Miracle-dz/UniFAR-FTUs huggingface dataset:
A modulator of the low-voltage activated T-type calcium channel that reverses HIV glycoprotein 120-, paclitaxel-, and spinal nerve ligation-induced peripheral neuropathies.

The voltage-gated calcium channels CaV3.1-3.3 constitute the T-type subfamily, whose dysfunctions are associated with epilepsy, psychiatric disorders, and chronic pain. The unique properties of low voltage-activation, faster inactivation, and slower deactivation of these channels support their role in modulation of cellular excitability and low-threshold firing. Thus, selective T-type calcium channel antagonists are highly sought after. Here, we explored Ugi-azide multicomponent reaction (MCR) products to identify compounds targeting T-type calcium channel. Of the 46 compounds tested, an analog of benzimidazolonepiperidine - 5bk (1-{1-[(R)-{1-[(1S)-1-phenylethyl]-1H-1,2,3,4-tetrazol-5-yl}(thiophen-3-yl)methyl]piperidin-4-yl}-2,3-dihydro-1H-1,3-benzodiazol-2-one) modulated depolarization-induced calcium influx in rat sensory neurons. Modulation of T-type calcium channels by 5bk was further confirmed in whole-cell patch clamp assays in dorsal root ganglion (DRG) neurons, where pharmacological isolation of T-type currents led to a time- and concentration-dependent regulation with a low micromolar IC50. Lack of an acute effect of 5bk argues against a direct action on of T-type channels. Genetic knockdown revealed CaV3.2 to be the isoform preferentially modulated by 5bk. High voltage-gated calcium, as well as tetrodotoxin-sensitive and -resistant sodium, channels were unaffected by 5bk. 5bk inhibited spontaneous excitatory post synaptic currents and depolarization-evoked release of calcitonin gene-related peptide (CGRP) from lumbar spinal cord slices. Notably, 5bk did not bind human mu, delta, or kappa opioid receptors. 5bk reversed mechanical allodynia in rat models of HIV-associated neuropathy, chemotherapy-induced peripheral neuropathy (CIPN), and spinal nerve ligation (SNL)-induced neuropathy, without effects on locomotion or anxiety. Thus, 5bk represents a novel T-type modulator that could be used to develop non-addictive pain therapeutics.
Protein folding from heterogeneous unfolded state revealed by time-resolved X-ray solution scattering

Significance Protein undergoes a folding pathway to find a three-dimensional structure that expresses its biological function in a living cell. From vast theoretical studies, the funnel-like free-energy landscape has been recognized as a prominent scheme to describe protein folding, but it has been unclear how the dynamic behavior of protein folding is linked to conformational heterogeneity. Here we employ the time-resolved X-ray scattering method combined with systematic structural analysis to track the folding of cytochrome c. The kinetics and structural changes obtained from the data reveal that various protein conformations in the unfolded state take the complex folding pathways, resulting in the stretched exponential kinetics. This study may provide structural insights into fundamental principles governing protein folding. One of the most challenging tasks in biological science is to understand how a protein folds. In theoretical studies, the hypothesis adopting a funnel-like free-energy landscape has been recognized as a prominent scheme for explaining protein folding in views of both internal energy and conformational heterogeneity of a protein. Despite numerous experimental efforts, however, comprehensively studying protein folding with respect to its global conformational changes in conjunction with the heterogeneity has been elusive. Here we investigate the redox-coupled folding dynamics of equine heart cytochrome c (cyt-c) induced by external electron injection by using time-resolved X-ray solution scattering. A systematic kinetic analysis unveils a kinetic model for its folding with a stretched exponential behavior during the transition toward the folded state. With the aid of the ensemble optimization method combined with molecular dynamics simulations, we found that during the folding the heterogeneously populated ensemble of the unfolded state is converted to a narrowly populated ensemble of folded conformations. These observations obtained from the kinetic and the structural analyses of X-ray scattering data reveal that the folding dynamics of cyt-c accompanies many parallel pathways associated with the heterogeneously populated ensemble of unfolded conformations, resulting in the stretched exponential kinetics at room temperature. This finding provides direct evidence with a view to microscopic protein conformations that the cyt-c folding initiates from a highly heterogeneous unfolded state, passes through still diverse intermediate structures, and reaches structural homogeneity by arriving at the folded state.
A cross‐sectional community‐based observational study of asymptomatic SARS‐CoV‐2 prevalence in the greater Indianapolis area

