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Abstract Background Alanine aminotransferase (ALT) is an enzyme crucial for energy and protein metabolism in muscle cells. Despite this, its association with sarcopenia remains inadequately explored. This study aims to investigate the correlation between serum levels of ALT-related indicators (ALT activity, ALT1, ALT2, and ALT1/ALT2 ratio) and sarcopenia measures, as well as to develop a diagnostic model for sarcopenia in older individuals. Methods This retrospective study assessed 653 older adults (aged ≥ 55 years), 109 of whom were studied for the association of ALT1, ALT2, and ALT1/ALT2 ratio with sarcopenia measures. Muscle mass was measured by dual energy X-ray absorptiometry. Hand grip strength (HGS) was measured with a digital dynamometer, and physical performance was assessed through the 6-meter gait speed and the five-times sit-to-stand test (FTSST). Binary logistic regression analysis was used to evaluate associations between ALT-related indicators (ALT activity and ALT1/ALT2 ratio) and sarcopenia. The diagnostic model was developed using binary logistic regression with backward selection, and the diagnostic performance of the model was evaluated by the receiver operator characteristic curve (ROC) curve. Results Older adults with sarcopenia exhibited a lower serum ALT activity and a higher ALT1/ALT2 ratio compared to those without sarcopenia. ALT activity tertiles, but not ALT1 or ALT2 tertiles alone, correlated with HGS, gait speed, FTSST, and appendicular skeletal muscle mass index (ASMI), serving as independent protective factors for low HGS, low physical performance, low ASMI, and sarcopenia. Tertiles of the ALT1/ALT2 ratio were significantly associated with HGS and FTSST, and were proved independent risk factors for low physical performance and sarcopenia by binary logistic regression analysis. An optimal Model A (based on ALT activity) was established for sarcopenia to develop a new Logit_P1 (p

Background: Muscle atrophy or sarcopenia is the loss of muscle mass and strength and leads to an increased risk of disability and death including osteoporotic fractures. Currently, there are no available clinical biologic agents for the treatment of sarcopenia. Since exosomes have become increasingly attractive as a novel therapeutic approach due to their ability to facilitate cell-cell transfer of proteins and RNAs, promoting cell repair and function recovery, we hypothesized that human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-Exos) might benefit muscle atrophy in age-related and dexamethasone-induced sarcopenia animal models. Methods: HucMSC-Exos were harvested by ultrafast centrifugation and identified by transmission electron microscopy, particle size analysis, and Western blot analysis. The effects of hucMSC-Exos on muscle atrophy were evaluated using age-related and dexamethasone-induced muscle atrophy mice models. Body weight, grip strength, muscle weight, and muscle histology of these mice were assessed. The expression levels of muscle RING finger 1 (MuRF1) and muscle atrophy F-box (atrogin-1) were measured by Western blot. Dexamethasone-induced C2C12 myotube atrophy was used to establish the cell model of muscle atrophy. Myotube diameter was evaluated by immunofluorescence staining. Bioinformatic analysis, RNA sequencing analysis, and Western blot analysis were performed to explore the underlying mechanisms. Results: In vivo experiments, hucMSC-Exos demonstrated a remarkable capacity to improve grip strength, increase muscle mass, and muscle fiber cross-sectional area, while concurrently reducing the expression of MuRF1 and atrogin-1 in age-related and dexamethasone-induced muscle atrophy mice. In vitro experiments, hucMSC-Exos can promote the proliferation of C2C12 cells, and rescue the dexamethasone-induced decline in the viability of C2C12 myotubes. In addition, hucMSC-Exos can increase the diameter of C2C12 myotubes, and reduce dexamethasone-induced upregulation of MuRF1 and atrogin-1. Combined with bioinformatics analysis and RNA sequencing analysis, we further showed that miR-132-3p was one of the essential miRNAs in hucMSC-Exos and played an important role by targeting FoxO3. Conclusion: Our findings suggested that hucMSC-Exos can improve age-related and dexamethasone-induced muscle atrophy in mice models. This study first demonstrated that hucMSC-Exos may ameliorate muscle atrophy via the miR-132-3p/FoxO3 axis. These data may provide novel and valuable insights into the clinical transformation of hucMSC-Exos for the treatment of sarcopenia. The translational potential of this article: HucMSC-Exos are easily available for clinical application, this study further consolidates the evidence for the clinical transformation potential of hucMSC-Exos for sarcopenia and provides its new target pathway.

Objectives: Pulmonary hypertension (PH) is known to be associated with increased mortality in patients suffering from left ventricular disease. The aim of this study was to assess the incidence of PH among patients diagnosed with hypertrophic cardiomyopath (HCM) and to evaluate its prognostic significance. Methods: The study cohort consisted of 2781 patients with HCM. Among them, 226 patients had PH (8.1%), and 2555 patients did not have PH (91.8%). The fourteen demographic and clinical variables were matched between the two groups using a 1:3 propensity score matching (PSM) method. Kaplan–Meier survival curves and Cox proportional hazard regression models were used to evaluate the correlation between PH and mortality. Moreover, a competing risk regression analysis was conducted to assess the competing risk. Results: Before matching, there were 519 (18.7 %) patients with all-cause mortality, including 292 (10.5 %) patients who experienced cardiovascular mortality and 128 (4.6 %) patients who experienced SCD. There was a significant difference in the Kaplan–Meier survival curves for all-cause mortality (log-rank P

Abstract Background Colorectal cancer (CRC) arises from complex interactions between host and environment, which include the gut and tissue microbiome. It is hypothesized that epigenetic regulation by gut microbiota is a fundamental interface by which commensal microbes dynamically influence intestinal biology. The aim of this study is to explore the interplay between gut and tissue microbiota and host DNA methylation in CRC. Methods Metagenomic sequencing of fecal samples was performed on matched CRC patients (n = 18) and healthy controls (n = 18). Additionally, tissue microbiome was profiled with 16S rRNA gene sequencing on tumor (n = 24) and tumor-adjacent normal (n = 24) tissues of CRC patients, while host DNA methylation was assessed through whole-genome bisulfite sequencing (WGBS) in a subset of 13 individuals. Results Our analysis revealed substantial alterations in the DNA methylome of CRC tissues compared to adjacent normal tissues. An extensive meta-analysis, incorporating publicly available and in-house data, identified significant shifts in microbial-derived methyl donor-related pathways between tumor and adjacent normal tissues. Of note, we observed a pronounced enrichment of microbial-associated CpGs within the promoter regions of genes in adjacent normal tissues, a phenomenon notably absent in tumor tissues. Furthermore, we established consistent and recurring associations between methylation patterns of tumor-related genes and specific bacterial taxa. Conclusions This study emphasizes the pivotal role of the gut microbiota and pathogenic bacteria in dynamically shaping DNA methylation patterns, impacting physiological homeostasis, and contributing to CRC tumorigenesis. These findings provide valuable insights into the intricate host-environment interactions in CRC development and offer potential avenues for therapeutic interventions in this disease.

