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BACKGROUND: Pneumonia is the leading cause of death in young children globally. However, the underlying pathological mechanism of pediatric pneumonia remains unclear. In infection disease contexts, small extracellular vesicles (sEVs) have been shown to be a useful source of markers for pathogenesis and immune response. We hypothesized that functional molecules such as protein harbored by sEVs would provide mechanistic insights into the immune response in children with pneumonia. METHODS: We isolated sEVs from serum collected from children with and without pneumonia, performed proteomic analysis of the sEVs with label-free mass spectrometry, and then conducted functional enrichment analysis of proteomic data. RESULTS: We identified fifteen differentially expressed proteins and ten unique proteins in children with pneumonia as compared to healthy children. In the pneumonia group, immune-related processes and pathways were positively enriched as upregulated proteins were involved in neutrophil activation, complement regulation, defense against bacteria, humoral immune response and regulation of immune effector processes However, pathways associated with tissue development and extracellular matrix remodeling were negatively enriched, as downregulated proteins were linked to extracellular matrix structure and cell adhesions. CONCLUSIONS: Our findings provided insights into host responses to pathogen infection, which has contributed to understanding the pathogenesis of children with pneumonia. Furthermore, our studies suggested that serum sEVs proteins could be considered a potential source of biomarkers for diagnosing pediatric pneumonia.

Background: Recently, low estrogen and the age at menopause as independent risk factors for Pelvic Organ Prolapse (POP) were attracting high attention. In clinical practice, pre-/post-operative Local Estrogen Therapy (LET) shown effectiveness in alleviating POP symptoms. However, there is lack of scientific evidence to support the validity of these claims. Therefore, this study aimed to investigate the anti-senescence effect and mechanism of 17β-estradiol on POP derived fibroblasts. Methods: The primary fibroblasts cells were isolated and cultured form surgical POP samples (n = 8, age from 50–75), the passage-0 cells confluence at 80% takes about 15 days and the passage 3–5 cells were used for further test. Immunocytochemistry was used to characterize the primary fibroblasts, CCK8 assay was used to test the cell proliferative capacity and the Senescence-Associated β-Galactosidase (SA-β Gal) Staining was tested to calculate the senescence rate of fibroblasts. Moreover, western blotting was used to detect the expression of COL-I, COL-III, p16INK4A, p21, p-53, SIRT-1 and LC3-I/II protein. In addition, Transmission Electron Microscope (TEM) was used to observe the ultrastructure of fibroblasts. Results: The results showed that 17β-estradiol (E2) significantly promoted the POP derived-fibroblasts proliferation and reduced the staining rate of senescence-associated-β-galactosidase (SA-β-Gal), markedly enhanced the extracellular matrix protein COL-I and COL-III accompanied by the inhibition of senescent protein P16INK4a, as well as improved the cells autophagy and metabolic activity. In addition, E2 significantly up-regulated the anti-aging protein SIRT1 and markedly down-regulated p53 and p21, indicating the anti-senescence mechanism of E2 through mediated the Sirt1/p53/p21 axis pathway. Conclusion: We provide preliminary evidence that anti-aging effect and mechanism of estrogen on POP fibroblasts, hoping to provide a theoretical basis for estrogen against POP senescence, guide the clinical application and local administration of estrogen on POP treatment, thereby improve long-term maintenance and rejuvenation of the pelvic floor connective tissue.

Antecedentes Pocos estudios han investigado el impacto del síndrome metabólico (SM) en la enfermedad por coronavirus 2019 (COVID-19). Describimos las características clínicas y el pronóstico de los pacientes con COVID-19 confirmados con SM durante la hospitalización y después del alta. Métodos Se incluyeron retrospectivamente 233 pacientes con COVID-19 de los hospitales de 8 ciudades de Jiangsu, China. Se describieron las características clínicas de los pacientes con COVID-19 y se analizaron los factores de riesgo de enfermedad grave mediante un análisis de regresión logística. Resultados Cuarenta y cinco (19,3%) de los 233 pacientes de COVID-19 tenían EM. La mediana de edad de los pacientes de COVID-19 con EM fue significativamente mayor que la de los pacientes sin EM (53,0 años frente a 46,0 años, P=0,004). No hubo diferencias significativas en cuanto a los síntomas clínicos, las imágenes de TC torácica anormales y los fármacos de tratamiento entre los dos grupos. Hubo más pacientes con EM que tuvieron enfermedades graves (33,3% frente a 6,4%, P