The Asymptomatic novel CORonavirus iNfection (ACORN) study was designed to investigate the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection in the asymptomatic adult population of the Indianapolis metropolitan area, to follow individuals testing positive for the development of symptoms, and to understand duration of positive test results. ACORN is a cross‐sectional community‐based observational study of adult residents presenting asymptomatic for COVID‐like illness, defined as the self‐reported absence of the following three symptoms in the last 7 days: fever (≥100°F), new‐onset or worsening cough, and new‐onset or worsening shortness of breath. SARS‐CoV‐2 infection was determined by real‐time reverse transcription‐polymerase chain reaction in nasopharyngeal swab samples. SARS‐CoV‐2 infection prevalence was expressed as a point estimate with 95% confidence interval (CI). Test results are reported for 2953 participants who enrolled and underwent nasopharyngeal swab testing between 7 April 2020 and 16 May 2020. Among tested participants, 91 (3.1%; 95% CI: 2.5%‐3.7%) were positive for SARS‐CoV‐2. Overall, baseline characteristics, medical history, and infection risk factors were comparable between SARS‐CoV‐2 positive and negative participants. Within the ongoing 14‐day follow‐up period for positive participants, 58 (71.6%) of 81 assessed participants remained asymptomatic while others (n = 23, 28.4%) reported one or more symptoms. Indiana had “Stay‐at‐Home” orders in place during nearly the entire test period reported here, yet 3.1% of asymptomatic participants tested positive for SARS‐CoV‐2. These results indicate screening questions had limited predictive utility for testing in an asymptomatic population and suggest broader testing strategies are needed. Importantly, these findings underscore that more research is needed to understand the viral transmission and the role asymptomatic and presymptomatic individuals play in this global pandemic.
Simultaneous deletion of Prdm1 and Vsx2 enhancers in the retina alters photoreceptor and bipolar cell fate specification, yet differs from deleting both genes

ABSTRACT The transcription factor OTX2 is required for photoreceptor and bipolar cell formation in the retina. It directly activates the transcription factors Prdm1 and Vsx2 through cell type-specific enhancers. PRDM1 and VSX2 work in opposition, such that PRDM1 promotes photoreceptor fate and VSX2 bipolar cell fate. To determine how OTX2+ cell fates are regulated in mice, we deleted Prdm1 and Vsx2 or their cell type-specific enhancers simultaneously using a CRISPR/Cas9 in vivo retina electroporation strategy. Double gene or enhancer targeting effectively removed PRDM1 and VSX2 protein expression. However, double enhancer targeting favored bipolar fate outcomes, whereas double gene targeting favored photoreceptor fate. Both conditions generated excess amacrine cells. Combined, these fate changes suggest that photoreceptors are a default fate outcome in OTX2+ cells and that VSX2 must be present in a narrow temporal window to drive bipolar cell formation. Prdm1 and Vsx2 also appear to redundantly restrict the competence of OTX2+ cells, preventing amacrine cell formation. By taking a combinatorial deletion approach of both coding sequences and enhancers, our work provides new insights into the complex regulatory mechanisms that control cell fate choice. Highlighted Article: Simultaneous mutagenesis of two transcription factors or their cell type-specific enhancers causes divergent fate specification. Fate decisions involve the complex interplay of multiple factors within a temporally narrow window.
Body mass index, waist circumference and body fat are positively correlated with hair cortisol in children: A systematic review and meta‐analysis