In the context of the Corona Virus Disease 2019 (COVID-19) pandemic, medical staff have experienced traumatic stress events. Research on post-traumatic growth (PTG) was limited. We aimed to assess the relationship between perceived social support and PTG among medical staff 3 weeks after the policy opening of COVID-19 pandemic in Nanjing, China and explore the mediating roles of deliberate rumination. A multicenter study including a total of 842 medical staff was conducted at two general hospitals from December 10, 2022, to December 25, 2022, in Nanjing, China. SPSS was used for statistical description and univariate analysis, and AMOS was used for structural equation modeling (SEM) to analyze the medicating effect of deliberate social support on PTG. In the SEM, the total effect of perceived social support on PTG was significant (β = .332, 95% CI [0.259, 0.408], p

Background: There is a shortage of patients with hypertrophic cardiomyopathy (HCM) with concurrent coronary artery disease (CAD), and the influence of CAD on the prognosis of patients with HCM is uncertain. This real-world cohort study was conducted to evaluate the prognosis of patients with patients with CAD. Methods: This cohort study of patients with HCM was conducted from May 2003 to September 2021. The total number of patients enrolled was 2167, and the mean follow-up period was 6.4 years (interquartile range 2.8–9.5 years). Sudden cardiac death (SCD), cardiovascular death, and all-cause mortality were assessed as outcomes. Using logistic regression, nine indicators were selected for 1:1 propensity score matching (PSM). Additionally, Kaplan–Meier survival curves and Cox proportional hazards regression analyses were used to assess the impact of CAD on the prognosis of patients with HCM. Results: During an average of 6.4 years of follow-up, of the 2167 patients enrolled, 446 (20.6%) died. The patients were classified into two groups: CAD (n = 480) and non-CAD (n = 1,687). After imputation of missing values using the mean and 1:1 propensity score matching, there was no difference in SCD (log-rank χ2 = 0.4, p = 0.540), cardiovascular death (log-rank χ2 = 0.1, p = 0.995) and all-cause mortality (log-rank χ2 = 0.1, p = 0.776) between the CAD and non-CAD groups. After imputation of missing values using the median and 1:1 propensity score matching, patients with and without CAD were not significantly different in terms of SCD (log-rank χ2 = 0.1, p = 0.948), cardiovascular death (log-rank χ2 = 0.1, p = 0.811), and all-cause mortality (log-rank χ2 = 0.5, p = 0.499). In the Cox analysis, CAD was not a significant independent predictor of SCD, cardiovascular death, or all-cause mortality in patients with HCM. Conclusions: In this study, it was observed that there was no statistically significant disparity in mortality rates between patients diagnosed with HCM who concurrently had CAD and those who did not exhibit CAD. This finding underscores the notion that the presence of CAD did not exert a notable influence on the incidence of SCD, cardiovascular death, or all-cause mortality, thereby emphasizing the complexity and multifaceted nature of mortality risk factors in HCM patients.

Abstract Abiotic stresses are major factors constraining the growth, development and productivity of tomato (Solanum lycopersicum), the most cultivated vegetable crop worldwide. Uridine diphosphate glycosyltransferases (UDPGTs or UGTs) are essential enzymes that utilize 5-uridine diphosphate as a glycosyl donor molecule to facilitate the catalysis of glycosylation reactions across diverse substrates, thereby playing a pivotal role in conferring abiotic stress tolerance. Currently, there is a limited understanding of the structure and functions of the UDPGT gene family in tomato. In this work, 106 members of the SlUDPGT gene family were identified through in silico analysis, besides, their protein sequence properties, phylogenetic relationships, gene structure, chromosomal distribution, cis-acting elements, tissue expression and hormone- and stress-induced expression were comprehensively investigated. The expression of representative SlUDPGTs under abiotic stress and exogenous hormone treatments, including salt, polyethylene glycol, methyl viologen, gibberellic acid, jasmonic acid, abscisic acid and brassinolide, was investigated through qRT‒PCR analysis. Numerous cis-acting elements linked to stress and hormone signaling were present in the promoter regions of SlUDPGTs. According to microarray data, most SlUDPGT genes were responsive to hormones and abiotic stresses, while certain SlUDPGTs were specifically differentially expressed under Botrytis cinerea and tomato spotted wilt virus infection. Additionally, diverse expression profiles of SlUDPGTs were observed in various tissues and developmental stages. Furthermore, CRISPR/Cas9-mediated knockout of SlUDPGT52 led to enhanced drought tolerance due to enhanced reactive oxygen species (ROS) scavenging. These findings lay the foundations for the future functional characterization of specific UDPGT gene family members, assisting the biotechnology-mediated improvement of tomato and other horticultural crops.

Abstract Multiple myeloma bone disease is characterized by the development of osteolytic bone lesions. Recent work identified matrix metalloproteinase 13 as a myeloma-derived fusogen that induces osteoclast activation independent of its proteolytic activity. We now identify programmed death-1 homolog, PD-1H, as the bona fide MMP-13 receptor on osteoclasts. Silencing PD-1H or using Pd-1h -/- bone marrow cells abrogates the MMP-13-enhanced osteoclast fusion and bone-resorptive activity. Further, PD-1H interacts with the actin cytoskeleton and plays a necessary role in supporting c-Src activation and sealing zone formation. The critical role of PD-1H in myeloma lytic bone lesions was confirmed using a Pd-1h -/- myeloma bone disease mouse model wherein myeloma cells injected into Pd-1h -/- Rag2 -/- results in attenuated bone destruction. Our findings identify a role of PD-1H in bone biology independent of its known immunoregulatory functions and suggest that targeting the MMP-13/PD-1H axis may represent a potential approach for the treatment of myeloma associated osteolysis.

Background & aims: Sarcopenia is an age-related disease that increases the risk of falls and fractures in older adults. However, there is no blood biochemical marker to help to predict or diagnose sarcopenia in clinical practice. Soluble interleukin 2 receptor (sIL-2R) was reported to be associated with muscle satellite cell dysfunction which played an important role in the pathogenesis of sarcopenia. Thereby, we aimed to explore the association between serum sIL-2R and sarcopenia in older adults at high risk of fractures. Methods: A total of 429 hospitalized older adults (age ≥55 years) were enrolled in this cross-sectional study (mean age ​= ​66.62 ​± ​6.59 years; 62.7% female). Logistic regression analysis was performed to assess the association of sIL-2R with sarcopenia, muscle mass, muscle strength, and physical performance, respectively. The optimal models for the diagnosis of sarcopenia and low hand grip strength (HGS) were established by multivariable binary logistic regression analysis with backward selection, and further were evaluated for the diagnostic values by receiver operating characteristic (ROC) curve. Results: Higher sIL-2R levels were found in sarcopenia than no-sarcopenia group in male (median 421 U/mL (interquartile range [IQR] 217 U/mL) vs median 362 U/mL (IQR 157 U/mL); n ​= ​77 vs 83; p ​

