Miracle-dz/UniFAR-FTUs huggingface dataset:
Effects of rAAV-Mediated sox9 Overexpression on the Biological Activities of Human Osteoarthritic Articular Chondrocytes in Their Intrinsic Three-Dimensional Environment

Gene therapy for osteoarthritis offers powerful, long-lasting tools that are well adapted to treat such a slow, progressive disorder, especially those therapies based on the clinically adapted recombinant adeno-associated viral (rAAV) vectors. Here, we examined the ability of an rAAV construct carrying a therapeutic sequence for the cartilage-specific SOX9 transcription factor to modulate the phenotype of human osteoarthritic articular chondrocytes compared with normal chondrocytes in a three-dimensional environment where the cells are embedded in their extracellular matrix. Successful sox9 overexpression via rAAV was noted for at least 21 days, leading to the significant production of major matrix components (proteoglycans, type-II collagen) without affecting the proliferation of the cells, while the cells contained premature hypertrophic processes relative to control conditions (reporter rAAV-lacZ application, absence of vector treatment). These findings show the value of using rAAV to adjust the osteoarthritic phenotype when the chondrocytes are confined in their inherently altered environment and the possibility of impacting key cellular processes via gene therapy to remodel human osteoarthritic cartilage lesions.
Vitamin D in the Foot and Ankle - A review of the literature.

This manuscript reviews the role of Vitamin D and its deficiency in pathology of the foot and ankle. Vitamin D is an essential vitamin which targets a number of tissues and organs, and plays an important role in calcium homeostasis. Vitamin D deficiency is common, particularly at higher latitudes where there is reduced exposure to ultraviolet B radiation. The effects of Vitamin D deficiency have been extensively studied but only a small portion of the literature has focused on the foot and ankle. Most of the evidence regarding the foot and ankle consists of retrospective studies which cannot determine whether Vitamin D deficiency is in fact the cause for the pathologies being investigated. The available evidence suggests that insufficient levels of Vitamin D may result in an increased incidence of foot and ankle fractures. The effects of Vitamin D deficiency on fracture healing, bone marrow edema syndrome, osteochondral lesions of the talus, strength around the foot and ankle, tendon disorders, elective foot and ankle surgery, and other foot and ankle conditions are less clear. Based on the available evidence, we are unable to recommend routine testing or supplementation of Vitamin D in patients presenting with foot and ankle pathology. However, Vitamin D supplementation is cheap, safe and may be of benefit in patients at high risk of deficiency. When it is supplemented the evidence suggests calcium should be co-supplemented. Further high-quality research is needed into the effect of Vitamin D in the foot and ankle. Cost-benefit analyses of routine testing and / or supplementation of Vitamin D for foot and ankle pathology are also required.
Clinical Characteristics of Different Primary Constipation Subtypes in a Chinese Population

Goal: To investigate the clinical characteristics of different primary constipation subtypes, including symptom clusters, psychological problems, quality of life (QOL), and to explore the role of constipation symptoms and the mental state in the QOL of constipation subtypes. Background: Patients with chronic constipation (CC) may be unsatisfied with their therapy and suffer recurrent symptoms. Different constipation subtypes require different treatments; therefore, it is important to identify the features of different constipation subtypes. Study: CC patients (n=206) visiting our gastroenterology clinic were studied. CC subtypes were diagnosed using the Rome-IV criteria. We used validated questionnaires to investigate the symptom severity, mental state, and QOL of patients. QOL was assessed with the Patient Assessment of Constipation Quality of Life (PAC-QOL) and SF-36 questionnaire. Results of symptom, mental and QOL scores are expressed as means with 95% confidence interval. Results: Three groups of CC patients differed in their constipation scoring system and the Patient Assessment of Constipation Symptoms (PAC-SYM) total scores, and both were significantly higher in the functional defecation disorder (FDD) group compared with that in the normal transit constipation (NTC) group. FDD patients tended to have more severe “abdominal symptoms,” “rectal symptoms” than NTC group. No significant difference in General Anxiety Disorder 7-item or Patient Health Questionnaire-9 results was found among the 3 groups. Significantly more patients with FDD suffered more “physical discomfort” and had poorer QOL in the “physical function” dimension of SF-36. FDD and NTC patients mainly showed associations between CC-related QOL and constipation severity, while slow transit constipation patients’ QOL was significantly associated with anxiety and depression. Conclusion: Patients with FDD suffer more severe constipation symptoms and have a lower QOL than patients in other CC subgroups. FDD and NTC patients’ QOL is mainly linked to constipation symptoms, while that of slow transit constipation is mainly related to mental states such as anxiety and depression.
Mitochondrial Dysfunction Underlies Cardiomyocyte Remodeling in Experimental and Clinical Atrial Fibrillation

