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Nondipping heart rate (HR), defined as a night/day HR ratio0.90, has been associated with increased mortality in epidemiologic studies. However, its prognostic value in stage 5 chronic kidney disease (CKD5) patients and the effects of parathyroidectomy (PTX) on nondipping HR remain unknown.This case-control study of 162 healthy controls and 502 CKD5 patients was performed between 2011 and 2018, in which CKD5 patients were further divided into non-PTX (n = 186) and severe secondary hyperparathyroidism (SHPT) with PTX (n = 316) subgroups. Each participant underwent 24-hour Holter monitoring for HR ratio. Mortality was followed up in CKD5 patients (median time: 46.0 months).The HR ratio in CKD5 patients was higher than in controls (0.92 ± 0.08 vs 0.81 ± 0.08, P.001), associated with a 44% increase in mortality risk per 0.1 increment (hazard ratio, 1.44; 95% CI: 1.02-2.03; P =.04), and was positively related to serum intact parathyroid hormone levels (P.001). PTX reversed nondipping HR in SHPT patients (n = 50, median time: 6.3 months, P.001). Survival probabilities for PTX (n = 294) were better than non-PTX (n = 47) (hazard ratio, 0.31; 95% CI: 0.14-0.67; P.01) in SHPT patients (serum intact parathyroid hormone500.0 pg/mL).CKD5 patients displayed a nondipping HR pattern, which is a prognostic marker of all-cause mortality. PTX for SHPT patients was associated with a reversal in nondipping HR ratio, which may mediate a better outcome.

Background: To investigate the causal link between early-life exposures and long-term health consequences, we established the Tianjin Birth Cohort (TJBC), a large-scale prospective cohort in northern China. Methods: TJBC aims to enroll 10,000 families with follow-ups from pregnancy until children’s six year-old. Pregnant women and their spouses were recruited through a three-tier antenatal healthcare system at early pregnancy, with follow-ups at mid-pregnancy, late pregnancy, delivery, 42 days after delivery, 6 months after delivery, and each year until 6 years old. Antenatal/neonatal examination, biological samples and questionnaires were collected. Results: From August 2017 to January 2019, a total of 3,924 pregnant women have already been enrolled, and 1,697 women have given birth. We observed the prevalence of gestational diabetes mellitus as 18.1%, anemia as 20.4%, and thyroid hypofunction as 2.0%. In singleton live births, 5.6% were preterm birth (PTB), 3.7% were low birth weight, and 7.3% were macrosomia. Based on current data, we also identified maternal/paternal factors which increased the risk of PTB, including paternal age (OR 1.07; 95% CI, 1.01–1.14 for each year increase), vaginal bleeding during pregnancy (OR 2.82; 95% CI, 1.54–5.17) and maternal early-pregnancy BMI (OR 1.08; 95% CI, 1.01–1.15 for each kg/m2 increase). Conclusion: TJBC has the strength of collecting comprehensive maternal, paternal, and childhood information. With a diverse range of biological samples, we are also engaging with emerging new technologies for multi-omics research. The study would provide new insight into the causal link between macro/micro-environmental exposures of early life and short/long-term health consequences.

The synaptic balance between excitation and inhibition (E/I balance) is a fundamental principle of cortical circuits, and disruptions in E/I balance are commonly linked to cognitive deficits such as impaired decision-making. Explanatory gaps remain in a mechanistic understanding of how E/I balance contributes to cognitive computations, and how E/I disruptions at the synaptic level can propagate to induce behavioral deficits. Here, we studied how E/I perturbations may impair perceptual decision-making in a biophysically-based association cortical circuit model. We found that both elevating and lowering E/I ratio, via NMDA receptor (NMDAR) hypofunction at inhibitory interneurons and excitatory pyramidal neurons, respectively, can similarly impair psychometric performance, following an inverted-U dependence. Nonetheless, these E/I perturbations differentially alter the process of evidence accumulation across time. Under elevated E/I ratio, decision-making is impulsive, overweighting early evidence and underweighting late evidence. Under lowered E/I ratio, decision-making is indecisive, with both evidence integration and winner-take-all competition weakened. The distinct time courses of evidence accumulation at the circuit level can be measured at the behavioral level, using multiple psychophysical task paradigms which provide dissociable predictions. These results are well captured by a generalized drift-diffusion model (DDM) with self-coupling, implementing leaky or unstable integration, which thereby links biophysical circuit modeling to algorithmic process modeling and facilitates model fitting to behavioral choice data. In general, our findings characterize critical roles of cortical E/I balance in cognitive function, bridging from biophysical to behavioral levels of analysis.SIGNIFICANCE STATEMENTCognitive deficits in multiple neuropsychiatric disorders, including schizophrenia, have been associated with alterations in the balance of synaptic excitation and inhibition (E/I) in cerebral cortical circuits. However, the circuit mechanisms by which E/I imbalance leads to cognitive deficits in decision-making have remained unclear. We used a computational model of decision-making in cortical circuits to study the neural and behavioral effects of E/I imbalance. We found that elevating and lowering E/I ratio produce distinct modes of dysfunction in decision-making processes, which can be dissociated in behavior through psychophysical task paradigms. The biophysical circuit model can be mapped onto a psychological model of decision-making which can facilitate experimental tests of model predictions.

Background Pristimerin, a natural flavonoid compound, has potential anti-tumor activities. These activities have been illustrated in various cancer cell lines, including MDA-MB-231 cells. MDA-MB-231 cells are a representative mesenchymal subtype of triple negative breast cancer (MES-TNBC) cell line. Currently, the main treatment for patients with advanced MES-TNBC is cytotoxic chemotherapy. We tried to examine the role and effect of pristimerin on epithelial–-mesenchymal transition (EMT) in MDA-MB-231 cells. Material and methods The effects of pristimerin on the proliferation of MDA-MB-231 cells were investigated by cloning formation growth assay. In vitro transwell and adhesion assays were performed for cell invasion and adhesion. The expression levels of EMT markers in E-cadherin and N-cadherin were examined by western blotting. We also established overexpressed- and silenced-integrin β3 cell lines to evaluate the role of integrin β3 in mediating the EMT reversion events in MDA-MB-231 cells. Results Pristimerin inhibited cell proliferation, and its inhibitory effect was dose-dependent. We demonstrated that pristimerin reserved EMT by upregulating E-cadherin and downregulating N-cadherin expression. Meanwhile, we revealed that pristimerin inhibited mRNA and protein expression of integrin β3, which is a key heterodimeric transmembrane receptor associated with EMT. These inhibitory effects and reversion of EMT were enhanced when integrin β3 was knockdown in MDA-MB-231 cells, while the overexpression of integrin β3 attenuated these effects. In vivo studies using xenograft mouse model demonstrated that pristimerin inhibited tumor growth. Conclusions Our findings provide important insights into the effects of pristimerin on inhibiting cancer progression and EMT reversion by suppression of integrin β3.

A nuclear-encoded sigma (σ) factor is essential for the transcriptional regulation of plant chloroplast-encoded genes. Five putative maize σ factors have been identified by database searches, but their functions are unknown. We report a maize leaf color mutant etiolated/albino leaf 1 (eal1) that was derived from space mutation breeding. The eal1 mutant displays etiolated or albino leaves that then gradually turn to normal green at the seedling stage. The changes in eal1 leaf color are associated with changes in photosynthetic pigment content and chloroplast development. Map-based cloning revealed that a single amino-acid deletion changing Val480-Val481-Val482 to Val480-Val481, in the C-terminal domain σ4 of the putative σ factor ZmSig2A, is responsible for the eal1 mutation. In comparison with the expression level of the wild-type (WT) allele ZmSig2A+ in WT plants, much higher expression of the mutant allele ZmSig2AΔV in eal1 plants was detected before the eal1 plants turned to normal green. ZmSig2A shows the highest similarity to rice OsSig2A and Arabidopsis SIG2. Ectopic expression of ZmSig2A+ or ZmSig2AΔV driven by the cauliflower mosaic virus 35S promoter rescued the pale green leaf of the sig2 mutant, but ectopic expression of ZmSig2AΔV driven by the SIG2 promoter did not. We propose that the Val deletion generated a new weak allele of ZmSig2A that cannot completely abolish the ZmSig2A function. Some genes involved in chloroplast development and photosynthesis-associated nuclear genes showed significant expression differences between eal1 and WT plants. We conclude that ZmSig2A encoding a σ factor is essential for maize chloroplast development. The eal1 mutant with a weak allele of ZmSig2A represents a valuable genetic resource for investigating the regulation of ZmSig2A-mediated chloroplast development in maize. The eal1 mutation may be useful as a marker for early identification and elimination of false hybrids or transgene transmission in the application of genetic male sterility to commercial hybrid seed production.