The Saxi tungsten-beryllium deposit is located in the Laojunshan tungsten-tin polymetallic metallogenic area in southeastern Yunnan. Determining the fluid nature, source, and evolution process of early layered orebodies and late vein-like orebodies and constraining their fluid geochemistry and isotopes can effectively explore the metallogenic mechanism of the Saxi tungsten-beryllium deposit, which is a collection of Laojunshan deposits. This study provides theoretical thinking for future prospecting work in the district. The formation of vein-like ore bodies in this deposit experienced a silicate stage, an oxide-sulfide stage, and a carbonate-fluorite stage. Scheelite and beryl were mainly formed in the first two stages. This article studies the fluid inclusions in quartz at different stages of the orebodies of the Saxi tungsten-beryllium deposit, including petrographic characteristics, microscopic temperature measurements, and laser Raman spectroscopy. The quartz sample's hydrogen-oxygen isotope composition in the ore-like ore body was tested. Three primary types of fluid inclusions (FIs) in vein-like ore bodies are detected, i.e.: liquid-rich FIs, gas-rich FIs, and aughter minerals bearing FIs. The gas phase composition of FIs is mainly H2O, with a small amount of reducing gas such as C2H2, and the liquid phase composition is also mainly H2O. From the silicate stage to the carbonate-fluorite stage, the peak homogenization temperature and salinity (NaCleq) of FIs are 240-360℃, 2.35%-13.81%; 220-310℃, 4.03%-9.86%, and 190-270℃, 2.41%-6.88%. From early to late, both homogenization temperature and salinity of the ore-forming fluid decreased obviously. The ore-forming fluid is generally a medium temperature, low salinity, CO2-poor NaCl-H2O fluid system. The δD and δ18O values of the quartz samples from early quasi-layered ore body are -102.8‰ to -99.0‰ and 11.7‰-13.0‰ respectively, and the corresponding δ18O value of the H2O value is 3.16‰-6.46‰. The δD and δ18O values of the quartz samplesfrom bulk oxide-sulfide section are -99.6‰ to -69.5‰ and 11.2‰-14.1‰ resoectively, and the corresponding δ18O value of H2O value is 3.08‰-6.73‰. This indicates that the ore-forming fluid mainly sourced from magmatic water mixed with a small amount of atmospheric precipitation or organic water.The fluid may boil, forming the precipitation of the main ore-forming minerals in the late vein-like ore body oxide-sulfide stage. The Saxi tungsten-beryllium deposit belong to a medium-to high-temperature hydrothermal system.

Abstract Background In mice, liver fibrosis is the most serious pathologic change during Schistosoma japonicum (S. japonicum) infection. Schistosomiasis is mainly characterized by schistosome egg-induced granulomatous fibrosis. Hepatic stellate cells (HSCs) are mainly responsible for the net accumulation of collagens and fibrosis formation in the liver. Activated HSCs regulated by transforming growth factor-β1 (TGF-β1)/Smad signaling have emerged as the critical regulatory pathway in hepatitis virus or carbon tetrachloride-induced liver fibrosis. However, the detailed mechanism of HSC activation in schistosome-induced liver fibrosis is poorly understood. Methods Schistosoma japonicum-induced murine models and a control group were generated by abdominal infection with 15 (± 1) cercariae. The purity of cultured primary HSCs was evaluated by immunocytochemistry. The histopathological changes in the livers of infected mice were estimated by hematoxylin–eosin and Masson staining. Dynamic expression of pro-fibrotic molecules and microRNAs was detected by real-time quantitative PCR (RT-qPCR). Mainly members involved in the TGF-β1/Smad signaling pathway were examined via RT-qPCR and Western blot. Results The egg-induced granulomatous inflammation formed at 4 weeks post-infection (wpi) and developed progressively. Alpha-smooth muscle actin (α-SMA), collagen I, collagen III, TGF-β1, Smad2, Smad3, and Smad4 showed a significant increase in mitochondrial RNA (mRNA) and protein expression compared with the control group at 7 and 9 weeks post-infection (wpi), while an opposite effect on Smad7 was observed. In addition, the mRNA expression of microRNA-21 (miRNA-21) was significantly increased at 7 wpi, and the mRNA expression of miRNA-454 was decreased starting from 4 wpi. Conclusion Our present findings revealed that HSCs regulated by the TGF-β1/Smad signaling pathway play an important role in liver fibrosis in S. japonicum-infected mice, which may provide proof of concept for liver fibrosis in schistosomiasis. Graphical Abstract

Abstract Background Familial dilated cardiomyopathy (DCM) is a genetic cardiomyopathy that is associated with reduced left ventricle function or systolic function. Fifty-one DCM-causative genes have been reported, most of which are inherited in an autosomal dominant manner. However, recessive DCM-causative gene is rarely observed. Methods Whole-exome sequencing (WES) was performed in a consanguineous family with DCM to identify candidate variants. Sanger sequencing was utilized to confirm the variant. We then checked the DCM candidate gene in 210 sporadic DCM cases. We next explored BICD2 function in both embryonic and adult bicd2-knockout zebrafish models. In vivo cardiac function of bicd2-knockout fish was detected by echocardiography and RNA-seq. Results We identified an autosomal recessive and evolutionarily conserved missense variant, NM_001003800.1:c.2429G > A, in BICD2, which segregated with the disease phenotype in a consanguineous family with DCM. Furthermore, we confirmed the presence of BICD2 variants in 3 sporadic cases. Knockout of bicd2 resulted in partial embryonic lethality in homozygotes, suggesting a vital role for bicd2 in embryogenesis. Heart dilation and decreased ejection fraction, cardiac output and stroke volume were observed in bicd2-knockout zebrafish, suggesting a phenotype similar to human DCM. Furthermore, RNA-seq confirmed a larger transcriptome shift in in bicd2 homozygotes than in heterozygotes. Gene set enrichment analysis of bicd2-deficient fish showed the enrichment of altered gene expression in cardiac pathways and mitochondrial energy metabolism. Conclusions Our study first shows that BICD2 is a novel candidate gene associated with familial DCM, and our findings will facilitate further insights into the molecular pathological mechanisms of DCM.

Objectives: Hypertrophic cardiomyopathy (HCM) is the most common hereditary cardiomyopathy. However, few studies have investigated the prognosis of familial HCM (FHCM) through clinical data. The purpose of this study was to compare the clinical outcomes of FHCM and non-FHCM through propensity score matching analysis. Methods and results: The cohort study included 1243 patients with HCM between 1996 and 2013 in Fuwai Hospital, Chinese Academy of Medical Sciences, among whom 125 patients had FHCM. During a mean follow-up of 7.6 ± 3.8 years (interquartile range: (IQR) 5.0–10.0 years), 217 (16.57%) of the 1243 patients had died, including 3 patients who underwent cardiac transplantation. Using 30 demographic and clinical variables, a 4:1 propensity score matched cohort for FHCM was established. The stepwise variable selection procedure for the Cox proportional hazards model was performed to identify the factors associated with mortality and competing risk regression analysis was performed to analyze the competitive risk of cardiovascular and non-cardiovascular mortality. The results showed that FHCM patients had a higher risk of cardiovascular mortality/cardiac transplantation (log-rank χ2 = 6.8, P = 0.0084) and an increased tendency of sudden cardiac death (SCD) (log-rank χ2 = 3.2, P = 0.074) compared with non-FHCM patients, but there was no difference in all-cause mortality (log-rank χ2 = 2.7, P = 0.1) between the two groups. Moreover, the Cox model showed that FHCM was an independent prognostic predictor for cardiovascular mortality/cardiac transplantation in HCM patients. Conclusion: FHCM patients had a higher risk of cardiovascular mortality/cardiac transplantation and a higher tendency of SCD than non-FHCM patients, but there was no difference in all-cause mortality. Moreover, FHCM was an independent prognostic predictor for cardiovascular mortality/cardiac transplantation in HCM patients.

