Miracle-dz/UniFAR-FTUs huggingface dataset:
Bmi1 marks gastric stem cells located in the isthmus in mice

In the mammalian stomach, the isthmus has been considered as a stem cell zone. However, various locations and proliferative activities of gastric stem cells have been reported. We focused here on the stem cell marker Bmi1, a polycomb group protein, aiming to elucidate the characteristics of Bmi1‐expressing cells in the stomach and to examine their stem cell potential. We investigated the Bmi1‐expressing cell lineage in Bmi1‐CreERT; Rosa26‐YFP, LacZ or Rosa26‐Confetti mice. We examined the in vivo and ex vivo effects of Bmi1‐expressing cell ablation by using Bmi1‐CreERT; Rosa26‐iDTR mice. The Bmi1 lineage was also traced during regeneration after high‐dose tamoxifen‐, irradiation‐ and acetic acid‐induced mucosal injuries. In the lineage‐tracing experiments using low‐dose tamoxifen, Bmi1‐expressing cells in the isthmus of the gastric antrum and corpus provided progeny bidirectionally, towards both the luminal and basal sides over 6 months. In gastric organoids, Bmi1‐expressing cells also provided progeny. Ablation of Bmi1‐expressing cells resulted in impaired gastric epithelium in both mouse stomach and organoids. After high‐dose tamoxifen‐induced gastric mucosal injury, Bmi1‐expressing cell lineages expanded and fully occupied all gastric glands of the antrum and the corpus within 7 days after tamoxifen injection. After irradiation‐ and acetic acid‐induced gastric mucosal injuries, Bmi1‐expressing cells also contributed to regeneration. In conclusion, Bmi1 is a gastric stem cell marker expressed in the isthmus of the antrum and corpus. Bmi1‐expressing cells have stem cell potentials, both under physiological conditions and during regeneration after gastric mucosal injuries. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Ciprofloxacin HCl and quercetin functionalized electrospun nanofiber membrane: fabrication and its evaluation in full thickness wound healing

Abstract Microbial infection and oxidative damage of the fibroblast often results in prolonged and incomplete wound healing. Therefore, there is an increasing demand for a scaffold being effective to prevent any possible infection and neutralize excessively released free radicals. Herein, we designed a PCL-based nanofiber loaded with ciprofloxacin hydrochloride (CHL) and quercetin. Developed nanofiber showed the formation of smooth and continuous nanofiber with 101.59 ± 29.18 nm average diameter and entrapping the drugs in amorphous form without any possible physico-chemical interaction between drugs and excipient. High entrapment efficiency (CHL: 92.04% and Que: 94.32%) and prolonged in-vitro release (for 7 days) demonstrated the capability of scaffold to suppress any probable infection and oxidative damage, which was further confirmed by in-vitro antibacterial and antioxidant activity. The biocompatibility of scaffold for direct application to wound site was evaluated through hemocompatibility and cytocompatibility assay. The wound healing efficacies of nanofiber were assessed using full thickness wound model in rats, which displayed accelerated wound healing with complete re-epithelialization and improved collagen deposition within 16 days. In-vivo wound healing finding was further corroborated by SOD, catalase, and hydroxyproline assay. The current study validates the application of ciprofloxacin HCl and quercetin functionalized nanofiber as a potential wound dressing material.
Metoprolol Inhibits Profibrotic Remodeling of Epicardial Adipose Tissue in a Canine Model of Chronic Obstructive Sleep Apnea

Background Whether chronic obstructive sleep apnea (OSA) could promote epicardial adipose tissue (EAT) secretion of profibrotic adipokines, and thereby contribute to atrial fibrosis, and the potential therapeutic effects of metoprolol remain unknown. Methods and Results A chronic OSA canine model was established by repeatedly clamping the endotracheal tube for and then reopening it for 4 hours every other day for 12 weeks. In a metoprolol treatment group, metoprolol succinate was administered daily for 12 weeks. The EAT infiltration and left atrial fibrosis were examined. The expressions of adipokines secreted by EAT and hypoxic 3T3‐L1 adipocytes were detected. The changes in collagen synthesis, transforming growth factor‐β1 expression, and cell differentiation and proliferation in cardiac fibroblasts induced by hypoxic 3T3‐L1 adipocyte‐derived conditioned medium were further analyzed. Chronic OSA induced infiltration of EAT into the left atrium. OSA enhanced the profibrotic effect of EAT on the adjacent atrial myocardium. Moreover, OSA induced profibrotic cytokine secretion from EAT. We also found that hypoxia induced adipokine secretion in cultured adipocytes, and the medium conditioned by the hypoxic adipocytes increased collagen and transforming growth factor‐β1 protein expression and cell proliferation of cardiac fibroblasts. More importantly, metoprolol attenuated infiltration of EAT and alleviated the profibrotic effect of EAT by inhibiting adipokine secretion. Metoprolol also inhibited hypoxia‐induced adipokine secretion in adipocytes and thereby blocked the hypoxic adipocyte–derived conditioned medium–induced fibrotic response of cardiac fibroblasts. Conclusions Chronic OSA enhanced the profibrotic effect of EAT on the neighboring atrial myocardium by stimulating the secretion of profibrotic adipokines from EAT, which was significantly attenuated by metoprolol. This study gives insights into mechanisms underlying OSA‐induced atrial fibrillation and also provides experimental evidence for the protective effects of metoprolol.
Postoperative microcirculatory perfusion and endothelial glycocalyx shedding following cardiac surgery with cardiopulmonary bypass