Resistance to immunotherapy is a significant challenge, and the scarcity of human models hinders the identification of the underlying mechanisms. To address this limitation, we constructed an autologous humanized mouse (aHM) model with hematopoietic stem and progenitor cells (HSPC) and tumors from 2 melanoma patients progressing to immunotherapy. Unlike mismatched humanized mouse (mHM) models, generated from cord blood–derived HSPCs and tumors from different donors, the aHM recapitulates a patient-specific tumor microenvironment (TME). When patient tumors were implanted on aHM, mHM, and NOD/SCID/IL2rg−/− (NSG) cohorts, tumors appeared earlier and grew faster on NSG and mHM cohorts. We observed that immune cells differentiating in the aHM were relatively more capable of circulating peripherally, invading into tumors and interacting with the TME. A heterologous, human leukocyte antigen (HLA-A) matched cohort also yielded slower growing tumors than non–HLA-matched mHM, indicating that a less permissive immune environment inhibits tumor progression. When the aHM, mHM, and NSG cohorts were treated with immunotherapies mirroring what the originating patients received, tumor growth in the aHM accelerated, similar to the progression observed in the patients. This rapid growth was associated with decreased immune cell infiltration, reduced interferon gamma (IFNγ)–related gene expression, and a reduction in STAT3 phosphorylation, events that were replicated in vitro using tumor-derived cell lines. Implications: Engrafted adult HSPCs give rise to more tumor infiltrative immune cells, increased HLA matching leads to slower tumor initiation and growth, and continuing immunotherapy past progression can paradoxically lead to increased growth.

Background Ginsenoside Rg1 (Rg1) has been well documented to be effective against various cardiovascular disease. The aim of this study is to evaluate the effect of Rg1 on mechanical stress-induced cardiac injury and its possible mechanism with a focus on the calcium sensing receptor (CaSR) signaling pathway. Methods Mechanical stress was implemented on rats through abdominal aortic constriction (AAC) procedure and on cardiomyocytes and cardiac fibroblasts by mechanical stretching with Bioflex Collagen I plates. The effects of Rg1 on cell hypertrophy, fibrosis, cardiac function, [Ca2+]i, and the expression of CaSR and calcineurin (CaN) were assayed both on rat and cellular level. Results Rg1 alleviated cardiac hypertrophy and fibrosis, and improved cardiac decompensation induced by AAC in rat myocardial tissue and cultured cardiomyocytes and cardiac fibroblasts. Importantly, Rg1 treatment inhibited CaSR expression and increase of [Ca2+]i, which similar to the CaSR inhibitor NPS2143. In addition, Rg1 treatment inhibited CaN and TGF-β1 pathways activation. Mechanistic analysis showed that the CaSR agonist GdCl3 could not further increase the [Ca2+]i and CaN pathway related protein expression induced by mechanical stretching in cultured cardiomyocytes. CsA, an inhibitor of CaN, inhibited cardiac hypertrophy, cardiac fibrosis, [Ca2+]i and CaN signaling but had no effect on CaSR expression. Conclusion The activation of CaN pathway and the increase of [Ca2+]i mediated by CaSR are involved in cardiac hypertrophy and fibrosis, that may be the target of cardioprotection of Rg1 against myocardial injury., Graphical abstract The mechanism of cardioprotection by Ginsenoside Rg1 via downregulation of CaSR. AAC induces overload of [Ca2+]i through CaSR/IP3R pathway. The increased [Ca2+]i leads to activation of CaN signaling pathway, resulting in cardiac hypertrophy and fibrosis. Ginsenoside Rg1 inhibits cardiac hypertrophy and fibrosis through inhibiting [Ca2+]i and downregulation of CaSR, CaN and TGF-β1 signaling pathways.Image 1

Chemotherapy-induced side effects affect the quality of life and efficacy of treatment of cancer patients. Current approaches for treating the side effects of chemotherapy are poorly effective and may cause numerous harmful side effects. Therefore, developing new and effective drugs derived from natural non-toxic compounds for the treatment of chemotherapy-induced side effects is necessary. Experiments in vivo and in vitro indicate that Panax ginseng (PG) and its ginsenosides are undoubtedly non-toxic and effective options for the treatment of chemotherapy-induced side effects, such as nephrotoxicity, hepatotoxicity, cardiotoxicity, immunotoxicity, and hematopoietic inhibition. The mechanism focus on anti-oxidation, anti-inflammation, and anti-apoptosis, as well as the modulation of signaling pathways, such as nuclear factor erythroid-2 related factor 2 (Nrf2)/heme oxygenase-1 (HO-1), P62/keap1/Nrf2, c-jun N-terminal kinase (JNK)/P53/caspase 3, mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinases (ERK), AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR), mitogen-activated protein kinase kinase 4 (MKK4)/JNK, and phosphatidylinositol 3-kinase (PI3K)/AKT. Since a systemic review of the effect and mechanism of PG and its ginsenosides on chemotherapy-induced side effects has not yet been published, we provide a comprehensive summarization with this aim and shed light on the future research of PG., Graphical abstract Image 1

This study aimed to determine the prevalence of radioiodine-induced salivary gland damage by evaluating progressive changes in salivary glands using ultrasound. Four hundred forty-six patients with differentiated thyroid carcinoma who underwent total or near-total thyroidectomy and postoperative radioiodine therapy were retrospectively reviewed. From the first to the fifth follow-up visits, the positive rate of major salivary gland changes on ultrasound gradually increased from 2.0% to 33.0% (P

Objective To investigate the influence of tolerance dendritic cells (tolDCs), generated from Bone marrow mesenchymal stem cells (BM-MSCs) treated with rapamycin (Rapa) on liver allograft survival in a rat acute liver transplantation model. Methods Different GM-CSF induction project was used to obtain immature DCs (imDCs), mature DCs (matDCs) or tolDCs from BM-MSCs. First, MLR was performed to analyze the activity of tolDCs on polyclonaly stimulated total T cells. Then, co-cultured imDCs, matDCs and tolDCs with CD8+T cells isolated by magnetic activated cell sorting to analyze the influence on its regulatory characteristic. Last, the established rat acute liver transplantation model were adoptive transfused with imDCs, matDCs or tolDCs isolated by anti-CD11c immunomagnetic beads. The phenotype of DC cells and level of CD8+Treg in the culture system and in vivo, the expression of CD8 and CD45RC in the tissues were analyzed by flow cytometry and immunohistochemistry, respectively. Results The loGM-CSF plus IL-4 decreased the costimulatory molecules of CD80/86 and MHC class II of DCs comparison with hiGM-CSF from BM-MSCs no matter whether stimulation by LPS (P Conclusion Rapa modified tolDCs derived from BM-MSCs reversed graft rejection by improve tolerance characteristics of CD8+CD45RC−Treg in acute liver rat transplantation.

miRNAs in circulating extracellular vesicles (EVs) are promising biomarkers for cancer. However, their diagnostic ability for early‐stage non‐small‐cell lung cancer (NSCLC) is not well known. In this study, the circulating EV miRNAs profiling was initially performed in 36 untreated NSCLC patients and 36 healthy controls by TaqMan Low Density Array (TLDA). Subsequently, we performed quantitative reverse‐transcription PCR assay (RT‐qPCR) validation in several independent cohorts that included 159 NSCLC patients, 120 age/sex‐matched healthy controls and 31 benign nodule patients enrolled from three different clinical centres. In addition, 38 cases of NSCLC were analysed before and after surgery. We demonstrated that miR‐520c‐3p and miR‐1274b were significantly and steadily increased in NSCLC patients in comparison with healthy controls and benign nodule patients (P, Sensitive and specific biomarkers for the detection of non‐small‐cell lung cancer (NSCLC) are urgently needed. Here, we investigated the diagnostic potential of extracellular vesicle (EV) miRNAs as biomarkers for NSCLC in a multiphase case–control study. We report that EV‐miR‐520c‐3p and miR‐1274b hold potential as novel diagnostic biomarkers for early‐stage NSCLC.

Systemic immunosuppression for the mitigation of immune rejection after organ transplantation causes adverse side effects and constrains the long-term benefits of the transplanted graft. Here we show that protecting the endothelial glycocalyx in vascular allografts via the enzymatic ligation of immunosuppressive glycopolymers under cold-storage conditions attenuates the acute and chronic rejection of the grafts after transplantation in the absence of systemic immunosuppression. In syngeneic and allogeneic mice that received kidney transplants, the steric and immunosuppressive properties of the ligated polymers largely protected the transplanted grafts from ischaemic reperfusion injury, and from immune-cell adhesion and thereby immunocytotoxicity. Polymer-mediated shielding of the endothelial glycocalyx following organ procurement should be compatible with clinical procedures for transplant preservation and perfusion, and may reduce the damage and rejection of transplanted organs after surgery. Protection of the endothelial glycocalyx in vascular allografts via the enzymatic ligation of immunosuppressive glycopolymers prevents allograft rejection after transplantation in the absence of systemic immunosuppression.