The study follows the Coase theorem to solve the externality dilemma. By taking China's carbon compensation practice as a research case, this paper aims to provide evidence on pushing forward carbon compensation among regions. From the perspective of carbon neutrality, this paper takes China's regional net carbon source, which is the carbon source that differs from the carbon sink, as the environmental background value. This study modifies each China's environmental background value twice by considering each region's carbon resources endowment and the national carbon neutrality goal. With the method of principal component analysis and carbon compensation priority theory, this study builds each region's carbon compensation coefficient, recognizes the major compensation-related regions in priority, and reports the carbon compensation dollar values for each region. The main contribution of this paper is the theoretical model constructed by considering the theory of sustainable economic development with regional equality and a case study. This case study prioritizes carbon compensation order, which complements the existing literature that presents the amount of carbon compensation.

Abstract This study aimed to investigate the relationship between weight change patterns across adulthood and the risk of incident asthma later in life using data from the National Health and Nutrition Examination Survey (NHANES) 2001–2018. In this retrospective cohort study, asthma was defined by self-report questionnaires, and age at diagnosis was used to estimate the time of asthma onset. Based on BMI at 25 years old (young adulthood) and BMI at 10 years before the survey (middle adulthood), patterns of weight change were divided into five categories including stable normal, non-obese to obese, obese to non-obese, maximum overweight and stable obese. A total of 27,359 participants (female 13,582, 49.6%) were enrolled in this study and during a mean follow-up of 9.8 years, 1035 subjects occurred asthma. After adjusting for age, gender, race, education, family income and smoking status, participants changing from non-obese to obese, stable obese had significantly higher risks of incident asthma than those with normal weight during adulthood (HR1.70, 95% CI 1.35–2.15, P

Dissolved organic matter (DOM) plays a major role in ecological systems, affecting the fate and transportation of iron (Fe) and phosphorus (P). To better understand the geochemical cycling of these components, soil and sediment samples were collected around a reservoir downstream of a typical temperate forest in Northeast China. The DOM fractions from these soils, river, and reservoir sediments were extracted and then characterized by spectroscopic techniques. Comparative characterization data showed that the DOM pool of the Xishan Reservoir was partly autochthonous and derived from runoff and deposition of material in terrestrial ecosystems upstream. The upper reaches of the reservoir had significantly lower total Fe (TFe) content in the DOM extracts than those found in the reservoir (p

Inflammation induced by nonspecific pathogenic or endogenous danger signals is an essential mechanism of innate immune response. The innate immune responses are rapidly triggered by conserved germline-encoded receptors that recognize broad patterns indicative of danger, with subsequent signal amplification by modular effectors, which have been the subject of intense investigation for many years. Until recently, however, the critical role of intrinsic disorder-driven phase separation in facilitating innate immune responses went largely unappreciated. In this review, we discuss emerging evidences that many innate immune receptors, effectors, and/or interactors function as “all-or-nothing” switch-like hubs to stimulate acute and chronic inflammation. By concentrating or relegating modular signaling components to phase-separated compartments, cells construct flexible and spatiotemporal distributions of key signaling events to ensure rapid and effective immune responses to a myriad of potentially harmful stimuli.

The absence of IFN-γ receptor (IFN-γR) or STAT1 signaling in donor cells has been shown to result in reduced induction of acute graft-versus-host disease (GVHD). In this study, we unexpectedly observed increased activation and expansion of donor lymphocytes in both lymphohematopoietic organs and GVHD target tissues of IFN-γR/STAT1–deficient recipient mice, leading to rapid mortality following the induction of GVHD. LPS-matured, BM-derived Ifngr1–/– Stat1–/– DCs (BMDCs) were more potent allogeneic stimulators and expressed increased levels of MHC II and costimulatory molecules. Similar effects were observed in human antigen-presenting cells (APCs) with knockdown of Stat1 by CRISPR/Cas9 and treatment with a JAK1/2 inhibitor. Furthermore, we demonstrated that the absence of IFN-γR/STAT1 signaling in hematopoietic APCs impaired the presentation of exogenous antigens, while promoting the presentation of endogenous antigens. Thus, the indirect presentation of host antigens to donor lymphocytes was defective in IFN-γR/STAT1–deficient, donor-derived APCs in fully donor chimeric mice. The differential effects of IFN-γR/STAT1 signaling on endogenous and exogenous antigen presentation could provide further insight into the roles of the IFN-γ/STAT1 signaling pathway in the pathogenesis of GVHD, organ rejection, and autoimmune diseases.

Background: Hypertrophic obstructive cardiomyopathy (HOCM) patients are reported to have a potential risk of sudden cardiac death (SCD); however, HCM with left ventricular outflow tract (LVOT) obstruction, which is regarded as a risk indicator of SCD, is doubtful since the LVOT gradient is dynamic and may be confounded by various environmental factors and routine activities. The purpose of this study was to explore the clinical prognosis of HOCM through a multicenter cohort study with data-driven propensity score matching (PSM) analysis. Methods: The cohort included 2268 patients with HCM from 1996 to 2021 in 13 tertiary hospitals. In the present study, we excluded 458 patients who underwent alcohol septal ablation (ASA) and septal myectomy (SM) surgery so 1810 HCM patients were eventually included. We developed a data-driven propensity score using 24 demographic and clinical variables to create 1:1 propensity-matched cohorts. A Cox proportional hazard regression model was constructed to assess the effect of HOCM on mortality. Results: After logit-matching, there were no significant differences in all-cause mortality (log-rank χ2 = 1.509, p = 0.22), cardiovascular mortality/cardiac transplantation (log-rank χ2 = 0.020, p = 0.89) or SCD (log-rank χ2 = 0.503, p = 0.48) between patients with HOCM and hypertrophic nonobstructive cardiomyopathy (HNCM), and according to the Cox proportional hazard regression model, LVOT obstruction was not a risk predictor in patients with HCM. Conclusions: In both matched and unmatched cohorts, there were no significant differences in clinical prognosis between HOCM and HNCM patients, and LVOT obstruction was not an independent risk predictor of prognosis in patients with HCM. Clinical Trial Registration: ChiCTR1800017330.

Peroral endoscopic myotomy (POEM) has been shown to be an effective treatment for achalasia and with few adverse events. Only a few cases of delayed bleeding have been described. This current case report describes a patient with delayed bleeding in the submucosal tunnel on the eighth day after POEM. The patient was a 21-year-old woman with a 4-month history of dysphagia, vomiting and excessive weight loss. Achalasia was diagnosed according to her symptoms, barium oesophagogram, oesophageal manometry and endoscopy examination. POEM was performed by an experienced operator. On the eighth day after POEM, the patient suddenly developed continuous haematemesis presented with vomiting of fresh blood and melena. An emergency exploratory esophagogastroduodenoscopy was performed. A large number of blood clots were found at the wound and a long haematoma was found along the lining of the submucosal tunnel. Re-entry into the submucosal tunnel and exposure of the haemorrhagic site was attempted but failed because of severe submucosal tissue adhesion. An emergency angiography was undertaken and haemostasis was achieved with superselective arterial microcoil embolization.

