. If validated, this may provide a useful tool for individualized counseling regarding likely outcomes after device implantation, while also informing the design of further studies to focus the clinical effectiveness and cost-effectiveness of ICD therapy. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrials. gov. Unique identifier: NCT00000609.
The Placebo and Nocebo effect on sports performance: A systematic review

Abstract The aim of this review was to determine the magnitude of the placebo and nocebo effect on sport performance. Articles published before March 2019 were located using Medline, Web of Science, PubMed, EBSCO, Science Direct, and Scopus. Studies that examined placebo and nocebo effects of an objective dependent variable on sports performance, which included a control or baseline condition, were included in the analysis. Studies were classified into two categories of ergogenic aids: (1) nutritional and (2) mechanical. Cohen’s d effect sizes were calculated from 32 studies involving 1513 participants. Small to moderate placebo effects were found for both placebo (d = 0.36) and nocebo (d = 0.37) effects and when separated by nutritional (d = 0.35) and mechanical (d = 0.47) ergogenic aids. The pooled effect size revealed a small to moderate effect size across all studies (d = 0.38). Results suggest that placebo and nocebo effects can exert a small to moderate effect on sports performance.
Disparity of Race Reporting and Representation in Clinical Trials Leading to Cancer Drug Approvals From 2008 to 2018.

Importance Representative racial/ethnic participation in research, especially in clinical trials that establish standards of care, is necessary to minimize disparities in outcomes and to uphold societal equity in health care. Objective To evaluate the frequency of race reporting and proportional race representation in trials supporting US Food and Drug Administration (FDA) oncology drug approvals. Design, Setting, and Participants Database study of all reported trials supporting FDA oncology drug approvals granted between July 2008 and June 2018. Primary reports of trials were obtained from PubMed and ClinicalTrials.gov. Food and Drug Administration approvals were identified using the FDA archives. The US population-based cancer estimates by race were calculated using National Cancer Institute-Surveillance, Epidemiology, and End Results and US Census databases. Main Outcomes and Measures Primary outcomes were the proportion of trials reporting race and the proportion of patients by race participating in trials. Secondary outcomes included race subgroup analyses reporting and gaps between race proportion in trials and the US population. Descriptive statistics, Fisher exact, and χ2 tests were used to analyze the data. Proportions and odds ratios (OR) with 95% CIs were reported. Results Among 230 trials with a total of 112 293 participants, 145 (63.0%) reported on at least 1 race, 18 (7.8%) documented the 4 major races in the United States (white, Asian, black, and Hispanic), and 58 (25.2%) reported race subgroup analyses. Reporting on white, Asian, black, and Hispanic races was included in 144 (62.6%), 110 (47.8%), 88 (38.2%), and 23 (10.0%) trials, respectively. Between July 2008 and June 2013 vs July 2013 and June 2018, the number of trials reporting race (45 [56.6%] vs 100 [67.1%]; OR, 1.63; 95% CI, 0.93-2.87; P = .09) and race subgroup analysis (13 [16.1%] vs 45 [30.2%]; OR, 2.26, 95% CI, 1.16-4.67; P = .03) changed minimally and varied across races. Whites, Asians, blacks, and Hispanics represented 76.3%, 18.3%, 3.1% and 6.1% of trial participants, respectively, and the proportion for each race enrolled over time changed nominally (blacks, 3.6% vs 2.9% and Hispanics, 5.3% vs 6.7%) from July 2008 to June 2013 vs July 2013 to June 2018. Compared with their proportion of US cancer incidence, blacks (22% of expected) and Hispanics (44% of expected) were underrepresented compared with whites (98% of expected) and Asians (438% of expected). Conclusions and Relevance Race and race subgroup analysis reporting occurs infrequently, and black and Hispanic races are consistently underrepresented compared with their burden of cancer incidence in landmark trials that led to FDA oncology drug approvals. Enhanced minority engagement is needed in trials to ensure the validity of results and reliable benefits to all.
In Silico Identification of Novel Aromatic Compounds as Potential HIV-1 Entry Inhibitors Mimicking Cellular Receptor CD4

Despite recent progress in the development of novel potent HIV-1 entry/fusion inhibitors, there are currently no licensed antiviral drugs based on inhibiting the critical interactions of the HIV-1 envelope gp120 protein with cellular receptor CD4. In this connection, studies on the design of new small-molecule compounds able to block the gp120-CD4 binding are still of great value. In this work, in silico design of drug-like compounds containing the moieties that make the ligand active towards gp120 was performed within the concept of click chemistry. Complexes of the designed molecules bound to gp120 were then generated by molecular docking and optimized using semiempirical quantum chemical method PM7. Finally, the binding affinity analysis of these ligand/gp120 complexes was performed by molecular dynamic simulations and binding free energy calculations. As a result, five top-ranking compounds that mimic the key interactions of CD4 with gp120 and show the high binding affinity were identified as the most promising CD4-mimemic candidates. Taken together, the data obtained suggest that these compounds may serve as promising scaffolds for the development of novel, highly potent and broad anti-HIV-1 therapeutics.
New concepts in the pathogenesis of sarcoidosis