Fungal dimorphism is the ability of certain fungi to switch between two different cellular forms, yeast and mycelial forms, in response to external environmental factors. The pacC/Pal signal transduction pathway responds to neutral and alkaline environments and is also involved in the fungal dimorphic transition. In this study, we investigated the function of the pacC homolog, MripacC, which regulates the dimorphic transition and modulates virulence of the insect pathogenic fungus Metarhizium rileyi. MripacC expression was upregulated under alkaline condition, with increased number of yeast-like cells compared to the number of hyphae cells. A MripacC deletion mutant (ΔMripacC) was obtained by homologous replacement and exhibited decreased blastospore budding, with direct development of conidia into hyphae without entering the yeast-like stage when cultured on alkaline medium. Observation of host hemolymph morphology and analysis of samples to detect the main immune factors revealed a decreased ability of ΔMripacC to evade the host immune system. The results of insect bioassays showed that ΔMripacC had decreased virulence with extended median lethality time. Together, the results suggested that MripacC not only regulated adaptation to acidic and alkaline environments, but also influenced virulence by budding blastospores. This elucidation of the function of MripacC adds to our understanding of blastospore budding and virulence of this fungal pathogen.

Background Starches and proteins are two major types of biopolymer components, especially in many flour (starch)-based foods consumed worldwide, which provide energy and nutrition needed by the human body. In many such starch-based matrices (the main structural component of such foods), proteins and their interactions with starches greatly influence the matrix structure and properties. Studying the different roles played by proteins (endogenous and exogenous) in various starch-based food systems can provide a frame of reference for the design and production of improved starch-based food products with tailored properties and desirable nutritional functions. Scope and approach Significant efforts have recently been made to tailor the morphology, structure, and properties of many starch-based food systems, and thus to design various starch-based food products with satisfactory attributes. This review surveys the latest literature on starch-based matrices containing proteins. Discussed are the influences of proteins and their interactions with starches on the morphologies and structures (e.g. short- and long-range orders) of starch-based matrices, as well as on their pasting, thermal, rheological, textural, sensory, and digestive properties. Also, current understandings of structure–property links are presented, along with their implications on the production of various starchy foods (e.g. pastas, breads, cakes, and biscuits), including gluten-free versions. Key findings and conclusions Proteins in many starchy food matrices can encapsulate the starch phase (or be adsorbed on its surfaces) on a micron scale, and thereby interact with starch chains via both non-covalent (e.g. hydrogen bonding, hydrophobic, and electrostatic) and covalent bonds (e.g. via Maillard reactions). These facts and protein features (e.g. hydration and gelation abilities) can play major roles in inhibiting starch retrogradation (the reassembly of cooked starch chains into ordered structures) and in regulating various other properties of such starch-based matrices, including viscosity, transition temperatures, moduli, hardness, sensory, digestibility, and shelf-life. Despite the fact that the current literature presents considerable information on the structure–property relationships of many different starch-based matrices and their applications in the processing of various starchy foods (e.g. pastas, noodles, and biscuits), it is still highly necessary to define more comprehensive correlations among starch–protein interactions, starch–protein matrix structures, and the resulting properties of such food products.

Background In recent years, LRG1 was found to be closely related to atrial fibrillation, heart failure, and myocardial remodeling after myocardial infarction. While its role in cerebral infarction was still controversial. We aimed to explore the value of LRG1 to identify the cardioembolic stroke. Methods 283 acute ischemic stroke(AIS) patients and 169 controls were enrolled. The AIS patients were divided into a CE(cardiogenic embolism) group and a non-CE group. Serum LRG1 levels were quantified by ELISA. Results The serum LRG1 levels were decreased in the AIS patients. CE group had higher serum LRG1 levels than the non-CE group. LRG1 was an independent risk factor for cardioembolic stroke. The area under the curve (AUC) was 0.768 with a sensitivity of 72.5% and specificity of 69.5%, which was not second to BNP and LAD. The combined predictive model we designed, including LRG1, BNP, and LAD, greatly improved the prediction effect. A positive correlation was shown between LRG1 and stroke severity in the CE group. Those who experienced poor outcomes had higher serum LRG1 levels compared with good ones. Conclusion Serum LRG1 was a promising indicator to predict cardioembolic stroke, as well as stroke severity and the 3-month prognosis of it.

With the dramatic development of single-cell RNA sequencing (scRNA-seq) technologies, the systematic decoding of cell-cell communication has received great research interest. To date, several in-silico methods have been developed, but most of them lack the ability to predict the communication pathways connecting the insides and outsides of cells. Here, we developed CellCall, a toolkit to infer inter- and intracellular communication pathways by integrating paired ligand-receptor and transcription factor (TF) activity. Moreover, CellCall uses an embedded pathway activity analysis method to identify the significantly activated pathways involved in intercellular crosstalk between certain cell types. Additionally, CellCall offers a rich suite of visualization options (Circos plot, Sankey plot, bubble plot, ridge plot, etc.) to present the analysis results. Case studies on scRNA-seq datasets of human testicular cells and the tumor immune microenvironment demonstrated the reliable and unique functionality of CellCall in intercellular communication analysis and internal TF activity exploration, which were further validated experimentally. Comparative analysis of CellCall and other tools indicated that CellCall was more accurate and offered more functions. In summary, CellCall provides a sophisticated and practical tool allowing researchers to decipher intercellular communication and related internal regulatory signals based on scRNA-seq data. CellCall is freely available at https://github.com/ShellyCoder/cellcall.

Identifying small extracellular vesicle (sEV) subpopulations based on their different molecular signatures could potentially reveal the functional roles in physiology and pathology. However, it is a challenge to achieve this aim due to the nano-sized dimensions of sEVs, low quantities of biological cargo each sEV carries, and our incomplete knowledge of identifying features capable of separating heterogeneous sEV subpopulations. Here, a sensitive, multiplexed, and nano-mixing-enhanced sEV subpopulation characterization platform (ESCP) is proposed to precisely determine the sEV phenotypic heterogeneity and understand the role of sEV heterogeneity in cancer progression and metastasis. The ESCP utilizes spatially patterned anti-tetraspanin-functionalized micro-arrays for sEV subpopulation sorting and nanobarcode-based surface-enhanced Raman spectroscopy for multiplexed read-outs. An ESCP has been used for investigating sEV phenotypic heterogeneity in terms of canonical sEV tetraspanin molecules and cancer-associated protein biomarkers in both cancer cell line models and cancer patient samples. Our data explicitly demonstrate the selective enrichment of tetraspanins and cancer-associated protein biomarkers, in particular sEV subpopulations. Therefore, it is believed that the ESCP could enable the evaluation and broader application of sEV subpopulations as potential diagnostic disease biomarkers.

Background Extracellular vesicles (EVs) derived from tumor cells are implicated in the progression of malignancies through the transfer of molecular cargo microRNAs (miRNAs or miRs). We aimed to explore the role of EVs derived from breast cancer cells carrying miR-182-5p in the occurrence and development of breast cancer. Methods Differentially expressed miRNAs and their downstream target genes related to breast cancer were screened through GEO and TCGA databases. miR-182-5p expression was examined in cancer tissues and adjacent normal tissues from patients with breast cancer. EVs were isolated from breast cancer cell line MDA-MB-231 cells and identified. The gain- and loss-of function approaches of miR-182-5p and CKLF-like MARVEL transmembrane domain-containing 7 (CMTM7) were performed in MDA-MB-231 cells and the isolated EVs. Human umbilical vein endothelial cells (HUVECs) were subjected to co-culture with MDA-MB-231 cell-derived EVs and biological behaviors were detected by CCK-8 assay, flow cytometry, immunohistochemical staining, Transwell assay and vessel-like tube formation in vitro. A xenograft mouse model in nude mice was established to observe the tumorigenesis and metastasis of breast cancer cells in vivo. Results miR-182-5p was highly expressed in breast cancer tissues and cells, and this high expression was associated with poor prognosis of breast cancer patients. miR-182-5p overexpression was shown to promote tumor angiogenesis in breast cancer. Moreover, our data indicated that miR-182-5p was highly enriched in EVs from MDA-MD-231 cells and then ultimately enhanced the proliferation, migration, and angiogenesis of HUVECs in vitro and in vivo. Moreover, we found that CMTM7 is a target of miR-182-5p. EVs-miR-182-5p promotes tumorigenesis and metastasis of breast cancer cells by regulating the CMTM7/EGFR/AKT signaling axis. Conclusions Taken altogether, our findings demonstrates that EVs secreted by breast cancer cells could carry miR-182-5p to aggravate breast cancer through downregulating CMTM7 expression and activating the EGFR/AKT signaling pathway.