In this article, we develop a martingale approach to localized Bismut-type Hessian formulas for heat semigroups on Riemannian manifolds. Our approach extends the Hessian formulas established by Stroock (1996) and removes in particular the compact manifold restriction. To demonstrate the potential of these formulas, we give as application explicit quantitative local estimates for the Hessian of the heat semigroup, as well as for harmonic functions on regular domains in Riemannian manifolds., 18

Multicellular organisms undergo several developmental transitions during their life cycles. In contrast to animals, the plant germline is derived from adult somatic cells. As such, the juvenility of a plant must be reset in each generation. Previous studies have demonstrated that the decline in the levels of miR156/7 with age drives plant maturation. Here we show that the resetting of plant juvenility during each generation is mediated by de novo activation of MIR156/7 in Arabidopsis. Blocking this process leads to a shortened juvenile phase and premature flowering in the offspring. In particular, an Arabidopsis plant devoid of miR156/7 flowers even without formation of rosette leaves in long days. Mechanistically, we find that different MIR156/7 genes are reset at different developmental stages through distinct reprogramming routes. Among these genes, MIR156A, B and C are activated de novo during sexual reproduction and embryogenesis, while MIR157A and C are reset upon seed germination. This redundancy generates a robust reset mechanism that ensures accurate restoration of the juvenile phase in each plant generation.

The study aimed to investigate the incidence of and risk factors for liver damage in patients with human immunodeficiency virus type-1 (HIV-1) mono-infection receiving antiretroviral therapy (ART).We retrospectively analyzed the clinical data of patients who were diagnosed with HIV-1 infection and initiated ART from January to December 2017. Among them, 382 patients with HIV-1 mono-infection and normal baseline liver function were included in the analysis. The incidence of liver damage at each follow-up point, and possible risk factors for liver damage were evaluated via COX regression survival analyses.The overall incidence of liver damage (grade I-IV) was 27.23% (interquartile range [IQR]: 26.38%-28.72%). Grade I liver damage was most common and accounted for 22.13% of cases (IQR: 21.06%-24.04%), while grade II liver damage accounted for 3.40% of cases (IQR: 3.19%-4.26%). COX regression and survival analyses revealed that baseline body mass index (BMI), alanine aminotransferase (ALT) level, CD4Liver damage is common in patients with HIV-1 mono-infection undergoing ART. Patients with risk factors for liver damage should be well-informed before the initiation of ART, and liver function should be closely monitored during ART even in patients with normal liver function before ART.

For a complete connected Riemannian manifold M let V∊ C^2(M) be such that µ(dx)=exp(-V(x))vol(dx) is a probability measure on M. Taking µ as reference measure, we derive inequalities for probability measures on M linking relative entropy, Fisher information, Stein discrepancy and Wasserstein distance. These inequalities strengthen in particular the famous log-Sobolev and transportation-cost inequality and extend the so-called Entropy/Stein-discrepancy/Information (HSI) inequality established by Ledoux, Nourdin and Peccati (2015) for the standard Gaussian measure on Euclidean space to the setting of Riemannian manifolds.

Hepatic fibrosis is a damage repair response caused by multiple factors. A growing body of research suggests that long non-coding RNAs (lncRNAs) are involved in a wide range of biological processes, and thus regulate disease progression, including hepatic fibrosis. In this study, we investigated the mechanisms of the long non-coding RNA-non-coding RNA activated by DNA damage (NORAD) in modulating hepatic fibrosis development. Platelet-derived growth factor-BB (PDGF-BB) was used to activate LX-2 hepatic stellate cells (HSCs). The expression of NORAD and microRNA (miR)-495-3p was determined by quantitative real-time polymerase chain reaction (qRT-PCR) analysis. The effects of PDGF-BB on LX-2 cell viability, migration, invasion, and apoptosis were evaluated using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), Transwell, flow cytometry, and Western blot assays. The activation of HSCs was further verified by examining the expression of the typical markers, alpha smooth muscle actin (α-SMA) and collagen I (Col1α1), using qRT-PCR and Western blot assays. StarBase and dual-luciferase reporter assays were used to assess the binding relationship between miR-495-3p and NORAD. The NORAD levels remarkably increased, whereas the miR-495-3p levels decreased, in PDGF-BB-treated LX-2 cells. miR-495-3p was a putative downstream target of NORAD. NORAD silencing played an anti-fibrotic role by targeting miR-495-3p; this was accomplished by hindering PDGF-BB-treated LX-2 cell viability, migration, and invasion, decreasing the levels of α-SMA and Col1α1, and promoting apoptosis. miR-495-3p protected against hepatic fibrosis by inhibiting sphingosine 1-phosphate receptor 3 (S1PR3) expression. In summary, NORAD silencing inhibited hepatic fibrosis by suppressing HSC activation via the miR-495-3p/S1PR3 axis.