We investigated microcirculatory perfusion disturbances following cardiopulmonary bypass in the early postoperative period and whether the course of these disturbances mirrored restoration of endothelial glycocalyx integrity. We performed sublingual sidestream dark field imaging of the microcirculation during the first three postoperative days in patients who had undergone on‐pump coronary artery bypass graft surgery. We calculated the perfused vessel density, proportion of perfused vessels and perfused boundary region. Plasma was obtained to measure heparan sulphate and syndecan‐1 levels as glycocalyx shedding markers. We recruited 17 patients; the mean (SD) duration of non‐pulsatile cardiopulmonary bypass was 103 (18) min, following which 491 (29) ml autologous blood was transfused through cell salvage. Cardiopulmonary bypass immediately decreased both microcirculatory perfused vessel density; 11 (3) vs. 16 (4) mm.mm−2, p = 0.052 and the proportion of perfused vessels; 92 (5) vs. 69 (9) %, p < 0.0001. The proportion of perfused vessels did not increase after transfusion of autologous salvaged blood following cardiopulmonary bypass; 72 (7) %, p = 0.19 or during the first three postoperative days; 71 (5) %, p < 0.0001. The perfused boundary region increased after cardiopulmonary bypass; 2.2 (0.3) vs. 1.9 (0.3) μm, p = 0.037 and during the first three postoperative days; 2.4 (0.3) vs. 1.9 (0.3) μm, p = 0.003. Increased plasma heparan sulphate levels were inversely associated with the proportion of perfused vessels during cardiopulmonary bypass; R = −0.49, p = 0.02. Plasma syndecan‐1 levels were inversely associated with the proportion of perfused vessels during the entire study period; R = −0.51, p < 0.0001. Our study shows that cardiopulmonary bypass‐induced acute microcirculatory perfusion disturbances persist in the first three postoperative days, and are associated with prolonged endothelial glycocalyx shedding. This suggests prolonged impairment and delayed recovery of both microcirculatory perfusion and function after on‐pump cardiac surgery.
Spike-timing-dependent ensemble encoding by non-classically responsive cortical neurons

Neurons recorded in behaving animals often do not discernibly respond to sensory input and are not overtly task-modulated. These non-classically responsive neurons are difficult to interpret and are typically neglected from analysis, confounding attempts to connect neural activity to perception and behavior. Here, we describe a trial-by-trial, spike-timing-based algorithm to reveal the coding capacities of these neurons in auditory and frontal cortex of behaving rats. Classically responsive and non-classically responsive cells contained significant information about sensory stimuli and behavioral decisions. Stimulus category was more accurately represented in frontal cortex than auditory cortex, via ensembles of non-classically responsive cells coordinating the behavioral meaning of spike timings on correct but not error trials. This unbiased approach allows the contribution of all recorded neurons – particularly those without obvious task-related, trial-averaged firing rate modulation – to be assessed for behavioral relevance on single trials.
In silico prediction of chemical reproductive toxicity using machine learning