To study the key aroma components and flavor profile differences of Cheddar cheese with different maturity and from different countries, the flavor components of 25 imported commercial Cheddar cheese samples in the China market were determined by gas chromatography-mass spectrometry. The quality and quantity of 40 flavor compounds were analyzed by gas chromatography-olfactometry among 71 aroma compounds determined by gas chromatography-mass spectrometry. Combined with odor activity value calculation, principal component analysis (PCA) was conducted to analyze the relationship among 26 flavor compounds with odor activity values >1 and the maturity of Cheddar cheese. The PCA results showed significant differences between the group of mild Cheddar cheese and the groups of medium Cheddar cheese and mature Cheddar cheese, and no significant differences were observed between medium Cheddar cheese and mature Cheddar cheese. According to the results of PCA and consumers' preference test, representative Cheddar cheese samples with different ripening times were selected for the flavor profile analysis. Partial least squares regression analysis was conducted to obtain the relationship between sensory properties and flavor compounds of different Cheddar cheeses. Based on partial least squares regression analysis, 1-octen-3-one, hexanal, acetic acid, 3-methylindole, and acetoin were positively correlated with milky, sour, and yogurt of mild Cheddar cheese. Dimethyl trisulfide, phenylacetaldehyde, ethyl caproate, octanoic acid, and furaneol and other compounds were positively correlated with fruity, caramel, rancid, and nutty notes of the medium and mature Cheddar cheeses.

High-fat (HF) diets cause obesity, gut microbial dysbiosis and associated disorders and inflammatory bowel disease (IBD) due to increased intestinal permeability, which is an important reason for chronic inflammation and oxidative stress. This study was to investigate the effects and mechanism by which walnut green husk polysaccharides (WGHP) prevents obesity, oxidative stress, inflammation, liver and colon damage in HF diet induced rats. We found that WGHP alleviated HF-induced abnormal weight gain, disordered lipid metabolism, inflammation, oxidative stress, colonic tissue injury and up-regulate the expression level of colonic tight junction protein in the rats. Besides, the administration of WGHP promoted browning of iWAT and thermogenesis in BAT of HF-fed rats, and improved gut microbiota dysbiosis by increasing the bacterial diversity and reducing the relative abundance of potential pathogenic bacteria in the colon of the rats. Furthermore, WGHP consumption not only increased the SCFAs content but also improved the relative abundance of Prevotellaceae and Allobaculum in the gut of rats. Our results suggest that the protective effect of WGHP on metabolic inflammation caused by HF may be due to the regulation of gut microbiota and SCFAs.

Objectives The integrated model of frailty shifted the physiologically-dominated view to an integrated and multidisciplinary view of frailty and adopted an integrated and holistic approach to the complex challenges facing frail older adults and their caregivers. There is an urgent need for researchers to identify multi-faceted frailty among older adults and to explore contributors to it. We assessed the level of frailty among older residents in long-term care (LTC) facilities in Shanghai, China and explored risk factors of multiple dimensions of frailty among older residents. Methods It is a cross-sectional descriptive study. We interviewed 218 older residents from nine LTC facilities. We used Tilburg Frailty Indicator to assess older residents’ physiological, psychological, and social frailty. The Geriatric Depression Scale, Mini-Mental state examination, Athens Insomnia Scale, and Activity of Daily Living (ADL) Scale were used to assess their depressive symptoms, cognitive function, sleep quality and ADL abilities, respectively. Results Older residents have a moderate level of frailty in physiological, psychological and social domains. There is a high correlation among dimensions of frailty. Older residents' depressive symptoms have remained positively associated with their overall and each domain of frailty. Older residents' actual activity participation and exercise in LTC facilities are negatively associated with older residents’ overall, physiological and social frailty. Conclusions Frailty is a multi-dimensional concept and is prevalent among older residents in LTC facilities. It is important to take an integrated view on frailty and carry out appropriate and comprehensive interventions to prevent adverse outcomes and provide holistic care for frail older residents in LTC facilities. There is an urgent need to improve the quality and expand the number of activities offered within LTC facilities that would engage older residents in a person-centered way, despite their age, ADL abilities, frailty and functional limitations.

Background Hepatocellular carcinoma (HCC) is a common cause of cancer mortality worldwide. Recent studies have shown that the polytopic enzyme membrane associated ring-CH-type finger 6 (MARCH6) participates in tumorigenesis, but its function in HCC development needs to be investigated. This study aimed to explore the role of MARCH6 in HCC. Methods Expression of MARCH6 in human HCC samples was checked by immunohistochemical staining assay. Clinical relevance of MARCH6 and activating transcription factor 2 (ATF2) was analyzed from TCGA database. CCK-8, EdU staining, colony formation and transwell were performed to assess cell proliferation, growth and migration. Xenografted tumorigenesis was used to examine in vivo role MARCH6. Immunoblotting was applied to detect protein abundance. Results We found that MARCH6 expression was elevated in human HCC samples. Over-expression of MARCH6 was associated with poor prognosis of HCC patients. Up-expression of MARCH6 promoted cell growth and migration of HCC cells. In contrast, the HCC cell growth and migration were suppressed by MARCH6 knockdown. Furthermore, the DNA synthesis was enhanced by MARCH6. The expression of ATF2 was potentiated by MARCH6 over-expression, while it was suppressed by MARCH6 silencing. TCGA database showed positive correlation between the expression of MARCH6 and ATF2. Importantly, ATF2 expression contributed to the oncogenic function of HCC cells. Conclusion Our findings suggest that MARCH6-mediated ATF2 up-regulation contributes to HCC development. MARCH6 may be a promising target for the diagnosis and treatment of HCC.

OBJECTIVES Transcranial direct current stimulation (tDCS) facilitates or inhibits spontaneous neuronal activity by low-intensity current. In this study, we evaluated the effects of tDCS and sham stimulation combined with speech language therapy (SLT) on nonfluent poststroke aphasia (PSA) patients. MATERIALS AND METHODS Patients with PSA were randomly divided into the anode tDCS (A-tDCS) group (n = 8) and sham tDCS (S-tDCS) group (n = 10). The anodes and cathodes were fixed over left inferior gyrus frontalis (L-IFG) and the deltoid muscle of the right shoulder. A-tDCS consisted of 2 mA for 20 min, while S-tDCS current started at 2 mA but automatically decreased to 0 mA after 30 sec. Stimulation was concurrent with 30 min of SLT. Stimulation + SLT sessions occurred five times a week for four weeks. The Western Aphasia Battery (WAB) was given before treatment to obtain the baseline score and once more after all sessions were completed, and the Aphasia Quotient (AQ) was calculated. RESULTS After tDCS treatment, the AQ mean(SD) in both groups was significantly higher than before treatment (p

Epsilon toxin (ETX) is a key pathogenic factor of C. perfringens type B and D, causing fatal enterotoxemia in sheep and goats. Excessive production of ETX increases intestinal permeability; its entrance into the bloodstream leads to severe edema in organs such as the brain and kidneys. At present, very few cell lines are known to be sensitive to ETX, with the most sensitive cell model for in vitro research being the MDCK cell line. Recently, more tissue-derived cell lines have been shown to be sensitive to ETX, but the mechanism of cytotoxicity remains unknown. Herein, for the first time, we aimed to evaluate the effects of ETX on HaCaT keratinocytes and human epidermal keratinocytes (HEKa). In addition, the median lethal dose of subcutaneous injection of ETX in mice was 109 ng/kg. At this dose, ETX rapidly entered the blood circulation, causing hemorrhage and edema in the brain and kidneys. ETX also increased the expression of aquaporin 3 in the muscle layer and hair follicles of the skin. We further showed the presence of the MAL protein in HaCaT keratinocytes and HEKa and skin tissues, supporting the hypothesis that it is a key element in the mechanism of cytotoxicity of ETX. In conclusion, skin cell lines were used for the first time as a model for studying the toxic effects of ETX, which will help elucidate the cytotoxicity induced by ETX and the related molecular mechanisms.