Synthesis of aryl-fused 1,4-oxathiepines from pyridinium 1,4-zwitterionic thiolates with vinylidene ortho-quinone methides generated in situ via a formal (3 + 4) pathway.

The first enantioselective synthesis of axially chiral styrene-type allylamines through chiral phosphoric acid mediated atroposelective reductive amination of 1-enal substituted 2-naphthols is achieved.

Purpose To evaluate the early activity of ankylosing spondylitis(AS)is very important for clinical decision. Owing to lacking of uniform standard and some other limitations, the methods for it are still difficult to practice by clinicians. The study aimed to explore the value of texture analysis of radiomics based on STIR to evaluate the activity of bone marrow edema of sacroiliac joint in early AS. Methods A total of 43 patients with early AS were collected in our hospital, including 30 males and 13 females. According to the ratio of 7:3, all the patients were randomly divided into the training cohort (n = 116) and verification cohort (n = 56). Optimal feature subsets were obtained by the Mann-Whitney U test, the minimum-Redundancy Maximum-Relevancy (mRMR), and then the least absolute shrinkage and selection operator (LASSO) using these texture feature parameters. The optimal feature subset was used to construct the final prediction model, and Radscore was obtained by summing the selected features after being weighted by their coefficients. The effectiveness of Radscore value, SPARCC score and ADC value was evaluated by ROC curve. The correlations between Radscore values and the values of SPARCC score, ADC, BASDAI, ESR, CRP, ASDAS-ESR, ASDAS-CRP were analyzed by the Spearman correlation test. Results The eight texture feature subsets were selected to obtain Redscore. In the training cohort, to differentiate early AS sacroiliac joint bone marrow edema between between active and stable group,the AUC values of Radscore, SPARCC score and ADC were 0.81,0.91,0.78, respectively. In the validation cohort, the AUC values of them were 0.87,0.89,0.85. In the two cohorts, there were no significant differences in AUC values between values of Radscore and SPARCC score, ADC (P > 0.05). There was a significant difference in AUC values betweenvalues of SPARCC score and ADC in the training cohort (P 0.05). The correlations were all low between Radscore values and the values of the ESR, CRP, BASDAI, ASDAS-ESR, ASDAS-CRP (P

The nuclear factor kappa B (NF-κB) pathway and inhibitor of NF-κB kinase β (IKKβ) are involved in Alzheimer disease (AD) pathogenesis. This study explored the mechanisms underlying IKKβ-mediated Aβ aggregation and neuron regeneration in APP.PS1 mice. Adenoviral transduction particles were injected into the hippocampal CA1 region of the mice to knock down or inhibit target genes. Morris water maze was performed to evaluate the cognitive function of the mice. Aβ deposition was determined by histological examination. sh-IKKβ plasmids and microRNA (miR)-155-5p inhibitor were transfected into Aβ1-42-induced N2a cells. The expressions of AD-related proteins were detected by Western blot. The interaction between S-phase kinase-associated protein 2 (SKP2) and IKKβ was assessed by co-immunoprecipitation. IKKβ knockdown (KD) and miR-155-5p inhibition ameliorated cognitive impairment, improved neuron regeneration, and attenuated Aβ deposition in APP/PS1 mice. SKP2 KD aggravated cognitive impairment, inhibited neuron regeneration, and promoted Aβ deposition in the mice. SKP2 regulated the stability of IKKβ protein via ubiquitination. MiR-155-5p regulates Aβ deposition and the expression of Aβ generation-related proteins in N2a cells via targeting SKP2. These results indicate that the miR-155-5p/SKP2/IKKβ axis was critical for pathogenesis in this AD model and suggest the potential of miR-155-5p as a target for AD treatment.