Reproductive toxicity is an important regulatory endpoint in health hazard assessment. Because the in vivo tests are expensive, time consuming and require a large number of animals, which must be killed, in silico approaches as the alternative strategies have been developed to assess the potential reproductive toxicity (reproductive toxicity) of chemicals. Some prediction models for reproductive toxicity have been developed, but most of them were built only based on one single endpoint such as embryo teratogenicity; therefore, these models may not provide reliable predictions for toxic chemicals with other endpoints, such as sperm reduction or gonadal dysgenesis. Here, a total of 1823 chemicals for reproductive toxicity characterized by multiple endpoints were used to develop structure‐activity relationship models by six machine‐learning approaches with nine molecular fingerprints. Among the models, MACCSFP‐SVM model has the best performance for the external validation set (area under the curve = 0.900, classification accuracy = 0.836). The applicability domain was analyzed, and a rational boundary was found to distinguish inaccurate predictions and accurate predictions. Moreover, several structural alerts for characterizing reproductive toxicity were identified using the information gain combining substructure frequency analysis. Our results would be helpful for the prediction of the reproductive toxicity of chemicals.
Balance problems and dizziness after neck surgery – associations with pain and health-related quality of life

ABSTRACT Introduction: Symptoms of dizziness or imbalance are often present in individuals with a variety of neck-disorders. The aims of this study were to determine the prevalence of patient-reported balance problems and dizziness 10–13 years after surgery for cervical degenerative disc disease; evaluate associations with neck pain and health-related quality of life; and investigate how these individuals described dizziness. Material and methods: Sixty-eight individuals, 10 years or more after anterior cervical decompression and fusion surgery, who previously participated in a randomized controlled trial were included. Participants completed questionnaires including ratings of dizziness and balance problems, the Dizziness Handicap Inventory, and an open-ended question regarding their experience of dizziness. Secondary outcomes were neck pain and quality of life. Results: Seventy-two percent experienced occasional or daily symptoms of unsteadiness and/or dizziness. Intensity ratings for dizziness during movement and for balance problems were similar and rather low, but had an impact on quality of life. Ratings of dizziness at rest were even lower. Dizziness ratings were associated with neck pain. Strenuous activities were related to dizziness and dizziness was primarily described as intermittent and non-rotatory. Conclusions: Dizziness or balance problems in the long-term after surgery for cervical degenerative disc disease are common and have an impact on daily life. Ratings of problem frequency and intensity were usually low. Dizziness and balance problems may affect quality of life. Patients’ descriptions of these problems are in line with common symptoms of cervicogenic dizziness.
Interset Stretching vs. Traditional Strength Training: Effects on Muscle Strength and Size in Untrained Individuals.

Evangelista, AL, De Souza, EO, Moreira, DCB, Alonso, AC, Teixeira, CVLS, Wadhi, T, Rauch, J, Bocalini, DS, Pereira, PEDA, and Greve, JMDA. Interset stretching vs. traditional strength training: effects on muscle strength and size in untrained individuals. J Strength Cond Res XX(X): 000-000, 2019-This study compared the effects of 8 weeks of traditional strength training (TST) and interset stretching (ISS) combined with TST on muscular adaptations. Twenty-nine sedentary, healthy adults were randomly assigned to either the TST (n = 17; 28.0 ± 6.4 years) or ISS (n = 12; 26.8 ± 6.1 years) group. Both groups performed 6 strength exercises encompassing the whole body (bench press, elbow extension, seated rows, biceps curl, knee extension, and knee flexion) performing 4 sets of 8-12 repetition maximum (RM) with a 90-second rest between sets. However, the ISS group performed static passive stretching, at maximum amplitude, for 30 seconds between sets. Both groups performed training sessions twice a week on nonconsecutive days. Muscle strength (i.e., 1RM) and hypertrophy (i.e., muscle thickness [MT] by ultrasonography) were measured at pre-test and after 8 weeks of training. Both groups increased 1RM bench press (p ≤ 0.0001): ISS (23.4%, CIdiff: 4.3 kg-11.1 kg) and TST (22.2%, CIdiff: 5.2 kg-10.9 kg) and 1RM knee extension (p ≤ 0.0001): ISS (25.5%, CIdiff: 5.6 kg-15.0 kg) and TST (20.6%, CIdiff: 4.4 kg-12.3 kg). Both groups increased MT of biceps brachii (BIMT), triceps brachii (TRMT), and rectus femoris (RFMT) (p ≤ 0.0001). BIMT: ISS (7.2%, CIdiff: 1.14-3.5 mm) and TST (4.7%, CIdiff: 0.5-2.5 mm), TRMT: ISS (12.3%, CIdiff: 1.1-4.4 mm) and TST (7.1%, CIdiff: 0.3-3.1 mm), and RFMT: ISS (12.4%, CIdiff: 1.1-2.9 mm) and TST (9.1%, CIdiff: 0.7-2.2 mm). For vastus lateralis muscle thickness (VLMT) and sum of the 4 muscle thickness sites (ΣMT), there was a significant group by time interaction (p ≤ 0.02) in which ISS increased VLMT and ΣMT to a greater extent than TST. Vastus lateralis muscle thickness: ISS (17.0%, CIdiff: 1.5-3.1 mm) and TST (7.3%, CIdiff: 0.7-2.1 mm), and ΣMT: ISS (10.5%, CIdiff: 6.5-9.0 mm) and TST (6.7%, CIdiff: 3.9-8.3 mm). Although our findings might suggest a benefit of adding ISS into TST for optimizing muscle hypertrophy, our data are not sufficient enough to conclude that ISS is superior to TST for inducing muscle hypertrophic adaptations. More studies are warranted to elucidate the effects of ISS compared with TST protocols on skeletal muscle. However, our findings support that adding ISS to regular TST regimens does not compromise muscular adaptations during the early phase of training (<8 weeks) in untrained individuals.
Assessing Fine-Grained Speech Discrimination in Young Children With Bilateral Cochlear Implants.