Atrial fibrillation (AF), the most common progressive tachyarrhythmia, results in structural remodeling which impairs electrical activation of the atria, rendering them increasingly permissive to the arrhythmia. Previously, we reported on endoplasmic reticulum stress and NAD+ depletion in AF, suggesting a role for mitochondrial dysfunction in AF progression. Here, we examined mitochondrial function in experimental model systems for AF (tachypaced HL-1 atrial cardiomyocytes and Drosophila melanogaster) and validated findings in clinical AF. Tachypacing of HL-1 cardiomyocytes progressively induces mitochondrial dysfunction, evidenced by impairment of mitochondrial Ca2+-handling, upregulation of mitochondrial stress chaperones and a decrease in the mitochondrial membrane potential, respiration and ATP production. Atrial biopsies from AF patients display mitochondrial dysfunction, evidenced by aberrant ATP levels, upregulation of a mitochondrial stress chaperone and fragmentation of the mitochondrial network. The pathophysiological role of mitochondrial dysfunction is substantiated by the attenuation of AF remodeling by preventing an increased mitochondrial Ca2+-influx through partial blocking or downregulation of the mitochondrial calcium uniporter, and by SS31, a compound that improves bioenergetics in mitochondria. Together, these results show that conservation of the mitochondrial function protects against tachypacing-induced cardiomyocyte remodeling and identify this organelle as a potential novel therapeutic target.
Exploring the Antioxidant Effects and Periodic Regulation of Cancer Cells by Polyphenols Produced by the Fermentation of Grape Skin by Lactobacillus plantarum KFY02

Lactobacillus plantarum KFY02 (LP-KFY02) was isolated from naturally fermented yoghurt in Xinjiang. We previously demonstrated that LP-KFY02 has good biological activity in vitro. In this study, LP-KFY02 was used to ferment grape skin, and the LP-KFY02 fermented grape skin extract solution (KFSE) was examined for its antioxidant ability in a human embryonic kidney (293T) cell oxidative damage model caused by H2O2 and its inhibitory effect on human hepatoma (HepG2) cells. The results showed that KFSE reduced the degree of oxidative damage in 293T cells, increased the relevant expression levels of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and GSH-peroxidase (GSH-Px), and total antioxidant capacity (T-AOC), and decreased the expression levels of lactate dehydrogenase (LDH), malondialdehyde (MDA), and nitric oxide (NO). The expression of genes and proteins of SOD, CAT, GSH, and GSH-Px was up-regulated. In addition, KFSE-induced growth inhibition appeared to be through induction of cell-cycle arrest. This induction was accompanied by a reduction in the expression of cell-cycle genes, such as cyclin-D1 and CDK4. In addition, KFSE induced gene expression of p21, the apoptosis gene wild-type p53 and the caspase family. At the protein expression level, Bax and Caspase-8 were up-regulated, and the inflammatory marker Nuclear Factor Kappa-B (NF-κB) was down-regulated. The fermentation solution polyphenols were separated and identified as epicatechin gallate, coumarin, new chlorogenic acid, rutin, resveratrol, chlorogenic acid, rosmarinic acid, etc. by HPLC. Overall, these results demonstrate that KFSE significantly attenuated oxidative damage in 293T cells and inhibited tumor growth in HepG2 cancer cells, induces cell-cycle arrest and affects proteins involved in cell-cycle regulation and proliferation. This suggests that KFSE may also be explored as a neo-adjuvant to expansion of hepatoma.
Cichorium intybus L. Extract Suppresses Experimental Gout by Inhibiting the NF-κB and NLRP3 Signaling Pathways

Background: The production and maturation of interleukin (IL)-1β, regulated by the NF-κB and NLRP3 signaling pathways, lie at the core of gout. This study aimed to evaluate the antigout effect of Cichorium intybus L. (also known as chicory) in vivo and in vitro. Methods: A gout animal model was established with monosodium urate (MSU) crystal injections. Rats were orally administered with chicory extract or colchicine. Levels of ankle edema, inflammatory activity, and IL-1β release were observed. Several essential targets of the NF-κB and NLRP3 signaling pathways were detected. Primary macrophages were isolated to verify the antigout mechanism of chicory extract as well as chicoric acid in vitro. Results: Improvements of swelling degree, inflammatory activity, and histopathological lesion in MSU-injected ankles were observed in the treatment with chicory extract. Further, the chicory extract significantly decreased IL-1β release by suppressing the NF-κB and NLRP3 signaling pathways in gout rats. Similar to the in vivo results, IL-1β release was also inhibited by chicory extract and chicoric acid, a specific effective compound in chicory, through the NF-κB and NLRP3 signaling pathways. Conclusion: This study suggests that chicory extract and chicoric acid may be used as promising therapeutic agents against gout by inhibiting the NF-κB and NLRP3 signaling pathways.
STRUCTURE OF CALCIUM SILICATE HYDRATE Ca_4Si_6O_(14)(OH)_4·2H_2O SIMULATED BY THE MOLECULAR DYNAMICS