MicroRNAs (miRNAs) are noncoding RNAs with 18–26 nucleotides; they pair with target mRNAs to regulate gene expression and produce significant changes in various physiological and pathological processes. In recent years, the interaction between miRNAs and their target genes has become one of the mainstream directions for drug development. As a large-scale biological database that mainly provides miRNA–target interactions (MTIs) verified by biological experiments, miRTarBase has undergone five revisions and enhancements. The database has accumulated >2 200 449 verified MTIs from 13 389 manually curated articles and CLIP-seq data. An optimized scoring system is adopted to enhance this update’s critical recognition of MTI-related articles and corresponding disease information. In addition, single-nucleotide polymorphisms and disease-related variants related to the binding efficiency of miRNA and target were characterized in miRNAs and gene 3′ untranslated regions. miRNA expression profiles across extracellular vesicles, blood and different tissues, including exosomal miRNAs and tissue-specific miRNAs, were integrated to explore miRNA functions and biomarkers. For the user interface, we have classified attributes, including RNA expression, specific interaction, protein expression and biological function, for various validation experiments related to the role of miRNA. We also used seed sequence information to evaluate the binding sites of miRNA. In summary, these enhancements render miRTarBase as one of the most research-amicable MTI databases that contain comprehensive and experimentally verified annotations. The newly updated version of miRTarBase is now available at https://miRTarBase.cuhk.edu.cn/.

Autoimmune diseases are diseases that cause damage to the body’s own tissues as a result of immune dysfunction, often involving multiple organs and systems. The heart is one of the common target organs of autoimmune diseases. The whole structure of the heart can be affected, causing microcirculatory disorders, arrhythmias, pericardial damage, myocarditis, myocardial fibrosis, and impaired valvular function. However, early clinical manifestations of autoimmune heart damage are often overlooked because they are insidious or have no typical features. The damage is often severe and irreversible when symptoms are apparent, even life-threatening. Therefore, early detection and treatment of heart damage in autoimmune diseases is particularly important. Herein, we review the clinical features and mechanisms of cardiac damage in common rheumatic diseases.

HLA-B*55:131 differs from HLA-B*55:02:01:01 by one nucleotide in exon 4.

Selective defunctionalization of synthetic intermediates is a valuable approach in organic synthesis. Here, we present a theoretical study on the recently developed B(C6F5)3/hydrosilane-mediated reductive deamination reaction of primary amines. Our computational results provide important insights into the reaction mechanism, including the active intermediate, the competing reactions of the active intermediate, the role of excess hydrosilane, and the origin of chemoselectivity. Moreover, the study on the substituent effect of hydrosilane indicated a potential way to improve the efficiency of the reductive deamination reaction.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent cause of autosomal dominant Parkinson's disease (PD), producing psychiatric and motor symptoms. We conducted this study to explore whether microglial dopaminergic (DAergic) fiber refinement and synaptic pruning are involved in the abnormal behavioral phenotypes of carriers of the LRRK2 G2019S mutation, by employing young and middle-aged PD model mice. The results revealed a characteristic late-onset hyperactivity and a progressive decline in the motor coordination of the LRRK2 G2019S mutation mice. LRRK2 G2019S mutation-induced aberrant microglial morphogenesis, with more branches and junctions per cell, resulted in excessive microglial refinement of dopaminergic (DAergic) fibers. Moreover, aberrant synaptic pruning distinctly impacted the prefrontal cortex (PFC) and dorsal striatum (DS), with significantly higher spine density in the PFC but the opposite effects in the DS region. Furthermore, LRRK2 G2019S mutation remodeled the inflammatory transcription landscape of microglia, rendering certain cerebral areas highly susceptible to microglial immune response. These findings indicate that LRRK2 G2019S mutation induces the production of inflammatory cytokines and mediates abnormal microglial morphogenesis and activity, resulting in abnormal phagocytosis, synaptic pruning and loss of DAergic fibers during aging, and, eventually, PD-related behavioral abnormalities.