Miracle-dz/UniFAR-FTUs huggingface dataset:
Garcinoic Acid Is a Natural and Selective Agonist of Pregnane X Receptor

Pregnane X receptor (PXR) is a master xenobiotic-sensing transcription factor and a validated target for immune and inflammatory diseases. The identification of chemical probes to investigate the therapeutic relevance of the receptor is still highly desired. In fact, currently available PXR ligands are not highly selective and can exhibit toxicity and/or potential off-target effects. In this study, we have identified garcinoic acid as a selective and efficient PXR agonist. The properties of this natural molecule as a specific PXR agonist were demonstrated by the screening on a panel of nuclear receptors, the assessment of the physical and thermodynamic binding affinity, and the determination of the PXR-garcinoic acid complex crystal structure. Cytotoxicity, transcriptional, and functional properties were investigated in human liver cells, and compound activity and target engagement were confirmed in vivo in mouse liver and gut tissue. In conclusion, garcinoic acid is a selective natural agonist of PXR and a promising lead compound toward the development of new PXR-regulating modulators.
SRPX2 Promotes Cell Proliferation and Invasion in Osteosarcoma Through Regulating Hippo Signaling Pathway

Background/Purpose Osteosarcoma (OS), a primary bone malignancy, is characterized by a high rate of metastasis. It has been found that Sushi repeat containing protein X-linked 2 (SRPX2) is involved in tumor cell proliferation, adhesion, invasion and migration. The current work aimed to explore the effect of SRPX2 on OS cell invasion and proliferation. Methods Immunohistochemistry (IHC), Western blotting and reverse transcription-polymerase chain reaction (RT-PCR) were used to detect the expression of the associated protein in OS tissues and cell lines. Cell counting kit-8 (CCK8), transwell and colony formation assays were used to determine cell viability, invasion, and proliferation, respectively. The in vivo tumorigenic ability of SRPX2 gene was determined using nude mouse tumorigenesis test. Results SRPX2 knockdown suppressed the viability, while SRPX2 overexpression increased the invasion and colony formation ability of the cells in vitro. In vivo experiments demonstrated that SRPX2 knockdown inhibited tumor growth and invasion as evidenced by decreased Ki67 and N-cadherin levels, and increased E-cadherin level. Downregulation of SRPX2 increased YAP phosphorylation resulting in reduced nuclear translocation to activate Hippo signaling pathway. The promotion of cell viability, colony-forming ability, and invasion, and the inhibition of CTGF, Cyr61, and Birc5 levels promoted by SRPX2 overexpression were reversed by YAP inhibition. Conclusion SRPX2 increased cell proliferation and invasion in osteosarcoma by activating Hippo signaling pathway.
Dysregulation of immune response in patients with COVID-19 in Wuhan, China

Abstract Background In December 2019, coronavirus disease 2019 (COVID-19) emerged in Wuhan and rapidly spread throughout China. Methods Demographic and clinical data of all confirmed cases with COVID-19 on admission at Tongji Hospital from January 10 to February 12, 2020, were collected and analyzed. The data of laboratory examinations, including peripheral lymphocyte subsets, were analyzed and compared between severe and non-severe patients. Results Of the 452 patients with COVID-19 recruited, 286 were diagnosed as severe infection. The median age was 58 years and 235 were male. The most common symptoms were fever, shortness of breath, expectoration, fatigue, dry cough and myalgia. Severe cases tend to have lower lymphocytes counts, higher leukocytes counts and neutrophil-lymphocyte-ratio (NLR), as well as lower percentages of monocytes, eosinophils, and basophils. Most of severe cases demonstrated elevated levels of infection-related biomarkers and inflammatory cytokines. The number of T cells significantly decreased, and more hampered in severe cases. Both helper T cells and suppressor T cells in patients with COVID-19 were below normal levels, and lower level of helper T cells in severe group. The percentage of naïve helper T cells increased and memory helper T cells decreased in severe cases. Patients with COVID-19 also have lower level of regulatory T cells, and more obviously damaged in severe cases. Conclusions The novel coronavirus might mainly act on lymphocytes, especially T lymphocytes. Surveillance of NLR and lymphocyte subsets is helpful in the early screening of critical illness, diagnosis and treatment of COVID-19.
Phytochemical profile and insecticidal activity of Drimia pancration (Asparagaceae) against adults of Stegobium paniceum (Anobiidae)