Background The γ-glutamyl peptides refer to a series of bioactive peptides containing γ-glutamyl residues. The unique γ-glutamyl linkage endows γ-glutamyl peptides with higher in vivo stability and longer half-life, which contributes to their potent physiological functions. Recently, γ-glutamyl peptides have become the focus of researchers due to the unique Kokumi taste and various potential bioactivities mediated through activation of the calcium-sensing receptor (CaSR). However, review articles on the emerging bioactivities and potential mechanisms responsible for intestinal absorption of γ-glutamyl peptides are very scanty. Scope and approach This article aimed to discuss the significance and role of γ-glutamyl peptides in human health. The present review systematically summarizes the available scientific information on the preparation, CaSR, bioactivity and bioavailability of food-derived γ-glutamyl peptides. Furthermore, the current scientific challenges and future research directions are also discussed. Key findings and conclusions γ-Glutamyl peptides have been reported to exhibit diverse bioactivities, including anti-inflammatory, hypoglycemic and appetite-suppressing effects as well as the ameliorating effect on colon health, which are attributed to CaSR activation. Moreover, due to the high resistance towards gastrointestinal digestion, γ-glutamyl peptides can play a key role in the gastrointestinal tract and also be transported across the intestinal epithelium mainly via peptide transporter 1 (PepT1) or paracellular routes to exhibit various in vivo activities. In addition, further and intensive investigations are urgently required to address the current challenges pertaining to the effective preparation, novel physiological functions and exact absorption mechanisms of γ-glutamyl peptides. This review contributes to a better understanding of γ-glutamyl peptides in terms of their cellular receptor, bioactivity and bioavailability.

Hypocotyl phototropism is redundantly mediated by phot1 and phot2, two blue light receptor phototropins, under the intensity of blue light>1 μmol m−2 s−1. As light intensity increases, phot1 inhibits the phot2-mediated response. To date, only Arabidopsis Root Phototropism2 (RPT2) has been shown to participate in phot1-mediated inhibition of phototropism. To dissect the signaling network that underlies phot1-mediated inhibition, we carried out a yeast two-hybrid (Y2H) screening assay for RPT2 interacting proteins and identified J-domain protein required for chloroplast accumulation response 1 (JAC1). The interaction between JAC1 and RPT2 was verified by bimolecular fluorescence complementation and Co-IP assays. JAC1 is expressed mainly in cotyledons and hypocotyls. Like RPT2, JAC1 can be induced by blue light, suggesting that it may function similarly to RPT2 in the inhibition of phototropism. Genetic analysis showed that jac1 mutation significantly enhanced the hypocotyl bending of phot1 mutants towards intermediate-intensity blue light, and this effect was inhibited by the constitutive expression of JAC1 in the phot1 jac1 mutant. The phot1 rpt2 double mutant also exhibited enhanced phototropism compared with the phot1 mutant. Taken together, our data clearly demonstrate that JAC1 cooperates with RPT2 to negatively regulate hypocotyl phototropism in plants and may act either downstream of or in parallel with phot1.

Purpose Accurate lymph node (LN) malignancy classification is essential for treatment target identification in head and neck cancer (HNC) radiation therapy. Given the constraints imposed by relatively small sample sizes in real-world medical applications, to classify LN malignancy status accurately, we proposed an attention-guided classification (AGC) scheme that (1) incorporates human knowledge (ie, LN contours) into model training to guide model’s “learning” direction, alleviating the critical requirement of large training samples by deep learning approaches; and (2) does not require accurate delineation of LNs in the inference stage but can highlight the discriminative region nearby the LN, which is important for malignancy determination. Methods and Materials In the proposed AGC scheme, there is an attention-guided convolutional neural network (agCNN) module, followed by a classification convolutional neural network (cCNN) module. The input of the proposed AGC scheme is a region of interest (ROI) containing the LN and its surrounding tissues. The agCNN is designed to find the discriminative region in the ROI, which outputs an activation map whose voxel values indicate the importance of the voxels in malignancy prediction. Through multiplying the activation map with the ROI, we obtain the input for the cCNN, which finally outputs the LN malignancy probability. To demonstrate the effectiveness of the proposed scheme, we performed experimental studies using positron emission tomography and contrast-enhanced computed tomography from 129 surgical HNC patients, including 791 LNs, with pathologic ground truth of malignancy status. To evaluate the performance, 5-folder cross validation was used. Results The sensitivity, specificity, accuracy, and area under the receiver operating characteristic (ROC) curve values obtained by the proposed AGC scheme were 0.91, 0.93, 0.92, and 0.98, respectively, significantly outperforming conventional convolutional neural network and radiomics approaches at a significance level of .05 under a paired ROC comparison statistical test. Conclusions We developed an AGC scheme that can highlight the discriminative region in an image for LN malignancy prediction, outperforming a conventional radiomics method that requires accurate segmentation and a standard convolutional neural network model without involving segmentation.

As a potential “Superbug,” Pseudomonas aeruginosa remains the leading concern in antimicrobial resistance. In this study, the emergence of clinical P. aeruginosa isolate was found to carry crpP and...

Background. Insomnia is often related to stressful events. The hypothalamus-pituitary-adrenal (HPA) axis is related to stress, and dopamine (DA) and DA receptors are involved in the regulation of HPA axis. Electroacupuncture (EA) can improve sleep in individuals with insomnia, but the mechanism is unclear. We demonstrated that EA can improve sleep in rats after cage change through DA and the DA receptors in the HPA axis. Methods. A rat model of insomnia was established by cage change to a dirty cage. The rats in treatment groups were intervened by EA and D1R (or D2R) antagonists. Electroencephalography (EEG) and electromyogram (EMG) were recorded to compare the changes in sleep. The DA, corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and cortisol (CORT) levels in the plasma and hypothalamus were measured by ELISAs, and the D1R and D2R levels were measured by RT-PCR and immunohistochemistry. Results. The dirty group showed a significant increase in the amount of wakefulness and decrease in the amount of NREM sleep, with decreased numbers of long NREM sleep bouts and REM sleep bouts and increased mean duration of wakefulness during the light period. EA and D1R (or D2R) antagonists intervention could improve sleep disturbance by decreasing wakefulness in the light period after cage change, EA and D1R (or D2R) antagonists could increase the hypothalamus DA, CRH, ACTH, CORT level, and the D1R and D2R mRNA levels in the HPA axis, and the effect of EA plus D1R (or D2R) antagonist was not superior to that of EA or D1R (or D2R) antagonists alone. Conclusions. EA can improve the sleep of rats after cage change, and the mechanism may be related to the regulation of DA and D1R or D2R in the HPA axis.

Chronic pain is characterized by discrete pain episodes of unpredictable frequency and duration. This hinders the study of pain mechanisms and contributes to the use of pharmacological treatments associated with side effects, addiction and drug tolerance. Here, we show that a closed-loop brain–machine interface (BMI) can modulate sensory-affective experiences in real time in freely behaving rats by coupling neural codes for nociception directly with therapeutic cortical stimulation. The BMI decodes the onset of nociception via a state-space model on the basis of the analysis of online-sorted spikes recorded from the anterior cingulate cortex (which is critical for pain processing) and couples real-time pain detection with optogenetic activation of the prelimbic prefrontal cortex (which exerts top–down nociceptive regulation). In rats, the BMI effectively inhibited sensory and affective behaviours caused by acute mechanical or thermal pain, and by chronic inflammatory or neuropathic pain. The approach provides a blueprint for demand-based neuromodulation to treat sensory-affective disorders, and could be further leveraged for nociceptive control and to study pain mechanisms. A closed-loop brain–machine interface modulates sensory-affective experiences in real time in freely behaving rats by coupling neural codes for nociception directly with therapeutic cortical stimulation.

Balancing selection is frequently invoked as a mechanism that maintains variation within and across populations. However, there are few examples of balancing selection operating on loci underpinning complex traits, which frequently display high levels of variation. We investigated mechanisms that may maintain variation in a focal polymorphism—leaf chemical profiles of a perennial wildflower (Boechera stricta, Brassicaceae)—explicitly interrogating multiple ecological and genetic processes including spatial variation in selection, antagonistic pleiotropy, and frequency-dependent selection. A suite of common garden and greenhouse experiments showed that the alleles underlying variation in chemical profile have contrasting fitness effects across environments, implicating two ecological drivers of selection on chemical profile: herbivory and drought. Phenotype-environment associations and molecular genetic analyses revealed additional evidence of past selection by these drivers. Together, these data are consistent with balancing selection on chemical profile, likely caused by pleiotropic effects of secondary chemical biosynthesis genes on herbivore defense and drought response., Editor’s Summary: Evidence for balancing selection acting on loci that control complex traits is limited. Here, the authors show evidence for past selection on chemical profile in a perennial wildflower by two ecological drivers, herbivory and drought, consistent with balancing selection on this trait.