Calcium silicate hydrate is main hydration product of portland cement.This product has a low calcium to silicate ratio,i.e.,Ca4Si6O14(OH)4·2H2O(C-S-H(Ⅰ)). Its primary structure has previously been established by the Hamid's model,and the structure was simulated by the molecular dynamics at the atomic level.According to simulation results,the differences in structures of crystal calcium silicate and calcium silicate hydrate were also studied.The reliability of the simulation results was also verified by comparison with experimental data.The simulation results show that the structural characteristic of crystal calcium silicate is not only long-range order but also short-range order,while that of calcium silicate hydrate is only short-range order.This is because its radial distribution function of atom pairs,including Ca—O,Si—O,O—O,and Si—Si,gradually approaches 1 as the interatomic distances increase.Calcium silicate hydrate's structural unit is a silicon-oxygen tetrahedron,which is the same as that of crystal calcium silicate,and the number of nearest neighbors of Si is 2,which indicates that the chains of silicon tetrahedral link as Q2.Structural parameters obtained by simulation,such as Si—O bond distances of 0.162 nm,Ca—O of 0.264 nm and the mean Si coordination number of 4,are generally consistent with the experimental data,which suggests that the simulation results are able to reflect the true structure of C-S-H(Ⅰ).
NITUMID: Nonnegative matrix factorization-based Immune-TUmor MIcroenvironment Deconvolution

MOTIVATION A number of computational methods have been proposed recently to profile tumor microenvironment from bulk RNA data, and they have proved useful for understanding microenvironment differences among therapeutic response groups. However, these methods are not able to account for tumor proportion nor variable mRNA levels across cell types. RESULTS In this article, we propose a Non-negative Matrix Factorization-based Immune-TUmor MIcroenvironment Deconvolution (NITUMID) framework for tumor microenvironment profiling that addresses these limitations. It is designed to provide robust estimates of tumor and immune cells proportions simultaneously, while accommodating mRNA level differences across cell types. Through comprehensive simulations and real data analyses, we demonstrate that NITUMID not only can accurately estimate tumor fractions and cell types' mRNA levels, which are currently unavailable in other methods; it also outperforms most existing deconvolution methods in regular cell type profiling accuracy. Moreover, we show that NITUMID can more effectively detect clinical and prognostic signals from gene expression profiles in tumor than other methods. AVAILABILITY The algorithm is implemented in R. The source code can be downloaded at https://github.com/tdw1221/NITUMID. SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.
Do physical therapists follow evidence-based guidelines when managing musculoskeletal conditions? Systematic review

Objectives Physicians often refer patients with musculoskeletal conditions to physical therapy. However, it is unclear to what extent physical therapists’ treatment choices align with the evidence. The aim of this systematic review was to determine what percentage of physical therapy treatment choices for musculoskeletal conditions agree with management recommendations in evidence-based guidelines and systematic reviews. Design Systematic review. Setting We performed searches in Medline, Embase, Cumulative Index to Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, Allied and Complementary Medicine, Scopus and Web of Science combining terms synonymous with ‘practice patterns’ and ‘physical therapy’ from the earliest record to April 2018. Participants Studies that quantified physical therapy treatment choices for musculoskeletal conditions through surveys of physical therapists, audits of clinical notes and other methods (eg, audits of billing codes, clinical observation) were eligible for inclusion. Primary and secondary outcomes Using medians and IQRs, we summarised the percentage of physical therapists who chose treatments that were recommended, not recommended and had no recommendation, and summarised the percentage of physical therapy treatments provided for various musculoskeletal conditions within the categories of recommended, not recommended and no recommendation. Results were stratified by condition and how treatment choices were assessed (surveys of physical therapists vs audits of clinical notes). Results We included 94 studies. For musculoskeletal conditions, the median percentage of physical therapists who chose recommended treatments was 54% (n=23 studies; surveys completed by physical therapists) and the median percentage of patients that received recommended physical therapy-delivered treatments was 63% (n=8 studies; audits of clinical notes). For treatments not recommended, these percentages were 43% (n=37; surveys) and 27% (n=20; audits). For treatments with no recommendation, these percentages were 81% (n=37; surveys) and 45% (n=31; audits). Conclusions Many physical therapists seem not to follow evidence-based guidelines when managing musculoskeletal conditions. There is considerable scope to increase use of recommended treatments and reduce use of treatments that are not recommended. PROSPERO registration number CRD42018094979.
Alternative Splicing in Heat Shock Protein Transcripts as a Mechanism of Cell Adaptation in Trichophyton rubrum