Abstract Chemical and spectroscopic investigation of the bulbs of Drimia pancration resulted in the isolation of one known flavonol (1), never isolated from this plant species, and of three previously described steroidal saponins (2–4), but whose configuration at their stereogenic centres was not clearly determined. By mean of 1H NMR, 13C NMR, nuclear overhauser effects (NOE) and two-dimensional NMR spectra the full stereochemical structures of compounds 2–4 were proved and all the 1H and 13C signals were assigned. Furthermore, the methanol and butanol extracts of D. pancration were tested against adults of Stegobium paniceum beetles. Despite the non-significant results regarding the repellent activity and contact toxicity, promising results were obtained from the feeding tests. Graphical Abstract
A Hereditable Mutation of MSH2 Gene Associated with Lynch Syndrome in a Five Generation Chinese Family

Purpose In order to clarify which variants of the MMR gene could provide current “healthy” members in affected families a more accurate risk assessment or predictive testing. Patients and Methods One family, which meets the criteria according to both Amsterdam I/II and Bethesda guidelines, is reported in this study. The proband and some relatives of the patient have been investigated for whole genome sequencing, microsatellite instability, immunohistochemical MMR protein staining and verified by Sanger sequencing. Results A heterozygous insertion of uncertain significance (c.420dup, p.Met141Tyrfs) in MSH2 gene was found in proband (III-16) and part of His relatives. The variant was associated with a lack of expression of MSH2 protein (MMR deficient) and high microsatellite instability analysis (MSI) status in tumor tissues of LS patients. In addition, we found that the variant could affect the expression of MSH2 and the response to chemotherapy drugs in vitro. Conclusion We identified an insertion mutation (rs1114167810, c.420dup, p.Met141Tyrfs) in MSH2 in LS using whole genome-wide sequencing (WGS). We further confirmed that this mutation plays an important role in LS patients of this pedigree based on in vivo and vitro study.
A new protein curbs the hypertrophic effect of myostatin inhibition, adding remarkable endurance to motor performance in mice

Current efforts to improve muscle performance are focused on muscle trophism via inhibition of the myostatin pathway: however they have been unsuccessful in the clinic to date. In this study, a novel protein has been created by combining the soluble activin receptor, a strong myostatin inhibitor, to the C-terminal agrin nLG3 domain (ActR-Fc-nLG3) involved in the development and maintenance of neuromuscular junctions. Both domains are connected via the constant region of an Igg1 monoclonal antibody. Surprisingly, young male mice treated with ActR-Fc-nLG3 showed a remarkably increased endurance in the rotarod test, significantly longer than the single domain compounds ActR-Fc and Fc-nLG3 treated animals. This increase in endurance was accompanied by only a moderate increase in body weights and wet muscle weights of ActR-Fc-nLG3 treated animals and were lower than expected. The myostatin inhibitor ActR-Fc induced, as expected, a highly significant increase in body and muscle weights compared to control animals and ActR-Fc-nLG3 treated animals. Moreover, the prolonged endurance effect was not observed when ActR-Fc and Fc-nLG3 were dosed simultaneously as a mixture and the body and muscle weights of these animals were very similar to ActR-Fc treated animals, indicating that both domains need to be on one molecule. Muscle morphology induced by ActR-Fc-nLG3 did not appear to be changed however, close examination of the neuromuscular junction showed significantly increased acetylcholine receptor surface area for ActR-Fc-nLG3 treated animals compared to controls. This result is consistent with published observations that endurance training in rats increased acetylcholine receptor quantity at neuromuscular junctions and provide evidence that improving nerve-muscle interaction could be an important factor for sustaining long term muscle activity.
Both Prediabetes and Type 2 Diabetes Are Associated With Lower Heart Rate Variability: The Maastricht Study