The current body of research lacks a meta‐analysis of the relationship between hair cortisol concentration (HCC) and anthropometry in children. Therefore, this systematic review and meta‐analysis was conducted to examine this relationship and explore possible moderators between HCC and body mass index (BMI/BMI z‐score). Eleven databases were searched: CINAHL, Cochrane, Embase, PsycEXTRA, Psychology and Behavioral Sciences, PsycINFO, PubMed, Scopus, Social Sciences Full Text, Sociological Abstracts and Web of Sciences. Random‐effects models and exploratory moderator analyses with mixed‐effects models were performed using the Comprehensive Meta‐Analysis software. The meta‐analysis showed small positive correlations between HCC and BMI (r = 0.08, 95% confidence interval [CI]: 0.02, 0.14, n = 18, p = .009), BMI z‐score (r = 0.10, 95% CI: 0.03, 0.16, n = 12, p = .003), waist circumference (r = 0.10, 95% CI: 0.04, 0.17, n = 10, p = .001) and body fat including fat mass index (r = 0.06, 95% CI: 0.02, 0.11, n = 3, p = .005). The relationship between HCC and BMI/BMI z‐score was significantly moderated by children's sex. Results from this meta‐analysis provide initial objective support for a small positive relationship between HCC and anthropometric factors.
Polarized-Electrochemiluminescence Biosensor Based on Surface Plasmon Coupling Strategy and Fluorine-doped BN Quantum Dots.

The first polarized-electrochemiluminescence (ECL) biosensor is reported in this work. Surface plasmon coupling ECL (SPC-ECL) strategy is developed for the amplified polarization light of fluorine-doped BN Quantum Dot (F-BN QD) emitters. The generation of polarized-ECL is attributed to the characteristic of polarization-angle-dependent SPC effect. A polarized sandwich-type biosensor based on F-BN QDs and Au Nanoparticles (Au NPs) is established to detect K-ras gene. The polarized-ECL sensor is more sensitive with lower detection limit than isotropic ECL sensing system. The sensor can quantify K-ras gene from 0.1 fM to 10 nM with the detection limit as 0.03 fM. This work not only explores polarized SPC-ECL, but also offers a new analytical method for clinical diagnosisn. The generation of polarized-ECL and the amplification strategy of SPC effect open a new path for ECL resolved analysis.
Endocrine markers of puberty timing and antisocial behaviour in girls and boys.

BACKGROUND Early puberty is associated with higher than average risk of antisocial behaviour, both in girls and boys. Most studies of such association, however, have focused on psychosocial mediating and moderating factors. Few refer to coterminous hormonal measures. AIM The aim of this review is to consider the role of hormonal markers as potential mediating or moderating factors between puberty timing and antisocial behaviour. METHOD A systematic literature search was conducted searching Medline, Embase, Web of Science, Scopus, Psycinfo, Cochrane and Google Scholar. RESULTS Just eight studies were found to fit criteria, all cross-sectional. Measurements were too heterogeneous to allow meta-analysis. The most consistent associations found were between adrenal hormones-both androgens and cortisol-which were associated with early adrenarche and antisocial behaviours in girls and later adrenarche and antisocial behaviour in boys. CONCLUSIONS The findings from our review suggest that longitudinal studies to test bidirectional hormone-behaviour associations with early or late puberty would be worthwhile. In view of the interactive processes between hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes, integrated consideration of the hormonal end products is recommended.
Quantitative assessment of optical coherence tomography angiography algorithms for neuroimaging

Optical coherence tomography (OCT) angiography can noninvasively map microvascular networks and quantify blood flow in a cerebral cortex with a resolution of 1 to 10 μm and a penetration depth of 2 to 3 mm incorporating OCT signals and angiography algorithms. Different angiography algorithms have been developed in recent years; however, the performance of the algorithms has not been assessed quantitatively for neuroimaging applications. In this paper, we developed four metrics including vascular connectivity, contrast‐to‐noise ratio, signal‐to‐noise ratio and processing time to quantitatively assess the performance of OCT angiography algorithms in image quality and computation speed. After the imaging of a rat cortex using an OCT system, the cerebral microvascular networks were visualized by seven algorithms, and the performance of the algorithms was quantified and compared. Quantitative performance assessment of the algorithms can provide suggestions for the selection of appropriate OCT angiography algorithms in neuroimaging.
Non-ST elevation acute coronary syndrome in patients aged 80 years or older in Vietnam: An observational study