Heat shock proteins (HSPs) are involved in critical processes like host tissue invasion, resistance, and pathogenicity in dermatophytes. RNA-Seq analysis of Trichophyton rubrum exposed to undecanoic acid (UDA) revealed intron retention events in HSP transcripts. Because HSPs are modulated in response to various stimuli and as alternative splicing (AS) can result in a broad diversity in the proteome of eukaryotic cells, our objective was to confirm the aforementioned retention events, investigating their consequences and extent. Furthermore, we aimed to determine: (1) the expression profile of HSP genes in an infection-like scenario and (2) the importance of Hsp90 for the keratinolytic potential of T. rubrum. RT and qPCR analyses comparing the exposure to UDA and terbinafine (TRB) confirmed the presence of two mRNA isoforms of the hsp7-like gene, with distinct expression patterns in response to UDA and TRB. The HSP expression profile revealed two upregulated, three downregulated, and four unmodulated transcripts; Hsp90 inhibition by 17-AAG resulted in a significant decrease in keratinolytic potential at 37 °C. Altogether, these results broaden the current knowledge on the importance of HSP-mediated pathways for cell adaptation and other aspects of dermatophyte biology, indicating that HSP network proteins can be potential targets for antifungal therapy.
Gut microbiome diversity is associated with sleep physiology in humans

The human gut microbiome can influence health through the brain-gut-microbiome axis. Growing evidence suggests that the gut microbiome can influence sleep quality. Previous studies that have examined sleep deprivation and the human gut microbiome have yielded conflicting results. A recent study found that sleep deprivation leads to changes in gut microbiome composition while a different study found that sleep deprivation does not lead to changes in gut microbiome. Accordingly, the relationship between sleep physiology and the gut microbiome remains unclear. To address this uncertainty, we used actigraphy to quantify sleep measures coupled with gut microbiome sampling to determine how the gut microbiome correlates with various measures of sleep physiology. We measured immune system biomarkers and carried out a neurobehavioral assessment as these variables might modify the relationship between sleep and gut microbiome composition. We found that total microbiome diversity was positively correlated with increased sleep efficiency and total sleep time, and was negatively correlated with wake after sleep onset. We found positive correlations between total microbiome diversity and interleukin-6, a cytokine previously noted for its effects on sleep. Analysis of microbiome composition revealed that within phyla richness of Bacteroidetes and Firmicutes were positively correlated with sleep efficiency, interleukin-6 concentrations and abstract thinking. Finally, we found that several taxa (Lachnospiraceae, Corynebacterium, and Blautia) were negatively correlated with sleep measures. Our findings initiate linkages between gut microbiome composition, sleep physiology, the immune system and cognition. They may lead to mechanisms to improve sleep through the manipulation of the gut microbiome.
Wellbeing and mental health among medical students in Paraguay

Abstract Medical students’ wellbeing and mental health are of extreme importance. Studies from around the world have shown that the rates of burnout appear to be high. It is also well recognized that individuals with mental illnesses frequently avoid seeking help for fear of stigma, affecting their careers and being rejected or treated differently by their peers, or due to the perception that they will be deemed unfit for practice or rejected from their preferred specialty. Students who are open about their mental health conditions are often ostracized by their own peers and dismissed or even mistreated by teachers who consider mental ‘toughness’ to be a requirement for success in the medical arena. The impact of socioeconomic conditions cannot be under-estimated. We carried out a survey of mental health and wellbeing of medical students in the National University of Asuncion. A sample of 180 students across different years showed that 21% had sought help and 4% had been diagnosed with a mental condition before entering medical school; 3% had been previously diagnosed with Attention Deficit Hyperactivity Disorder or Autism Spectrum Disorders; 14% currently consult with a health professional specifically about their mental health; and 8% reported currently taking medication for their mental health. The most common medication was Escitalopram at 21%, followed by Sertraline with 11%. Various sources of stress were identified, all of which were noted to be concerning four specific domains: financial difficulties, familial issues, housing issues, and difficulties surrounding studies. Of these students, 20% were CAGE positive and 9.4% reported using substances to feel better. These findings indicate that medical students need better support to ensure that they function better. They require in-depth exploration of the potential causes of their illnesses.