BackgroundLiver-type fatty acid-binding protein (FABP1) contributes to metabolic disorders. However, the relationship between FABP1 and hyperuricemia remains unknown. We aimed to evaluate the correlation between serum FABP1 and hyperuricemia in patients with obesity before and after laparoscopic sleeve gastrectomy (LSG).MethodsWe enrolled 105 patients (47 men and 58 women) with obesity who underwent LSG. They were divided into two groups: normal levels of uric acid (UA) (NUA, n = 44) and high levels of UA (HUA, n = 61) with matching sexes. FABP1 levels and other biochemical parameters were measured at baseline and 3, 6, and 12 months after LSG.ResultsSerum FABP1 levels were significantly higher in the HUA group than in the NUA group (34.76 ± 22.69 ng/mL vs. 25.21 ± 21.68 ng/mL, P=0.024). FABP1 was positively correlated with UA (r=0.390, P=0.002) in the HUA group. The correlation still existed after adjusting for confounding factors. Preoperative FABP1 levels were risk factors for hyperuricemia at baseline. UA and FABP1 levels decreased at 3, 6, and 12 months postoperatively. FABP1 showed a more significant decrease in the HUA group than in the NUA group at 12 months (27.06 ± 10.98 ng/mL vs. 9.54 ± 6.52 ng/mL, P=0.003). Additionally, the change in FABP1 levels positively correlated with changes in UA levels in the HUA group 12 months postoperatively (r=0.512, P=0.011).ConclusionsFABP1 was positively associated with UA and may be a risk factor for hyperuricemia in obesity. FABP1 levels were higher but decreased more after LSG in obese patients with hyperuricemia than in those without hyperuricemia.

Reservoirs have an important impact on riverine material migration and transformation. Taking a drinking water reservoir located in the cold-temperature forest in the Xiaoxing’an mountains as an example, we comprehensively analyzed the fractions and interrelationships of phosphorus (P) and iron (Fe) from soils to riverine and reservoir sediments and discussed the coordinated migration and transformation process of regional P and Fe and the effects of dam interception. The results showed that iron-bound P (Fe-P) and aluminum-bound P (Al-P) were significantly correlated with adsorbed Fe(II), carbonate-bound Fe (Fecarb), low-activity silicate-bound Fe (Feprs), and total contents of Fe (TFe), which indicated that the geochemical cycling of these P fractions and Fe fractions is likely closely related and active in the soils and sediments. Calcium-bound P (Ca-P) was significantly correlated with magnate (Femag) and Feprs, which may be due to the correlation between their background values in this area. The contents of active P including loosely sorbed P (L-P), Al-P, and Fe-P in the reservoir’s sediments were significantly higher than those in the upstream soils and sediments (p < 0.05). However, Ca-P and residual P (Res-P) in soil and sediment samples showed no significant difference between the reservoir and its upstream (p = 0.309 > 0.05 and p = 0.748 > 0.05, respectively). Construction of reservoirs has played a certain role in intercepting P, especially bioavailable P, transferred from upstream soils and riverine sediments. The contents of highly active Fe fractions including easily reducible (amorphous) Fe oxide (Feox1), reducible (crystalline) Fe oxide (Feox2) and Fecarb (p < 0.01), and other Fe fractions (p < 0.05) in the sediments of the reservoir were significantly higher than those in the soil or sediment samples from upstream. This indicated that all Fe fractions migrated in the river were affected by the dam interception. The effects of dam interception would affect the bioavailability of P and Fe and enhance the cycling of nutrients in the region. Finally, this also effects the bioavailability and cycling of P and Fe in the downstream rivers and even the oceans.

Abstract. Objective:. Emetine, an isoquinoline alkaloid that is enriched at high concentrations in the lung, has shown potent in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The aim of this study was to better understand the effectiveness of low-dose emetine for patients with coronavirus disease 2019 (COVID-19). Methods:. In this real-world study, 63 patients with mild or common COVID-19 were recruited from Wuhan Fangcang Shelter Hospital and five COVID-19-designated hospitals in Anhui Province, China from February to March 2020. Thirty-nine patients from Wuhan Fangcang Shelter Hospital were assigned to a pragmatic randomized controlled clinical trial, and 24 patients from the 5 COVID-19-designated hospitals in Anhui Province underwent a real-world study. The medication course of emetine was less than 10 days. The main symptoms and adverse reactions of all patients were observed and recorded. The primary outcome measure was the time required for a negative SARS-CoV-2 RNA result or the negative result rate on day 10. Secondary outcomes included axillary temperature, transcutaneous oxygen saturation, and respiratory frequency recovery. The study was approved by the Ethics Committee of The First Affiliated Hospital of Anhui Medical University on February 20, 2019 (approval No. PJ2020-03-19) and was registered with the Chinese Clinical Trial Registry on February 20, 2019 (registration number: ChiCTR2000030022). Results:. The oxygen saturation values were higher in the treatment group than in the control group on the first day after enrollment for patients treated at Fangcang Shelter Hospital. The axillary body temperature, respiratory rate, and oxygen saturation among patients in Fangcang Shelter Hospital were related to the time effect but not to the intervention measures. The respiratory rate and oxygen saturation of patients in the Anhui designated hospitals were related to the intervention measures but not to the time effect. The axillary body temperature of patients in Anhui designated hospitals was related to the time effect but not to the intervention measures. Conclusion:. Our preliminary study shows that low-dose emetine combined with basic conventional antiviral drugs improves clinical symptoms in patients with mild and common COVID-19 without apparent adverse effects, suggesting that moderately increased doses of emetine may have good potential for treatment and prevention of COVID-19.

Although the protective effects of naringenin (Nar) on vascular smooth muscle cells (VSMCs) have been confirmed, whether it has anti-proliferation and anti-migration effects in high-glucose-induced VSMCs has remained unclear. This study aimed to clarify the potential targets and molecular mechanism of Nar when used to treat high-glucose-induced vasculopathy based on transcriptomics, network pharmacology, molecular docking, and in vivo and in vitro assays. We found that Nar has visible anti-proliferation and anti-migration effects both in vitro (high-glucose-induced VSMC proliferation and migration model) and in vivo (type 1 diabetes mouse model). Based on the results of network pharmacology and molecular docking, vascular endothelial growth factor A (VEGFA), the proto-oncogene tyrosine-protein kinase Src (Src) and the kinase insert domain receptor (KDR) are the core targets of Nar when used to treat diabetic angiopathies, according to the degree value and the docking score of the three core genes. Interestingly, not only the Biological Process (BP), Molecular Function (MF), and KEGG enrichment results from network pharmacology analysis but also transcriptomics showed that phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) is the most likely downstream pathway involved in the protective effects of Nar on VSMCs. Notably, according to the differentially expressed genes (DEGs) in the transcriptomic analysis, we found that cAMP-responsive element binding protein 5 (CREB5) is a downstream protein of the PI3K/Akt pathway that participates in VSMCs proliferation and migration. Furthermore, the results of molecular experiments in vitro were consistent with the bioinformatic analysis. Nar significantly inhibited the protein expression of the core targets (VEGFA, Src and KDR) and downregulated the PI3K/Akt/CREB5 pathway. Our results indicated that Nar exerted anti-proliferation and anti-migration effects on high-glucose-induced VSMCs through decreasing expression of the target protein VEGFA, and then downregulating the PI3K/Akt/CREB5 pathway, suggesting its potential for treating diabetic angiopathies.