Background There is limited evidence of non-ST elevation acute coronary syndrome (NSTE-ACS) in patients aged 80 or older in Vietnam. Aim To describe the clinical characteristics of patients aged≥80 with NSTE-ACS in Vietnam, and to examine the effect of percutaneous coronary intervention (PCI) on adverse outcomes. Methods Consecutive patients aged ≥80 with a diagnosis of NSTE-ACS admitted to two tertiary hospitals in Vietnam from 12/2018 to 06/2019 were recruited. The major outcomes were: (1) the composite of all-cause mortality, recurrent myocardial infarction and stroke, (2) re-admission rate during 3 months. Cox proportional-hazards regressions were conducted to examine the impact of PCI on the study outcomes, with results presented as hazard ratios (HR) and 95% confidence intervals (CI). Results There were 120 participants, mean age 84.8 ± 3.8, 50% were female. Angiography and PCI were performed in 42 participants (35.0%). Most of the participants had multimorbidity and multiple coronary vessel disease. Compared to participants who did not receive PCI, participants who received PCI had significantly lower rates of adverse events during hospitalisation and during 3 months of follow up. Cox proportional hazards models adjusted to age and GRACE score show that PCI was significantly associated with reduced the composite outcome of all-cause mortality, recurrent myocardial infarction and stroke during 3 months follow-up (adjusted HR 0.32, 95%CI 0.12–0.86). PCI was also associated with reduced re-admission. Conclusions The rate of PCI was low in the very elderly patients with NSTE-ACS in this study, although PCI was significantly associated with reduced adverse outcomes.
Protective mechanisms of hydrogen sulfide in myocardial ischemia

Hydrogen sulfide (H2S), which has been identified as the third gaseous signaling molecule after nitric oxide (NO) and carbon monoxide (CO), plays an important role in maintaining homeostasis in the cardiovascular system. Endogenous H2S is produced mainly by three endogenous enzymes: cystathionine β‐synthase, cystathionine γ‐lyase, and 3‐mercaptopyruvate sulfur transferase. Numerous studies have shown that H2S has a significant protective role in myocardial ischemia. The mechanisms by which H2S affords cardioprotection include the antifibrotic and antiapoptotic effects, regulation of ion channels, protection of mitochondria, reduction of oxidative stress and inflammatory response, regulation of microRNA expression, and promotion of angiogenesis. Amplification of NO‐ and CO‐mediated signaling through crosstalk between H2S, NO, and CO may also contribute to the cardioprotective effect. Exogenous H2S donors are expected to become effective drugs for the treatment of cardiovascular diseases. This review article focuses on the protective mechanisms and potential therapeutic applications of H2S in myocardial ischemia.
Candidate genes involved in the defunctionalization and refunctionalization of the urinary bladder induced by bladder anuria and reperfusion

We develop a novel rabbit urinary diversion model of bladder defunctionalization due to bladder anuria followed by refunctionalization due to urine reperfusion to investigate the molecular biological background. To validate the results, we used reverse transcription‐polymerase chain reaction (RT‐PCR) to analyze human specimens from defunctionalized bladders in patients receiving dialysis before kidney transplantation.
Development of a small animal model for deer tick virus pathogenesis mimicking human clinical outcome

Powassan virus (POWV) is a tick-borne flavivirus that encompasses two genetic lineages, POWV (Lineage I) and deer tick virus (DTV, Lineage II). In recent years, the incidence of reported POWV disease cases has increased, coupled with an expanded geographic range of the DTV tick vector, Ixodes scapularis. POWV and DTV are serologically indistinguishable, and it is not known whether clinical manifestations, pathology, or disease outcome differ between the two viruses. Six-week-old male and female BALB/c mice were footpad-inoculated with DTV doses ranging from 101 to 105 FFU. Dose-independent mortality, morbidity, and organ viral loads were observed for mice inoculated with sequentially increasing doses of DTV. By study completion, all surviving mice had cleared their viremias but detectable levels of negative-sense DTV RNA were present in the brain, indicating viral persistence of infectious DTV in the central nervous system. For mice that succumbed to disease, neuropathology revealed meningoencephalitis characterized by microscopic lesions with widespread distribution of viral RNA in the brain. These findings, coupled with the rapid onset of neurological signs of disease and high viral titers in nervous tissue, highlight the neurotropism of DTV in this mouse model. Additionally, disease outcome for DTV-infected mice was not affected by sex, as males and females were equally susceptible to disease. This is the first study to comprehensively characterize the clinical disease outcome in a small animal model across a spectrum of POWV/DTV infection doses. Here, we developed a small animal model for DTV pathogenesis that mimics the manifestations of POWV disease in humans. Since it is currently not known whether DTV and POWV differ in their capacity to cause human disease, the animal model detailed in our study could be utilized in future comparative pathogenesis studies, or as a platform for testing the efficacy of vaccines, and anti-virals.
Learning from suicide deaths in Harris County, Texas