ABSTRACT Introduction: The pathogenesis of sarcoidosis is not yet completely understood, although in recent years our knowledge has made considerable progress. Areas covered: This review aims to highlight the latest findings, identified from PubMed, EMBASE, and Web of Science, on the pathogenetic mechanisms of sarcoidosis, considering the studies on potential environmental antigens, genetic background and host immune responses. Particular emphasis has been on recent studies on antigens, as it now seems clear that it is not a single, but various antigens of microbial and non-microbial origin that share the ability to induce the series of immune-inflammatory events that lead to granuloma formation, activating host genetically influenced immune responses that involve innate and even more adaptive immunity. The dysregulation of Th17, Th17.1 cells and Tregs, and their role in the resolution and maintenance of granulomatous inflammation has been reported. Expert opinion: The considerable amount of data that has been accumulated on sarcoidosis pathogenesis will have to be carefully interpreted, particularly to discover which pathways lead to severe forms with organ damage. There is an urgent need for a panel of biomarkers indicating the involvement of the various pathways, to be used for better characterizing patient phenotypes and developing targeted therapies.
Depicting the Core Transcriptome Modulating Multiple Abiotic Stresses Responses in Sesame (Sesamum indicum L.)

Sesame is a source of a healthy vegetable oil, attracting a growing interest worldwide. Abiotic stresses have devastating effects on sesame yield; hence, studies have been performed to understand sesame molecular responses to abiotic stresses, but the core abiotic stress-responsive genes (CARG) that the plant reuses in response to an array of environmental stresses are unknown. We performed a meta-analysis of 72 RNA-Seq datasets from drought, waterlogging, salt and osmotic stresses and identified 543 genes constantly and differentially expressed in response to all stresses, representing the sesame CARG. Weighted gene co-expression network analysis of the CARG revealed three functional modules controlled by key transcription factors. Except for salt stress, the modules were positively correlated with the abiotic stresses. Network topology of the modules showed several hub genes predicted to play prominent functions. As proof of concept, we generated over-expressing Arabidopsis lines with hub and non-hub genes. Transgenic plants performed better under drought, waterlogging, and osmotic stresses than the wild-type plants but did not tolerate the salt treatment. As expected, the hub gene was significantly more potent than the non-hub gene. Overall, we discovered several novel candidate genes, which will fuel investigations on plant responses to multiple abiotic stresses.
Visual epidural field potentials possess high functional specificity in single trials

Recordings of epidural field potentials (EFPs) allow to acquire neuronal activity over a large region of cortical tissue with minimal invasiveness. Because electrodes are placed on top of the dura and do not enter the neuronal tissue, EFPs offer intriguing options for both clinical and basic science research. On the other hand, EFPs represent the integrated activity of larger neuronal populations, possess a higher trial-by-trial variability, and a reduced signal-to-noise ratio due the additional barrier of the dura. It is thus unclear whether and to what extent EFPs have sufficient spatial selectivity to allow for conclusions about the underlying functional cortical architecture, and whether single EFP trials provide enough information on the short time scales relevant for many clinical and basic neuroscience purposes. We here use the high spatial resolution of primary visual cortex to address these issues and investigate the extent to which very short EFP traces allow reliable decoding of spatial information. We briefly presented different visual objects at one out of nine closely adjacent locations and recorded neuronal activity with a high-density, epidural multi-electrode array in three macaque monkeys. Using receiver-operating characteristics to identify most-informative data, machine-learning algorithms provided close-to-perfect classification rates for all 27 stimulus conditions. A binary classifier applying a simple max function on ROC-selected data further showed that single trials might be classified with 100% performance even without advanced offline classifiers. Thus, although highly variable, EFPs constitute an extremely valuable source of information and offer new perspectives for minimally invasive recording of large-scale networks.
A Different Approach to Estimate Temperature-Dependent Thermal Properties of Metallic Materials

Thermal conductivity, λ, and volumetric heat capacity, ρcp, variables that depend on temperature were simultaneously estimated in a diverse technique applied to AISI 1045 and AISI 304 samples. Two distinctive intensities of heat flux were imposed to provide a more accurate simultaneous estimation in the same experiment. A constant heat flux was imposed on the upper surface of the sample while the temperature was measured on the opposite insulated surface. The sensitivity coefficients were analyzed to provide the thermal property estimation. The Broydon-Fletcher-Goldfarb-Shanno (BFGS) optimization technique was applied to minimize an objective function. The squared difference objective function of the numerical and experimental temperatures was defined considering the error generated by the contact resistance. The temperature was numerically calculated by using the finite difference method. In addition, the reliability of the results was assured by an uncertainty analysis. Results showing a difference lower than 7% were obtained for λ and ρcp, and the uncertainty values were above 5%.