OBJECTIVE Low heart rate variability (HRV), a marker for cardiac autonomic dysfunction, is a known feature of type 2 diabetes, but it remains incompletely understood whether this also applies to prediabetes or across the whole glycemic spectrum. Therefore, we investigated the association among prediabetes, type 2 diabetes, and measures of glycemia and HRV. RESEARCH DESIGN AND METHODS In the population-based Maastricht Study (n = 2,107; mean ± SD age 59 ± 8 years; 52% men; normal glucose metabolism [n = 1,226], prediabetes [n = 331], and type 2 diabetes [n = 550, oversampled]), we determined 24-h electrocardiogram-derived HRV in time and frequency domains (individual z-scores, based upon seven and six variables, respectively). We used linear regression with adjustments for age, sex, and major cardiovascular risk factors. RESULTS After adjustments, both time and frequency domain HRV were lower in prediabetes and type 2 diabetes as compared with normal glucose metabolism (standardized β [95% CI] for time domain: −0.15 [−0.27; −0.03] and −0.34 [−0.46; −0.22], respectively, P for trend <0.001; for frequency domain: −0.14 [−0.26; −0.02] and −0.31 [−0.43; −0.19], respectively, P for trend <0.001). In addition, 1-SD higher glycated hemoglobin, fasting plasma glucose, and 2-h postload glucose were associated with lower HRV in both domains (time domain: −0.16 [−0.21; −0.12], −0.16 [−0.21; −0.12], and −0.15 [−0.20; −0.10], respectively; frequency domain: −0.14 [−0.19; −0.10], −0.14 [−0.18; −0.09], and −0.13 [−0.18; −0.08], respectively). CONCLUSIONS Both prediabetes and type 2 diabetes were independently associated with lower HRV. This is further substantiated by independent continuous associations between measures of hyperglycemia and lower HRV. These data strongly suggest that cardiac autonomic dysfunction is already present in prediabetes.
Biotechnology and Bioengineering

Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea Gene Therapy Unit, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea Department of Functional Genomics, Korea University of Science and Technology (UST), Daejeon, Republic of Korea Biomedical Translational Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
Immunoinformatics and Vaccine Development: An Overview

Abstract The use of vaccines have resulted in a remarkable improvement in global health. It has saved several lives, reduced treatment costs and raised the quality of animal and human lives. Current traditional vaccines came empirically with either vague or completely no knowledge of how they modulate our immune system. Even at the face of potential vaccine design advance, immune-related concerns (as seen with specific vulnerable populations, cases of emerging/re-emerging infectious disease, pathogens with complex lifecycle and antigenic variability, need for personalized vaccinations, and concerns for vaccines' immunological safety -specifically vaccine likelihood to trigger non-antigen-specific responses that may cause autoimmunity and vaccine allergy) are being raised. And these concerns have driven immunologists toward research for a better approach to vaccine design that will consider these challenges. Currently, immunoinformatics has paved the way for a better understanding of some infectious disease pathogenesis, diagnosis, immune system response and computational vaccinology. The importance of this immunoinformatics in the study of infectious diseases is diverse in terms of computational approaches used, but is united by common qualities related to host–pathogen relationship. Bioinformatics methods are also used to assign functions to uncharacterized genes which can be targeted as a candidate in vaccine design and can be a better approach toward the inclusion of women that are pregnant into vaccine trials and programs. The essence of this review is to give insight into the need to focus on novel computational, experimental and computation-driven experimental approaches for studying of host–pathogen interactions and thus making a case for its use in vaccine development.
Reducing potentially preventable health events among patients with asthma through multi-state, multi-center quality improvement program

Abstract Introduction Enhancing Care for Patients with Asthma is a multi-state, multi-center quality improvement program developed to augment guideline-based practice among health care providers through Plan-Do-Study-Act cycle. This study examined the association between the implementation of the guideline-based quality improvement program and subsequent changes in asthma-related emergency room visits and hospitalizations. Methods This retrospective, interrupted time-series study used administrative claims data from a private insurer that provided coverage to patients receiving care from participating health centers (15 centers in New Mexico, Oklahoma, Texas, and Illinois). The 12-month implementation period started in January 2013 for centers in Cohort 1 and October 2013 for centers in Cohort 2. The claims of 1,828 patients with asthma from January 2012 to May 2015 were analyzed. The data included 12-month pre-program implementation, 12-month program implementation, and 5-month post-program completion periods. Results The average number of asthma-related emergency room visits and hospitalizations decreased from 2.22 to 1.38 and 1.97 to 1.04 per 100 patients per month, respectively, in the 12-month pre-implementation period as compared to 12-month implementation period. The results of three-level generalized linear mixed models found that during the 12-month implementation period, patients had 37.7% and 47.1% lower rates of emergency room visits and hospitalizations, respectively, compared to the 12-month pre-implementation period (p < 0.001 in both comparisons). Conclusions Enhancing Care for Patients with Asthma is an effective quality improvement program that was successfully executed in diverse geographical states and associated with reductions in potentially preventable health events. The findings support the widespread use of the program in other settings.
The toxicity of alumina nanoparticles to immune system in mice.