Abstract This study examined individual and community demographic characteristics surrounding suicides in one of the most populous counties in the United States. We paired medical examiner records with U.S. Census data and analyzed them using geospatial software. The majority of decedents were non-Hispanic, white males who died primarily of gunshot wounds. Salient age characteristics included interpersonal violence and depression among ages younger than 40. Despite lower incomes and education levels, areas with higher population density and racial/ethnic minorities had fewer suicides. Additional research should address depression among males and the elderly, interpersonal violence, firearm access, and culture.
Impact of multidisciplinary engagement in a quality improvement blood conservation protocol for craniosynostosis.

OBJECTIVE Patients undergoing open cranial vault remodeling for craniosynostosis frequently experience substantial blood loss requiring blood transfusion. Multiple reports in the literature have evaluated the impact of individual blood conservation techniques on blood transfusion rates during craniosynostosis surgery. The authors engaged a multidisciplinary team and assessed the impact of input from multiple stakeholders on the evolution of a comprehensive quality improvement protocol aimed at reducing or eliminating blood transfusion in patients undergoing open surgery for craniosynostosis. METHODS Over a 4-year period from 2012 to 2016, 39 nonsyndromic patients were operated on by a single craniofacial plastic surgeon. Initially, no clear blood conservation protocol existed, and specific interventions were individually driven. In 2014, a new pediatric neurosurgeon joined the craniofacial team, and additional stakeholders in anesthesiology, transfusion medicine, critical care, and hematology were brought together to evaluate opportunities for developing a comprehensive blood conservation protocol. The initial version of the protocol involved the standardized administration of intraoperative aminocaproic acid (ACA) and the use of a cell saver. In the second version of the protocol, the team implemented the preoperative use of erythropoietin (EPO). In addition, intraoperative and postoperative resuscitation and transfusion guidelines were more clearly defined. The primary outcomes of estimated blood loss (EBL), transfusion rate, and intraoperative transfusion volume were analyzed. The secondary impact of multidisciplinary stakeholder input was inferred by trends in the data obtained with the implementation of the partial and full protocols. RESULTS Implementing the full quality improvement protocol resulted in a 66% transfusion-free rate at the time of discharge compared to 0% without any conservation protocol and 27% with the intermediate protocol. The administration of EPO significantly increased starting hemoglobin/hematocrit (11.1 g/dl/31.8% to 14.7 g/dl/45.6%, p < 0.05). The group of patients receiving ACA had lower intraoperative EBL than those not receiving ACA, and trends in the final-protocol cohort, which had received both preoperative EPO and intraoperative ACA, demonstrated decreasing transfusion volumes, though the decrease did not reach statistical significance. CONCLUSIONS Patients undergoing open calvarial vault remodeling procedures benefit from the input of a multidisciplinary stakeholder group in blood conservation protocols. Further research into comprehensive protocols for blood conservation may benefit from input from the full surgical team (plastic surgery, neurosurgery, anesthesiology) as well as additional pediatric subspecialty stakeholders including transfusion medicine, critical care, and hematology.
An overview of rotavirus vaccination programs in developing countries

ABSTRACT Introduction Rotavirus is the leading cause of acute diarrhea among children <5 years worldwide. As all children are equally susceptible to infection and disease development, rotavirus vaccination programs are the best upstream approach to preventing rotavirus disease, and the subsequent risk of hospitalization or death. Areas covered We provide an overview of global rotavirus vaccine policy, summarize the burden of rotavirus disease in developing countries, review data on the effectiveness, impact, safety, and the cost-effectiveness of rotavirus vaccination programs, and identify areas for further research and improvement. Expert opinion Rotavirus vaccines continue to be an effective, safe, and cost-effective solution to preventing rotavirus disease. As two new rotavirus vaccines enter the market (Rotasiil and Rotavac) and Asian countries continue to introduce rotavirus vaccines into their national immunization programs, documenting vaccine safety, effectiveness, and impact in these settings will be paramount.