BackgroundThe posterior flap is a conventional technique for closing a below-knee amputation (BKA) that uses the gastrocnemius and soleus muscle and relies on the popliteal and posterior compartment arteries. If the prior mentioned arterial blood supply is compromised, this flap likely relies on collateral flow. The purpose of this study is to identify and differentiate any significant associations between preoperative popliteal and tibial arterial flow and BKA outcomes and patient-reported function.MethodsA retrospective review identified patients from a single tertiary wound care center who received BKAs and angiogram between 2010 and 2017 by a single surgeon. BKA complications, wound healing, and amputee ambulatory status at latest follow-up were all stratified for differences according to baseline tibial vessel run-off (VRO) status, popliteal artery patency, and popliteal angioplasty outcome. Chi-square, Fisher’s exact, and Wilcoxon rank sum tests were used with significance defined as p ≤ 0.05 .ResultsBKAs were performed on 313 patients, of which, 167 underwent preoperative angiography. Thirty-two were excluded due to lack of adequate follow-up leaving a total of 135 patients in the studied population. Diabetes was present in 87%, and 36% had end-stage renal disease. By the study’s conclusion, 92% of BKAs had fully healed, with median time-to-healing of 79 days (range 19–1314 days). 60% of patients were ambulatory at 9.5 months. Higher VRO was associated with higher healing rates and lower complications and time-to-healing. The conversion rate of BKA to above-knee amputation (AKA) was 4%. Preoperative popliteal patency was associated with higher postoperative ambulation rates when compared to patients without popliteal flow preoperatively (patent: 71/109, 65%; occluded: 10/26, 40%; p = 0.02) and independently increased the likelihood of postoperative ambulation.ConclusionsThe posterior flap design for BKA works even in the setting of popliteal occlusion. Complication rates are higher in patients with more compromised blood flow, which may ultimately lead to AKA. Given poor ambulation rates in patients who undergo AKA, the results of this study should encourage surgeons to consider a more functional BKA, even in instances when the popliteal artery is occluded.

Higher-order structure governs function for many RNAs. However, discerning this structure for large RNA molecules in solution is an unresolved challenge. Here, we present SHAPE-JuMP (selective 2'-hydroxyl acylation analyzed by primer extension and juxtaposed merged pairs) to interrogate through-space RNA tertiary interactions. A bifunctional small molecule is used to chemically link proximal nucleotides in an RNA structure. The RNA cross-link site is then encoded into complementary DNA (cDNA) in a single, direct step using an engineered reverse transcriptase that "jumps" across cross-linked nucleotides. The resulting cDNAs contain a deletion relative to the native RNA sequence, which can be detected by sequencing, that indicates the sites of cross-linked nucleotides. SHAPE-JuMP measures RNA tertiary structure proximity concisely across large RNA molecules at nanometer resolution. SHAPE-JuMP is especially effective at measuring interactions in multihelix junctions and loop-to-helix packing, enables modeling of the global fold for RNAs up to several hundred nucleotides in length, facilitates ranking of structural models by consistency with through-space restraints, and is poised to enable solution-phase structural interrogation and modeling of complex RNAs.

The identification of cone photoreceptor cells is important for early diagnosing of eye diseases. We proposed automatic deep-learning cone photoreceptor cell identification on adaptive optics scanning laser ophthalmoscope images. The proposed algorithm is based on DeepLab and bias field correction. Considering manual identification as reference, our algorithm is highly effective, achieving precision, recall, and F 1 score of 96.7%, 94.6%, and 95.7%, respectively. To illustrate the performance of our algorithm, we present identification results for images with different cone photoreceptor cell distributions. The experimental results show that our algorithm can achieve accurate photoreceptor cell identification on images of human retinas, which is comparable to manual identification.

Voltage-gated sodium channel Nav1.7 robustly expressed in peripheral nociceptive neurons has been considered as a therapeutic target for chronic pain, but there is no selective Nav1.7 inhibitor available for therapy of chronic pain. Ralfinamide has shown anti- nociceptive activity in animal models of inflammatory and neuropathic pain and is currently under phase III clinical trial for neuropathic pain. Based on ralfinamide, a novel small molecule (S)-2-((3-(4-((2-fluorobenzyl) oxy) phenyl) propyl) amino) propanamide (QLS-81) was synthesized. Here, we report the electrophysiological and pharmacodynamic characterization of QLS-81 as a Nav1.7 channel inhibitor with promising anti-nociceptive activity. In whole-cell recordings of HEK293 cells stably expressing Nav1.7, QLS-81 (IC 50 at 3.5 ± 1.5 μM) was ten-fold more potent than its parent compound ralfinamide (37.1 ± 2.9 μM) in inhibiting Nav1.7 current. QLS-81 inhibition on Nav1.7 current was use-dependent. Application of QLS-81 (10 μM) caused a hyperpolarizing shift of the fast and slow inactivation of Nav1.7 channel about 7.9 mV and 26.6 mV, respectively, and also slowed down the channel fast and slow inactivation recovery. In dissociated mouse DRG neurons, QLS-81 (10 μM) inhibited native Nav current and suppressed depolarizing current pulse-elicited neuronal firing. Administration of QLS-81 (2, 5, 10 mg· kg −1 · d −1 , i.p.) in mice for 10 days dose- dependently alleviated spinal nerve injury-induced neuropathic pain and formalin-induced inflammatory pain. In addition, QLS-81 (10 μM) did not significantly affect ECG in guinea pig heart ex vivo; and administration of QLS-81 (10, 20 mg/kg, i.p.) in mice had no significant effect on spontaneous locomotor activity. Taken together, our results demonstrate that QLS-81, as a novel Nav1.7 inhibitor, is efficacious on chronic pain in mice, and it may hold developmental potential for pain therapy.

Summary Anti-neurofascin-155 (NF155) antibodies have been observed in two cases with neuromyelitis optica spectrum disorders (NMOSD). This study investigated the prevalence of anti-NF155 antibodies in patients with NMOSD and the clinical features of anti-NF155 antibody-positive patients. Sera from 129 patients with NMOSD were screened with anti-NF155 antibodies by cell-based assay (CBA) and re-examined using immunostaining of teased mouse sciatic nerve fibres. Fifty-six patients with multiple sclerosis (MS) and 50 healthy controls (HC) were also enrolled for detecting anti-NF155 antibodies. A total of 12.40% (16 of 129) of patients with NMOSD were positive for anti-NF155 antibodies confirmed by both CBA and immunostaining. Immunoglobulin (Ig) G1 was the predominant subclass. However, none of 56 MS patients or 50 HC were positive for anti-NF155 antibodies. Anti-NF155 antibody-positive NMOSD patients had a higher proportion of co-existing with autoimmune diseases (p

Background Survivin have been shown to play a crucial role in rheumatoid arthritis (RA); however, the regulatory mechanism of survivin in RA has not been fully elucidated. This study aims to investigate the effect of survivin on the proliferation and apoptosis of human RA fibroblast-like synoviocyte (RA-HFLS) cells in RA and its underlying mechanism through the NOTCH pathway. Methods The RA synovial tissues of 65 RA patients with partial resection of synovium of knee joint by arthroscopy were collected. The expression of survivin in synovial tissue was detected by immunohistochemistry, and the correlation of survivin expression and clinical-pathological parameters of patients was analyzed. In vitro, the proliferation of HFLS and RA-HFLS were detected by MTT; the apoptosis of HFLS and RA-HFLS were detected by flow cytometry; the expression of survivin proteins, key protein factors (Notch1, Jagged1, Hes1) in the Notch pathway, and angiogenesis-related proteins (vascular endothelial growth factor receptor 1 [VEGFR1], Ang1, Ang2) were determined by western blot. Results We found that survivin was highly expressed in RA synovial tissues and RA-HFLS cells, and was positively correlated with erythrocyte sedimentation rate, cyclic citrullinated peptide, C-reactive protein, Disease Activity Score of 28 joints and other pathological indexes. Knockdown survivin induces RA-HFLS cell apoptosis, suppresses proliferation and the expression of VEGFR1, Ang1, Ang2. In addition, blocking Notch pathway using FLI-06 significantly down-regulated survivin expression. When survivin is up-regulated, it promotes RA-HFLS cell proliferation, the expression of VEGFR1, Ang1, Ang2 and suppresses apoptosis by activating the NOTCH. Conclusion This study confirmed that survivin promotes RA-HFLS cell proliferation, the expression of angiogenesis-related proteins and suppresses apoptosis by activating the NOTCH pathway.