This paper investigates the problem of mixed far-field (FF) and near-field (NF) source localization using a linear electromagnetic-vector-sensor array with gain/phase uncertainties. Firstly, several special fourth-order cumulant matrices are constructed, such that the shift invariance structure in the cumulant domain can be derived to estimate the DOA and polarization angles of each source at two electromagnetic vector sensors (EMVSs). Then, by computing the determinant of the coefficient matrix, the sources types can be classified with the prior knowledge of the number of both the FF and NF sources. On this basis, the range of NF sources and the DOAs of mixed sources at the phase reference point are captured subsequently. Finally, these estimates can be employed to generate the unknown gain/phase errors. Compared to the existing methods, the proposed one exploits both the spatial and polarization information of sources and provides a satisfactory parameters estimation performance under unknown phase/gain responses. Moreover, it does not need to perform any spectral search and not impose restriction on EMVSs placement, as well as realizes a more reasonable classification of the signal types. Simulations are carried out to verify the effectiveness of the proposed method.

The objective of present study was to investigate the effects of alpha-lipoic acid (ALA) dietary supplementation on the behavior, physiological and oxidant stress indicators, and bone quality in broilers under high stocking density (HSD) stress. A total of one thousand eight hundred 22-day-old Arbor Acres male broiler chicks were randomly allocated to 18 pens (2.97 × 2.03 m) in 3 groups: 14 birds/m2 (NSD, normal stocking density) or 18 birds/m2 (HSD) or 18 birds/m2 plus 300 mg/kg ALA dietary supplement (HSD + ALA, high stocking density + alpha-lipoic acid). Each treatment had 6 replicates, and the experiment lasted 3 wk. The HSD group was significantly lower than the NSD group (P 0.05) in the standing and preening behavior, alkaline phosphatase activity, PTH concentration, H/L ratio, CAT, T-AOC, MDA, SOD, and GSH-Px. These results indicate that the increase of stocking density lowered the bone quality, increased the physiological and oxidative stress indicators, and modified the behavior of broilers, whereas ALA dietary supplementation could counteract the reduction in the performance and physiological responses of broilers under high-density environmental stress.

Glioblastoma multiforme (GBM) almost invariably acquires an invasive phenotype, resulting in limited therapeutic options. Protein palmitoylation markedly affects tumorigenesis and malignant progression in GBM. The role of protein palmitoylation in GBM, however, has not been systematically reported. This study aimed to investigate the effect of protein palmitoylation on GBM cell survival and the cell cycle. In this study, most palmitoyltransferases were upregulated in GBM and its cell lines, and protein palmitoylation participated in signaling pathways controlling cell survival and the GBM cell cycle. Inhibition of protein palmitoylation with substrate-analog inhibitors, that is, 2-bromopalmitate, cerulenin, and tunicamycin, induced G2 cell cycle arrest and cell death in GBM cells through enhanced endoplasmic reticulum (ER) stress. These effects are primarily attributed to the palmitoylation inhibitors activating pro-apoptotic pathways and ER stress signals. Further analysis revealed was the accumulation of SUMOylated XBP1 (X-box binding protein 1) and its transcriptional repression, along with a reduction in XBP1 palmitoylation. Taken together, the present results indicate that protein palmitoylation plays an important role in the survival of GBM cells, further providing a potential therapeutic strategy for GBM.

BackgroundMetabolic dysfunction associated fatty liver disease (MAFLD) is the most common hepatopathy worldwide due to the obesity epidemic and is associated with chronic low-grade inflammation. High-sensitive C-reactive protein (hsCRP) as an inflammatory marker has been used in diagnosing MAFLD. However, the association between hsCRP and the severity of liver steatosis and fibrosis among obese patients with MAFLD remains to be elucidated.ObjectiveTo explore the correlation of hsCRP with the severity of liver steatosis and fibrosis among Chinese obese patients with MAFLD.MethodsA total of 393 obese patients with mean BMI 34.8 ± 6.6 kg/m2 were selected and categorized as MAFLD and non-MAFLD groups. Anthropometric data, biochemical indices, and hsCRP were measured. The severity of hepatic steatosis and fibrosis was assessed using FibroScan. Multivariate logistic regression analysis was performed to determine the relationship between hsCRP and the risk of MAFLD and its disease severity.ResultsPatients with MAFLD showed significantly elevated hsCRP levels and were more likely to have severe steatosis and fibrosis compared to those without MAFLD. The proportions of MAFLD, severe steatosis, and severe fibrosis were significantly increased across the hsCRP quartiles (P-trend = 0.004, 0.021, and 0.006, respectively). After multivariable adjustments, the adjusted ORs (AORs) and 95%CI for MAFLD were 1.00 (reference), 1.298 (0.587-2.872), 2.407 (1.002-5.781), and 2.637(1.073-6.482) (Q1-Q4, P-trend = 0.014). Likewise, the AORs (95%CI) for severe steatosis and severe fibrosis were remarkably increased with the increment of serum hsCRP quartiles (P-trend < 0.001, P-trend = 0.021, respectively).ConclusionsElevated serum hsCRP levels were associated with increased risk of MAFLD among Chinese obese patients and correlated positively with the severity of liver steatosis and fibrosis, suggesting that hsCRP can be used as a potential biomarker to monitor and predict disease severity among Chinese obese population with MAFLD.

PurposeFactors related to the occurrence of obstructive sleep apnea syndrome (OSAS) in obesity have not been fully clarified. The aim of this study was to identify the association between OSAS and abdominal fat distribution in a cohort of Chinese obese patients.MethodsThis cross-sectional study collected demographic data of 122 obese patients who were admitted into the in-patient unit of the Department of Endocrinology, Shanghai Tenth People’s Hospital from July 2018 to January 2021. OSAS was diagnosed based on the results of overnight polysomnography, and the abdominal fat distribution was measured by bioelectrical impedance analysis (BIA). Univariate and multivariate logistic regression analyses were used to investigate the association between OSAS and the distribution of abdominal fat.Results(1) The mean age (SD) of the obese patients included was 32.44 (11.81) years old, and the overall incidence rate of OSAS was 51.06%. Twenty-four (25.53%) patients had mild OSAS, 10 (10.64%) had moderate OSAS, and 14 (14.89%) had severe OSAS. The apnea hypopnea index (AHI) of men was significantly higher than that of women (5.50, interquartile range (IQR) 3.80–30.6 vs. 4.2, IQR 1.4–12 events/h, p = 0.014). Meanwhile, men had a significantly higher visceral fat area when compared with women (180.29 ± 51.64 vs. 143.88 ± 53.42 cm2, p = 0.002). (2) Patients with OSAS had a significantly higher waist circumference, fasting plasma glucose, 2 h postprandial plasma glucose, glycated hemoglobin, and visceral fat area than patients without OSAS (all p