HYPOTHESIS Children of 2 to 3 years old with cochlear implants can perform consonant discriminations using fine-grained acoustic cues. BACKGROUND Children born with severe-to-profound deafness are provided with early cochlear implantation (<2 yr) to maximize oral communication outcomes. Little is known regarding their abilities to discriminate consonant contrasts for accurately identifying speech sounds. METHODS Using a Reaching for Sound paradigm to collect behavioral responses, consonant contrast discrimination was measured in 13 children with bilateral cochlear implants (BiCIs; aged 28-37 mo), and 13 age-matched normal-hearing (NH) children. Four contrast pairs were tested: 1) place + voicing, 2) place, 3) voicing, and 4) reduced voice-onset-time cue. Using standard processing strategies, electrodograms showing pulsatile stimulation patterns were created retrospectively to assess the spectral-temporal cues delivered through the clinical speech processors. RESULTS As a group, children with BiCIs were able to discriminate all consonant contrasts at a level that was above chance, but their performance was poorer than NH children. Larger individual variability in discrimination performance was found in children with BiCIs. Stepwise regression revealed that, in the place contrast, chronological age was correlated with improved discrimination performance among children with BiCIs. CONCLUSION Children with BiCIs were able to discriminate consonant contrasts using fine-grained spectral-temporal cues above chance level but more poorly than their NH peers. Electrodogram analysis confirmed the access to spectral-temporal cues in the consonant contrasts through clinical speech processors. However, the cue saliency might not have be enough for children with BiCIs to achieve the same discrimination accuracy as NH children.
Efficacy and Safety of Genotype-Guided Warfarin Dosing in the Chinese Population: A Meta-analysis of Randomized Controlled Trials

Aims: To evaluate the efficacy and safety of using genetic information to guide warfarin dosing in the Chinese population. Methods: This meta-analysis was conducted among the published, randomized, controlled trials (RCTs) in the Chinese population comparing genotype-guided warfarin dosing (PG group) with clinical or standard warfarin dosing (STD group). RCTs published on or before January 2018 were identified using the PubMed, Embase, Cochrane Library, CNKI, Chinese VIP database, and Chinese Wanfang database. Result: Intotal, 2137 participants from 14 RCTs were included in the meta-analysis. Primary analysis showed that both bleeding events [odds ratio (OR) = 0.24; 95% confidence interval (CI), 0.11–0.52; P = 0.0003] and adverse events (OR = 0.60; 95% CI, 0.43–0.83; P = 0.002) were significantly lower in the genotype-guided group than in the clinical or standard group. The percentage of patients who received a warfarin-stable therapeutic dose during follow-up was increased in the genotype-guided group compared with the percentage in the clinical or standard group (OR = 2.68; 95% CI, 1.82–3.95; P < 0.00001). In the genotype-guided group, the time to a stable therapeutic dose (mean difference = −7.98; 95% CI, −9.08 to −6.87; P < 0.00001) and the time to the first target value (mean difference = −1.87; 95% CI, −3.41 to −0.32; P = 0.02) were shortened compared with those of the clinical or standard group, but there was no difference for international normalized ratio >4, between the 2 groups (OR = 0.42; 95% CI, 0.14–1.25; P = 0.12). Conclusions: Genotype-guided warfarin-dosing algorithms could improve the efficacy and safety of warfarin anticoagulation in the Chinese population.
The impact of age on fertility rate in patients who underwent microsurgical varicocelectomy