Yuan-Yuan Du, Xiao-Jing Yan, Yan-Jing Guo, Jing Wang, Xiao-Duo Wen, Nan Wang, Yi Yang Department of Gynecology and Obstetrics Ultrasound, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, People’s Republic of ChinaCorrespondence: Yi YangDepartment of Gynecology and Obstetrics Ultrasound, The Fourth Hospital of Hebei Medical University, No. 12 of Jiankang Road, Chang’an District, Shijiazhuang, 050011, People’s Republic of ChinaTel/Fax +86 311 8609 5378Email yangyi_dr336@163.comBackground: To explore the value of transvaginal real-time shear wave elastography (SWE) in the diagnosis of endometrial lesions.Methods: A total of 140 female patients with endometrial lesions, confirmed by pathological results, were divided into three groups: 45 cases of endometrial polyps, 29 cases of endometrial hyperplasia and 66 cases of endometrial cancer. A total of 100 cases of normal endometrium were used as the control group, including 52 cases in the proliferative stage and 48 cases in the secretory stage. Transvaginal real-time shear wave elastography was performed in all four groups.Results: Emean, Emax and Esd were expressed as the average standard deviation. Among the control group, the results were 26.24± 9.74, 38.09± 9.18, and 4.25± 2.73 kPa, respectively, in the proliferative endometrium cases and 12.51± 7.46, 27.22± 11.32, 4.40± 2.52 kPa, respectively, in the secretory endometrium cases. Among the experimental group, the result was 15.68± 8.18, 27.28± 10.28 and 3.62± 1.81 kPa respectively in the endometrial polyps cases; 21.20 ± 12.57, 36.32 ± 15.04, and 5.09 ± 3.93 kPa in the endometrial hyperplasia cases; 49.36± 25.51, 86.66± 42.27 and 14.86± 10.63 kPa in the endometrial cancer cases. The difference was statistically significant (P < 0.05). When the truncation values of Emean, Emax and Esd were 28.50, 52.45 and 9.05 kPa, respectively, to distinguish between normal endometrium and endometrial cancer, Emax has the highest diagnostic value.Conclusion: Real-time SWE technology might be used as an auxiliary method in the diagnosis and differential diagnosis of endometrial cancer. More quantitative indicators are conducive to diagnosis.Keywords: ultrasound, endometrial lesions, real-time shear wave elastography, differential diagnosis

In the past two decades, significant progress has been made in the past two decades towards the understanding of the basic mechanisms underlying cancer growth and angiogenesis. In this context, receptor tyrosine kinases (RTKs) play a pivotal role in cell proliferation, differentiation, growth, motility, invasion, and angiogenesis, all of which contribute to tumor growth and progression. Mutations in RTKs lead to abnormal signal transductions in several pathways such as Ras-Raf, MEK-MAPK, PI3K-AKT and mTOR pathways, affecting a wide range of biological functions including cell proliferation, survival, migration and vascular permeability. Increasing evidence demonstrates that multiple kinases are involved in angiogenesis including RTKs such as vascular endothelial growth factor, platelet derived growth factor, epidermal growth factor, insulin-like growth factor-1, macrophage colony-stimulating factor, nerve growth factor, fibroblast growth factor, Hepatocyte Growth factor, Tie 1 & 2, Tek, Flt-3, Flt-4 and Eph receptors. Overactivation of RTKs and its downstream regulation is implicated in tumor initiation and angiogenesis, representing one of the hallmarks of cancer. This review discusses the role of RTKs, PI3K, and mTOR, their involvement, and their implication in pro-oncogenic cellular processes and angiogenesis with effective approaches and newly approved drugs to inhibit their unrestrained action.

Aims This study aimed to determine the effects of sodium‐glucose cotransporter‐2 inhibitor (SGLT2i) in heart failure with reduced ejection fraction (HFrEF), compare the effect of SGLT2i with angiotensin receptor neprilysin inhibitor (ARNI), and find whether combination of SGLT2i and ARNI is better than monotherapy. Methods and results Embase, Medline, and Cochrane Central Registry of Controlled Trials were searched for randomized controlled trials evaluating SGLT2i or ARNI in HFrEF. And a total of six trials were included. SGLT2i was found to significantly reduce the risk of cardiovascular death or hospitalization for heart failure by 27% [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.67–0.80], hospitalization for heart failure by 31% (HR 0.69, 95% CI 0.62–0.77), cardiovascular death by 16% (HR 0.84, 95% CI 0.74–0.95), and all‐cause death by 16% (HR 0.84, 95% CI 0.75–0.94) in HFrEF only with a statistically higher risk of genital infection (risk ratio (RR) 2.78, 95% CI 1.46–5.29). The reduction in cardiovascular death or hospitalization for heart failure was of similar magnitude in patients with or without diabetes mellitus (HR 0.71, 95% CI 0.64–0.80 vs. HR 0.75, 95% CI 0.65–0.87) using SGLT2i. Indirect treatment comparison showed that SGLT2i and ARNI had similar effects on primary outcome (HR 0.93, 95% CI 0.82–1.06). And combination of SGLT2i and ARNI achieved a better prognosis performance (HR 0.68, 95% CI 0.53–0.89) compared with ARNI monotherapy. Conclusions SGLT2i could safely reduce cardiovascular death or hospitalization for heart failure in HFrEF regardless of diabetes mellitus status. SGLT2i and ARNI demonstrate similar effects, while combination of SGLT2i and ARNI results in a better cardiovascular protective effect.

The Sip1Aa protein from Bacillus thuringiensis is highly toxic to Colaphellus bowringi Baly. In order to obtain mutant proteins with higher insecticidal activity, a random recombinant library of Sip1Aa protein was constructed using error-prone PCR. A total number of 100 positive transformants were randomly selected for sequence determination, and 25 mutants (M1 to M25) were selected and expressed the respective Sip1Aa mutants. These Sip1Aa variants had a total of 29 base mutations, with an average of 1.2 base mutations per mutant. Compared with that of the wild-type Sip1Aa protein, the insecticidal activity of the mutants M1 (A31G, Y118C, D227E), M5 (K168R) and M21 (I307T) was significantly decreased, with and LC50 values 4 to 6 times higher than the Sip1Aa protein. The mutant M8 (R174S) showed increase in the insecticidal activity against the Colaphellus bowringi Baly was obtained, with an LC50 value 4-fold less than the Sip1Aa protein. The results of this study provide reference for the molecular modification of Sip1Aa protein and the study of key sites of its insecticidal activity.

Long non-coding RNAs (lncRNAs), microRNAs (miRNAs or miRs), and genes are emerging players in cancer progression. In the present study, we explored the roles and interactions of oncogenic lncRNA small nucleolar RNA host gene 1 (SNHG1), miR-376, forkhead box protein K1 (FOXK1), and Snail in hepatocellular carcinoma (HCC). Expression of SNHG1, miR-376, and FOXK1 in HCC was characterized in clinical HCC tissues of 75 patients with HCC. The interactions between SNHG1 and miR-376 and between miR-376 and FOXK1 were predicted and confirmed by dual-luciferase reporter gene and RNA immunoprecipitation assays. Overexpression and knockdown experiments were performed in HCC cells to examine the effects of the SNHG1/miR-376/FOXK1/Snail axis on viability, apoptosis, invasiveness, and migrating abilities. Their effects on tumor growth and metastasis were validated in nude mouse models. SNHG1 and FOXK1 were upregulated, and miR-376a was downregulated in HCC. SNHG1 knockdown contributed to suppression of HCC cell viability, invasion, and migration properties and promotion of apoptosis. SNHG1 could competitively bind to miR-376a to upregulate its target gene FOXK1, which upregulated Snail. SNHG1 knockdown delayed cancer progression both in vitro and in vivo by upregulating miR-376a and downregulating FOXK1 and Snail. SNHG1 knockdown exerts anti-tumor activity in HCC, suggesting a therapeutic target., Graphical Abstract, SNHG1 is highly expressed in HCC. SNHG1 competitively binds to miR-376a and inhibits the expression of miR-376a, thereby promoting FOXK1 and Snail expression, leading to reduction of HCC cell proliferative, migrating, and invasive properties, and promotes cell apoptosis and promotion of tumor growth and metastasis in HCC.

The occurrence and characterization of carbapenemase-producing Enterobacteriaceae from companion animals in Guangzhou, China, are investigated. Six isolates (2.3%, 6/257) were positive for blaNDM-5...