BackgroundMetabolic-associated fatty liver disease (MAFLD) has become a worldwide epidemic. Prolactin (PRL), a pituitary hormone, has been linked to MAFLD. As a result, we set out to look into the relationship between serum PRL and the risk of MAFLD in patients with type 2 diabetes mellitus (T2DM).MethodsA total of 724 adults with T2DM were enrolled and categorized as MAFLD and non-MAFLD groups. Anthropometric data, biochemical parameters, and serum PRL levels were collected. Liver steatosis and fibrosis were assessed using FibroScan. Patients were stratified into normal PRL (NP) and high PRL (HP) groups and divided into four groups based on serum PRL quartiles. Multivariate logistic regression analysis was performed to evaluate the association between serum PRL and MAFLD risk.ResultsFemale but not male patients with MAFLD, liver steatosis, and fibrosis had significantly lower PRL levels in the NP group but higher PRL levels in the HP group than their counterparts. The proportions of MAFLD, liver steatosis, and fibrosis were significantly decreased in the NP group but increased in the HP group across the PRL quartiles in females but not in males. After multivariate adjustment, the adjusted ORs (AORs) and 95% CI for MAFLD among females were 18.165 (3.425–96.336), 1.784 (0.658–5.002), 1.744 (0.608–4.832), and 1.00 (reference) in the NP group (Q1–Q4, P-trend < 0.001) and 1.00 (reference), 11.098 (1.819–110.356), 15.225 (1.996–116.112), and 18.211 (2.579–128.568) in the HP group (Q1–Q4, P-trend = 0.020). Such associations were also found between serum PRL and liver fibrosis in females but not in males.ConclusionWe observed a J-shaped association between serum PRL and the risk of MAFLD and liver fibrosis in females but not in males with T2DM, indicating that PRL may be relevant to MAFLD and its progression in a gender-specific manner.Clinical Trial RegistrationChinese Clinical Trial Registry, number ChiCTR-OCS-12002381.

This study was conducted to evaluate the effects of Clostridium butyricum dietary supplementation on the growth, antioxidant, immune response, gut microbiota, and intestinal barrier function of broilers under high stocking density (HSD) stress. A total of 324 1-day-old Arbor Acres male broilers were randomly assigned to three treatments with six replicates, each replicate including 18 chickens (18 birds/m2). The experiment lasted 6 weeks. The three treatments were basal diet (control, CON), basal diet supplemented with 1 × 109 colony forming units (cfu)/kg C. butyricum (CB), and basal diet supplemented with 10 mg/kg virginiamycin (antibiotic, ANT). The results showed that the body weight (BW) and average daily gain (ADG) of broilers in the CB group were significantly higher than those in the CON group in three periods (p < 0.05). The total antioxidant capacity (T-AOC) and the superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity in serum of the CB group were significantly increased compared with those in the CON and ANT groups at 42 days (p < 0.05). At 42 days, the serum immunoglobulin M (IgM) and immunoglobulin G (IgG) levels of the CB group were significantly higher than those of the CON group. Compared with the CON group, interleukin-1β (IL-1β) in the CB group was significantly decreased in the starter and grower stages (p < 0.05), but there was no significant difference between the two treatment groups (p > 0.05). C. butyricum significantly decreased the high stocking density-induced expression levels of IL-1β and tumor necrosis factor-α (TNF-α) in the ileum of broilers at different stages. Additionally, C. butyricum could increase the expressions of claudin-1 and zonula occludens-1 (ZO-1) in intestinal tissue. Moreover, C. butyricum significantly increased the Sobs and Shannon indices in the CB group compared with the ANT group (p < 0.05), while the Ace index in the CB group was significantly higher than that of the CON group (p < 0.05). Furthermore, by using 16S rRNA gene sequencing, the proportion of Bacteroides in the CB group was increased compared to those in the CON and ANT groups at the genus level. In conclusion, C. butyricum supplemented into feed could improve the growth performance and feed utilization of broilers by promoting immune and intestinal barrier function and benefiting the cecal microflora.

Abstract Background Agropyron cristatum (L.) Gaertn. (2n = 4x = 28; genomes PPPP) is a wild relative of common wheat (Triticum aestivum L.) and provides many desirable genetic resources for wheat improvement. However, there is still a lack of reference genome and transcriptome information for A. cristatum, which severely impedes functional and molecular breeding studies. Results Single-molecule long-read sequencing technology from Pacific Biosciences (PacBio) was used to sequence full-length cDNA from a mixture of leaves, roots, stems and caryopses and constructed the first full-length transcriptome dataset of A. cristatum, which comprised 44,372 transcripts. As expected, the PacBio transcripts were generally longer and more complete than the transcripts assembled via the Illumina sequencing platform in previous studies. By analyzing RNA-Seq data, we identified tissue-enriched transcripts and assessed their GO term enrichment; the results indicated that tissue-enriched transcripts were enriched for particular molecular functions that varied by tissue. We identified 3398 novel and 1352 A. cristatum-specific transcripts compared with the wheat gene model set. To better apply this A. cristatum transcriptome, the A. cristatum transcripts were integrated with the wheat genome as a reference sequence to try to identify candidate A. cristatum transcripts associated with thousand-grain weight in a wheat-A. cristatum translocation line, Pubing 3035. Conclusions Full-length transcriptome sequences were used in our study. The present study not only provides comprehensive transcriptomic insights and information for A. cristatum but also proposes a new method for exploring the functional genes of wheat relatives under a wheat genetic background. The sequence data have been deposited in the NCBI under BioProject accession number PRJNA534411.

Objective The study was conducted to evaluate the effect of stocking density and alpha-lipoic acid (ALA) on the growth performance, feed utilization, carcass traits, antioxidative ability and immune response of broilers. Methods A total of 1,530 22-day-old male broilers (Arbor Acres) with comparable body weights (731.92±5.26) were placed into 18 cages (2.46×2.02 m) in groups of 75 birds (15 birds/m2, 37.5 kg/m2; low stocking density [LD]), 90 birds (18 birds/m2, 45.0 kg/m2; high stocking density [HD]) and 90 birds with 300 mg/kg ALA added to the basal diet (18 birds/m2, 45.0 kg/m2; HD+ALA, high stocking density+α-lipoic acid); each treatment was represented by 6 replicates. The experimental period was 3 weeks. Results The results showed that the high stocking density regimen resulted in a decreased growth, feed conversion ratio, carcass weight, thigh yield and bursa weight relative to body weight (p

Abstract Background Schistosomiasis is a debilitating neglected tropical disease that affects approximately 190 million people around the world. Praziquantel (PZQ) is the only drug available for use against all Schistosoma species. Although PZQ has a high efficacy, recognized concerns have prompted the development of new, alternative drugs for repeated use in endemic areas where PZQ efficacy against strains of Schistosoma is reduced. A hybrid drug containing different pharmacophores within a single molecule is a promising strategy. Our earlier in vivo studies showed the significant antiparasitic activity of a praziquantel derivative, DW-3-15, against Schistosoma japonicum. In the present study, DW-3-15 was synthesized in large amounts by a pharmaceutical company and its schistosomicidal efficacy and stability were further confirmed. Parameters such as parasite viability, pairing and oviposition were evaluated in vitro. An in vivo study was conducted to assess the effect of commercial DW-3-15 on worm burden, egg production and diameter of granulomas. Additionally, to gain insight into the mechanism of action for DW-3-15, morphological changes in the tegument of S. japonicum were also examined. Results The in vitro study showed the antiparasitic activity of DW-3-15 against S. japonicum, with significant reductions in viability of adult and juvenile worms, worm pairings and egg output. Compared to PZQ, DW-3-15 induced similar ultrastructural changes and evident destruction of the tegument surface in male worms. In vivo, the oral administration of DW-3-15 at a dose of 400 mg/kg per day for five consecutive days in mice significantly reduced the total worm burden and number of eggs in the liver. Histological analysis of the livers showed a marked reduction in the average diameter of the egg granuloma. Conclusions Our findings suggest that DW-3-15, a PZQ derivative with the prospect of commercial production, can be developed as a potential promising schistosomicide.