Impacts of a subinguinal microsurgical varicocelectomy on the sperm parameters and fertility rates were investigated in three different ages according to their age at the time of the varicocelectomy: Group 1 was ≤20 years old, Group 2 was 21–30 years old, and Group 3 was ≥31 years old. The patients were also classified both preoperatively and post‐operatively according to the total motile sperm count (TMSC) into the following categories: invitro fertilisation, intrauterine insemination and naturally fertile. The proportion of patients who upgraded to a higher TMSC category level was calculated, and natural fertility rates were recorded. The mean infertility duration was statistically longer in Group 3, compared to Group 1 and 2. The mean TMSCs and normal sperm morphology rates increased in all groups. The mean post‐operative natural fertility rates were similar. The highest rate of TMSC upgrade was observed in Grade 3 varicocele patients under 20 years of age, compared to other grades of varicocele in patients older than 20 years. A microsurgical subinguinal varicocele repair, which is an effective treatment modality reduces the need for any type of ART, has an important impact on the TMSC increase in patients, particularly in the younger population.
Dynamic ploidy changes drive fluconazole resistance in human cryptococcal meningitis

BACKGROUND. Cryptococcal meningitis (CM) causes an estimated 180,000 deaths annually, predominantly in sub-Saharan Africa, where most patients receive fluconazole (FLC) monotherapy. While relapse after FLC monotherapy with resistant strains is frequently observed, the mechanisms and impact of emergence of FLC resistance in human CM are poorly understood. Heteroresistance (HetR) — a resistant subpopulation within a susceptible strain — is a recently described phenomenon in Cryptococcus neoformans (Cn) and Cryptococcus gattii (Cg), the significance of which has not previously been studied in humans. METHODS. A cohort of 20 patients with HIV-associated CM in Tanzania was prospectively observed during therapy with either FLC monotherapy or in combination with flucytosine (5FC). Total and resistant subpopulations of Cryptococcus spp. were quantified directly from patient cerebrospinal fluid (CSF). Stored isolates underwent whole genome sequencing and phenotypic characterization. RESULTS. Heteroresistance was detectable in Cryptococcus spp. in the CSF of all patients at baseline (i.e., prior to initiation of therapy). During FLC monotherapy, the proportion of resistant colonies in the CSF increased during the first 2 weeks of treatment. In contrast, no resistant subpopulation was detectable in CSF by day 14 in those receiving a combination of FLC and 5FC. Genomic analysis revealed high rates of aneuploidy in heteroresistant colonies as well as in relapse isolates, with chromosome 1 (Chr1) disomy predominating. This is apparently due to the presence on Chr1 of ERG11, which is the FLC drug target, and AFR1, which encodes a drug efflux pump. In vitro efflux levels positively correlated with the level of heteroresistance. CONCLUSION. Our findings demonstrate for what we believe is the first time the presence and emergence of aneuploidy-driven FLC heteroresistance in human CM, association of efflux levels with heteroresistance, and the successful suppression of heteroresistance with 5FC/FLC combination therapy. FUNDING. This work was supported by the Wellcome Trust Strategic Award for Medical Mycology and Fungal Immunology 097377/Z/11/Z and the Daniel Turnberg Travel Fellowship.
Synovial Tissue Sampling in Rheumatological Practice—Past Developments and Future Perspectives

Synovial biopsies are performed in routine clinical care in order to refine diagnosis as well as within a research setting. Progress in the development of minimally invasive synovial sampling methods in the last century has accelerated and facilitated novel insights into disease pathogenesis. This review discusses the development of synovial biopsy techniques as well as examining the three currently most commonly used approaches: arthroscopic, blind needle biopsy and ultrasound guided approaches. It also highlights major research advances driven through synovial research and considers future developments.
Predicting Gene Ontology Function of Human MicroRNAs by Integrating Multiple Networks

MicroRNAs (miRNAs) have been demonstrated to play significant biological roles in many human biological processes. Inferring the functions of miRNAs is an important strategy for understanding disease pathogenesis at the molecular level. In this paper, we propose an integrated model, PmiRGO, to infer the gene ontology (GO) functions of miRNAs by integrating multiple data sources, including the expression profiles of miRNAs, miRNA-target interactions, and protein-protein interactions (PPI). PmiRGO starts by building a global network consisting of three networks. Then, it employs DeepWalk to learn latent representations as network features of the global heterogeneous network. Finally, the SVM-based models are applied to label the GO terms of miRNAs. The experimental results show that PmiRGO has a significantly better performance than existing state-of-the-art methods in terms of Fmax. A case study further demonstrates the feasibility of PmiRGO to annotate the potential functions of miRNAs.