In this study, we isolated a group of viruses that can cause a cytopathic effect in BHK-21 cells from sandfly specimens collected in Yangquan County, Shanxi Province, central China. The representative virus strain is SXYQ1860 and, with increased viral injection, the suckling mice became ill and died, with viral titers continually increasing. The results of molecular genetic evolution analysis of the three gene segments of the virus, L, M, and S, indicate that the newly isolated viruses from Yangquan County are the same as the Wuxiang virus (WUXV) previously isolated from sandflies collected in Wuxiang county, China. This is the first time that the WUXV was also isolated outside Wuxiang County. Therefore, strengthening the surveillance of neglected sandflies and the viruses they transmit to help prevent and control arboviruses and the associated diseases is essential for public health.

Background: To introduce the surgical procedure based on special space anatomy that can safely and efficiently complete the dissociation of the ureter and uterine artery during laparoscopic radical trachelectomy with uterine artery preservation. Methods: We introduce the key technique elements of this surgical procedure using a patient we treated as an example. A 27-year-old patient was diagnosed as well-differentiated cervical adenocarcinoma, stage IB1, and had a strong desire for future fertility. Laparoscopic radical trachelectomy with uterine artery preservation was performed in this patient by using this new surgical technique based on space anatomy. Results: The ureteral space that needs to be dealt with during laparoscopic radical trachelectomy is actually a potential avascular space located medial to the ureter between the anterior leaf (from the axillary space to the fourth space of Yabuki) and posterior leaf (between the paravesical space and paravaginal space) of the vesicouterine ligament. Exposure of the axillary space can help to separate the ureter from the lower uterine segment and uterine artery (uterine side), which is necessary for radical trachelectomy with uterine artery preserved. Multiple "shafts" called potential avascular space can be drilled on the anterior leaf of vesicouterine ligament, and the connective tissue and blood vessels between the "shafts" were cutoff with ultrasonic scalpel. After the paravesical space and paravaginal space were developed, the posterior leaf was isolated and congealed completely by Ligasure. Conclusions: In brief, this new surgical procedure consists of four spaces that can safely and efficiently perform complete excision of the vesicouterine ligament, reduce blood loss, avoid ureteral injury, and shorten the operation time.

Background Previous studies have indicated that host genetic factors play an essential role in immunity to human immunodeficiency virus (HIV) infection. We aimed to investigate the association between the toll-interacting protein (TOLLIP) and mannose-binding lectin 2 (MBL2) genes and HIV infection susceptibility among Chinese Han patients. Methods This is a case-control study. A total of 435 HIV-infected patients and 1013 seronegative healthy individuals were recruited. DNA was extracted from whole blood. Two SNPs in the MBL2 gene (rs7096206 and rs1800450) and three SNPs in the TOLLIP gene (rs5743899, rs3750920, and rs5743867) were selected and genotyped using a SNPscan Kit (Cat#: G0104, Genesky Biotechnologies Inc., Shanghai, China). Odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated using unconditional binary logistic regression. Results A significant association between the minor alleles rs5743899 (C allele) and rs5743867 (G allele) in the TOLLIP gene and susceptibility to HIV infection was found in this study after adjusting for age and sex (Pa = 0.011 and TOLLIP gene was significantly associated with the risk of HIV infection in dominant, recessive, and additive models when adjusted for age and sex (Pa MBL2 gene polymorphisms and HIV infection. Conclusion Our study found a statistically significant association between the two SNPs (rs5743867 and rs5743899) in the TOLLIP gene and susceptibility to HIV infection in a Chinese Han population.

BACKGROUND Polycystic ovarian syndrome (PCOS) is an endocrine disorder syndrome with reproductive dysfunction and abnormal glucose metabolism. Persistent non-ovulation, excessive androgens and insulin resistance are important features and they are the most common causes of menstrual disorders in women during childbearing years. At present, the cause of PCOS is not clinically clear. Current studies suggest that it may be due to the interaction of certain genetic genes with environmental factors. It is an important cause of infertility or early miscarriage with the characteristics of various causes and complex clinical manifestations. At present, for the treatment of PCOS patients, clinical treatment mainly includes hypoglycemia, insulin and menstrual regulation and other symptomatic and supportive treatment. Drospirone ethinyl estradiol and ethinyl estradiol cyproterone are 2 of the most commonly used drugs in clinical treatment of PCOS, but there is lack of the evidence of evidence-based medicine. Therefore, this study systematically evaluates the therapeutic effect and safety of PCOS patients with 2 short-acting oral contraceptives, drospirone ethinyl estradiol and ethinyl estradiol cyproterone, which provides the guidance for clinically selecting the appropriate drug to treat PCOS. METHODS Searching CNKI, WanFang Data, VIP, SinoMed, PubMed, EMbase, Web of Science, and The Cochrane Library database by computer, collecting the randomized controlled studies of DEE and EEC in the treatment of PCOS. The retrieval time limit is from the establishment of each database to July 1, 2020. In addition, tracing the references incorporated into the literature to supplement to the relevant literature. Using the retrieval method by combining the free words and the subject words, and the individual search of different databases is carried out. Meta-analysis is performed using RevMan 5.3 software after 2 researchers independently screens the literature, extracts the data, and evaluates the bias risk included in the study. RESULTS This study will systematically evaluate the DEE and EEC in the treatment of PCOS by collecting the required evidence to understand the effects of the 2 drugs on hypersotrophicemia, insulin resistance, lipid metabolism, and the safety during drug use in patients of this class, and the results will be published in highly influential academic journals. CONCLUSION The results of this study will provide theoretical basis for the drug treatment of polycystic ovarian syndrome and provide help in the decision-making of clinical treatment of the disease. ETHICS AND DISSEMINATION In this study, meta-analysis was used to conduct a second study on the published literature. Therefore, this type of systematic review research does not need to be approved by ethics. OSF REGISTRATION DOI 10.17605/OSF.IO/8GW9M.

Background Chronic kidney disease (CKD) is a progressive and irreversible loss of kidney function. After stage 3, there will be increased risks of hypertension, heart failure, bone disease, anemia, gastrointestinal symptoms, and progression to end-stage kidney failure without proper intervention and treatment. Compound α-ketoacid tablets (KA) administration plays an important role in clinical CKD adjunctive therapy for patients with restricted protein intake. Bailing Capsule (BC), a commonly used Chinese patent medicine for renal diseases, could regulate human immune function, repair renal tubular epithelial cells, prevent renal tubular atrophy, and reduce kidney damage to improve renal function. In this study, we try to conduct a double-blinded, randomized, controlled trial to observe the efficacy and safety of BC combined with KA in treating patients with stage 3 CKD. Methods This is a double-blinded, randomized, controlled trial. Patients will be randomly divided into treatment group (BC and KT) and control group (BC-simulation and KT) in a 1:1 ratio according to random number table. The treatment course will be 8 weeks, and the changes of subjective symptoms, patient global assessment (PGA) scale, serum creatinine, cystatin C, and estimated glomerular filtration rate, all related adverse events, vital sign measurements, and physical examinations will be recorded. SPSS 21.0 will be used for data analysis. Conclusions The results will show whether BC combined with KA could alleviate the symptoms of fatigue, anorexia, halitosis, nausea, itching, and edema, improve kidney function in patients with CKD at stage 3. Trial registration OSF Registration number: DOI 10.17605/OSF.IO/24AJ7.

： Backgoun：Asthma and dry eye disease are common clinical diseases. Studies have shown that asthma is related to dry eye, but there is no high-quality evidence-based medical evidence. Method：This protocol and final study will be conducted in accordance with the Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. We will search PubMed, EMBASE, ISI Web of Science, China National Knowledge Infrastructure for all relevant literature published from their inception up to August 1, 2020. Literature search, data extraction and quality assessment will be carried out independently by two researchers, and a third researcher will resolve differences when necessary. The association between dry eye disease and asthma will indicate as odds ratio (OR) with 95% confidence interval (95% CI) and statistically analyzed using RevMan 5.3 software. If the studies included have high heterogeneity, we will conduct sensitivity analysis and subgroup analysis. Results：The protocol is intended to guide a meta-analysis aimed at identifying and quantifying the association between asthma and dry eye disease.

Summary Curbing unwanted T cell responses by costimulation blockade has been a recognised immunosuppressive strategy for the last 15 years. However, our understanding of how best to deploy this intervention is still evolving. A key challenge has been the heterogeneity in the clinical response to costimulation blockade, and an inability to predict which individuals are likely to benefit most. Here, we discuss our recent findings based on the use of costimulation blockade in people with type 1 diabetes (T1D) and place them in the context of the current literature. We discuss how profiling follicular helper T cells (Tfh) in pre-treatment blood samples may have value in predicting which individuals are likely to benefit from costimulation blockade drugs such as abatacept.