Aim: Alumina nanoparticles (AlNPs) exert toxic effects in several organs. This study aimed to investigate the toxicity of AlNPs to the immune system. Materials & methods: AlNPs distribution was assessed using CRi in vivo fluorescence imaging. Inductively coupled plasma atomic emission spectrometry was used to detect the content of aluminum in the spleen. Cytokines expression was detected in the immune organs and blood of mice. Results & Conclusion: AlNPs can accumulate in mice spleen. Superoxide dismutase and glutathione levels decreased, whereas the level of malondialdehyde increased with decreasing particle size. AlNPs exposure caused cytokine level changes in the spleen, thymus and serum, besides causing damage to immune organs and dysfunction of immune cells, leading to abnormal immune-related cytokine expression.
Coronary vasculitis induced in mice by the cell wall mannoprotein of Candida krusei.

Kawasaki disease (KD) is an inflammatory disease that was identified by Professor Tomisaku Kawasaki in 1961. Candida albicans-derived substances, such as the hot water extract of C. albicans (CADS) and Candida water-soluble fraction (CAWS), induced coronary vasculitis similar to KD in mice. An increasing proportion of deep-seated candidiasis cases are caused by non-albicans Candida and are often resistant to antifungal drugs. We herein investigated whether the hot water extract of C. krusei, inherently resistant to fluconazole, induces vasculitis in mice. Three strains of C. krusei, NBRC1395, NBRC1162, and NBRC10737, were cultured in natural (Y) and chemically defined (C) media and cell wall mannoprotein (MN) fractions were prepared by autoclaving cells (CKY1395MN, CKC1395MN, CKY1162MN, CKC1162MN, CKY10737MN, and CKC10737MN). All MN fractions reacted strongly with Con A and dectin-2 and induced anaphylactoid shock in ICR mice. MNs induced severe coronary vasculitis in DBA/2 mice, resulting in cardiac hypertrophy. MNs also induced coronary vasculitis in C57Bl/6 mice. These results suggest that the MNs of non-albicans Candida, such as C. krusei, induce similar toxicity to those of C. albicans.
Silver-Containing Titanium Dioxide Nanocapsules for Combating Multidrug-Resistant Bacteria

Background Joint arthroplasty has improved the quality of life of patients worldwide, but infections of the prosthesis are frequent and cause significant morbidity. Antimicrobial coatings for implants promise to prevent these infections. Methods We have synthesized nanocapsules of titanium dioxide in amorphous or anatase form containing silver as antibacterial agent and tested their impact on bacterial growth. Furthermore, we explored the possible effect of the nanocapsules on the immune system. First, we studied their uptake into macrophages using a combination of electron microscopy and energy-dispersive spectroscopy. Second, we exposed immune cells to the nanocapsules and checked their activation state by flow cytometry and enzyme-linked immunosorbent assay. Results Silver-containing titanium dioxide nanocapsules show strong antimicrobial activity against both E. coli and S. aureus and even against a multidrug-resistant strain of S. aureus. We could demonstrate the presence of the nanocapsules in macrophages, but, importantly, the nanocapsules did not affect cell viability and did not activate proinflammatory responses at doses up to 20 μg/mL. Conclusion Our bactericidal silver-containing titanium dioxide nanocapsules fulfill important prerequisites for biomedical use and represent a promising material for the coating of artificial implants.
Underlying Primary Causes of Chronic Renal Failure: A Three-Year Study in Al-Thawra General Hospital, Sana'a, Yemen

Objective: To estimate the underlying primary diseases of chronic renal failure (CRF) among patients attending Al-Thawra General Hospital, Sana'a, and Yemen.Methods: This was a cross-sectional, hospital-based study of 566 patients diagnosed with chronic kidney diseases (CKD). It studied the cases attending Al-Thawra General Hospital over a three‐year period from January 2013 to December 2015.Results: Out of 566 patients, 339 (59.9%) were males. The mean age of the patients at diagnosis of CKD was 39.51 years, most of whom (36.6%) were of the age group of 21–35 years. Hypertension was the most frequent cause (43.2%) of CRF, followed by different infectious diseases such as malaria, schistosomiasis and bacterial infections (19%) and obstructive nephropathy (17.9%). On the other hand, CRF of unknown etiology represented 15.2% of cases. Other causes of CRF diabetic nephropathy (9.7%), effect of antibiotics and analgesics (7.0%), ischemic heart disease (4.8%, polycystic kidney disease (3.5%) and congenital anomalies (3.4%). The least common causes were autoimmune diseases, bleeding, traumatic accidents and chronic diarrhea, being responsible for 2.2%, 1.8%, 0.9% and 0.4% of CRF cases, respectively.Conclusions: The majority of CKD cases in our study were males aged between 21 and 35 years old. In addition, most cases of CKD are due to hypertension, followed by infections and obstructive nephropathy. Application of future prevention and control measures are highly recommended to reduce the burden of CRF in Yemen for early detection and proper management of its underlying primary conditions/diseases.
A toolbox for brain network construction and classification (BrainNetClass)

Brain functional network has been increasingly used in understanding brain functions and diseases. While many network construction methods have been proposed, the progress in the field still largely relies on static pairwise Pearson's correlation‐based functional network and group‐level comparisons. We introduce a “Brain Network Construction and Classification (BrainNetClass)” toolbox to promote more advanced brain network construction methods to the filed, including some state‐of‐the‐art methods that were recently developed to capture complex and high‐order interactions among brain regions. The toolbox also integrates a well‐accepted and rigorous classification framework based on brain connectome features toward individualized disease diagnosis in a hope that the advanced network modeling could boost the subsequent classification. BrainNetClass is a MATLAB‐based, open‐source, cross‐platform toolbox with both graphical user‐friendly interfaces and a command line mode targeting cognitive neuroscientists and clinicians for promoting reliability, reproducibility, and interpretability of connectome‐based, computer‐aided diagnosis. It generates abundant classification‐related results from network presentations to contributing features that have been largely ignored by most studies to grant users the ability of evaluating the disease diagnostic model and its robustness and generalizability. We demonstrate the effectiveness of the toolbox on real resting‐state functional MRI datasets. BrainNetClass (v1.0) is available at https://github.com/zzstefan/BrainNetClass.
Initial combination therapy of ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) in the modified intention-to-treat population of the AMBITION study: post hoc analysis

Objectives To evaluate initial combination therapy with ambrisentan plus tadalafil (COMB) compared with monotherapy of either agent (MONO), and the utility of baseline characteristics and risk stratification in predicting outcomes, in patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) and the systemic sclerosis (SSc)–pulmonary arterial hypertension (PAH) subpopulation. Methods This post hoc analysis of the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) study included patients with CTD-PAH from the modified intention-to-treat population. Time to clinical failure (TtCF) was assessed by baseline characteristics, treatment assignment and risk group (low, intermediate and high) at baseline and week 16. TtCF was compared between groups using Kaplan-Meier curves and Cox proportional hazards regression modelling. Results The analysis included 216 patients (COMB, n=117; MONO, n=99). The risk of clinical failure was lower with COMB versus MONO (risk reduction: CTD-PAH 51.7%, SSc-PAH 53.7%), particularly in patients with haemodynamic parameters characteristic of typical PAH without features of left heart disease and/or restrictive lung disease at baseline. The risk of clinical failure was lower with COMB versus MONO in the baseline low-risk group (HR not calculated due to no events in COMB), baseline intermediate-risk group (HR 0.519, 95% CI 0.297 to 0.905) and in the week 16 low-risk group (HR 0.069, 95% CI 0.009 to 0.548). Conclusions The benefit of COMB over MONO was demonstrated in patients with CTD-PAH, particularly in those with typical PAH haemodynamic characteristics at baseline. COMB is appropriate for patients categorised as low risk and intermediate risk at baseline and low risk at follow-up. Trial registration number NCT01178073.