As an important wild relative of wheat, Agropyron cristatum has been successfully used for wheat improvement. Currently, a few useful agronomic traits of A. cristatum, such as high grain number per spike and resistance to diseases, have been transferred into common wheat. However, the effective detection of small A. cristatum segmental introgressions in common wheat is still difficult. The objective of this study was to identify A. cristatum-specific single nucleotide polymorphisms (SNPs) for the detection of small alien segments in wheat. The transcriptome sequences of A. cristatum were aligned against wheat coding DNA sequences (CDS) for SNP calling. As a result, we discovered a total of 167,613 putative SNPs specific to the P genome of A. cristatum compared with the common wheat genomes. Among 230 selected SNPs with functional annotations related to inflorescence development and stress resistance, 68 were validated as P genome-specific SNPs in multiple wheat backgrounds using Kompetitive Allele Specific PCR (KASP) assays. Among them, 55 SNPs were assigned to six homoeologous groups of the P genome using wheat-A. cristatum addition lines, and 6P-specific SNP markers were further physically mapped on different segments of chromosome 6P in 6P translocation lines. The P genome-specific SNPs were also validated by Sanger sequencing and used to detect the P chromatin in wheat-A. cristatum cryptic introgression lines. Two SNP markers (Unigene20217-182 and Unigene20307-1420) were detected in two wheat-A. cristatum introgression lines that showed enhanced grain number per spike and high resistance to powdery mildew. Together, the developed P genome-specific SNP markers will accelerate the detection of large numbers of wheat-A. cristatum derivatives and will be helpful for marker-assisted transfer of desirable traits from A. cristatum into adapted wheat cultivars in wheat breeding programs. Keywords: KASP marker, Single nucleotide polymorphism, Agropyron cristatum, Triticum aestivum

A 32-year-old female with systemic lupus erythematosus (SLE) for more than 7 years, and long-term treatment with cyclophosphamide, cyclosporine, methotrexate, and tacrolimus, later found to be combined with hypertrophic cardiomyopathy (HCM) for one year. The patient denied a family history of cardiomyopathy and sudden cardiac death (SCD). Echocardiography suggested that uneven thickening of the left ventricle (LV), mainly in the lower middle segment. Cardiac magnetic resonance (CMR) showed that the walls of the left ventricular (LV) were significantly thickened, as about 21 mm, mainly in the middle and lower segments. Genetic tests showed no known or suspected pathogenic variations were found and no significant enhancement in CMR, so secondary HCM was diagnosed clinically. After symptomatic treatment, the patient was discharged, and long-term follow-up was conducted. The diagnosis of HCM, which combined with SLE or second to usage of tacrolimus, was based on symptoms, echocardiography, and CMR; no endomyocardial biopsies were performed.

Abstract Background Glioblastomas (GBM) comprise different subsets that exhibit marked heterogeneity and plasticity, leading to a lack of success of genomic profiling in guiding the development of precision medicine approaches against these tumors. Accordingly, there is an urgent need to investigate the regulatory mechanisms for different GBM subsets and identify novel biomarkers and therapeutic targets relevant in the context of GBM-specific niches. The DHHC family of proteins is associated tightly with the malignant development and progression of gliomas. However, the role of these proteins in the plasticity of GBM subsets remains unclear. Methods This study utilized human glioma proneural or mesenchymal stem cells as indicated. The effects of DHHC proteins on different GBM subsets were investigated through in vitro and in vivo assays (i.e., colony formation assay, flow cytometry assay, double immunofluorescence, western blot, and xenograft model). Western blot, co-immunoprecipitation, and liquid chromatograph mass spectrometer-mass spectrometry assays were used to detect the protein complexes of ZDHHC18 and ZDHHC23 in various GBM subtypes, and explore the mechanism of DHHC proteins in targeting different subsets of GSCs in specific niches. Results ZDHHC18 and ZDHHC23 could target the glioma stem cells of different GBM subsets in the context of their specific niches and regulate the cellular plasticity of these subtypes. Moreover, mechanistic investigations revealed that ZDHHC18 and ZDHHC23 competitively interact with a BMI1 E3 ligase, RNF144A, to regulate the polyubiquitination and accumulation of BMI1. These events contributed to the transition of glioma stem cells in GBM and cell survival under the stressful tumor microenvironment. Conclusions Our work highlights the role of DHHC proteins in the plasticity of GBM subsets and reveals that BMI1 represents a potential therapeutic target for human gliomas.

Abstract Background Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world and metastasis is the leading cause of death associated with HCC. Hypoxia triggers the epithelial-mesenchymal transition (EMT) of cancer cells, which enhances their malignant character and elevates metastatic risk. Supervillin associates tightly with the membrane and cytoskeleton, promoting cell motility, invasiveness, and cell survival. However, the roles of supervillin in HCC metastasis remain unclear. Methods Tissue microarray technology was used to immunohistochemically stain for supervillin antibody in 173 HCC tissue specimens and expression levels correlated with the clinicopathological variables. Tumor cell motility and invasiveness, as well as changes in the mRNA expression levels of genes associated with cancer cell EMT, were investigated. The relationship between supervillin and Rho GTPases was examined using Co-IP and GST pull-down. Results Hypoxia-induced upregulation of supervillin promoted cancer cell migration and invasion via the activation of the ERK/p38 pathway downstream of RhoA/ROCK signaling. Furthermore, supervillin regulated the expression of EMT genes during hypoxia and accelerated the metastasis of HCC in vivo. Conclusions Hypoxia-induced increase in supervillin expression is a significant and independent predictor of cancer metastasis, which leads to poor survival in HCC patients. Our results suggest that supervillin may be a candidate prognostic factor for HCC and a valuable target for therapy.

Abstract: We have previously shown that immunomodulatory drug (IMiD) compounds induce a shift into immature myeloid precursors with a maturational arrest and subsequent neutropenia. The mechanism of action is unknown. Here we found that IMiD compounds cause selective ubiquitination and degradation of the transcription factor IKZF1 in CD34+ cells by the Cereblon (CRBN) E3 ubiquitin ligase. Loss of IKZF1 is associated with a decrease of the IKZF1-dependent transcription factor PU.1, critical for the development and maturation of neutrophils. Using a thalidomide analog bead pull-down assay, we showed that IMiD compounds directly bind CRBN in CD34+ cells. Knockdown of CRBN in CD34+ cells resulted in resistance to POM-induced IKZF1 downregulation and reversed the POM-induced lineage shift in colony-formation assays, suggesting that the POM-induced degradation of IKZF1 in CD34+ cells requires CRBN. Chromatin immunoprecipitation assays revealed that IKZF1 binds to the promoter region of PU.1, suggesting that PU.1 is a direct downstream target of IKZF1 in CD34+ cells. POM failed to induce IKZF1 degradation in IKZF1-Q146H-OE CD34+ cells, indicating that CRBN binding to IKZF1 and subsequent IKZF1 ubiquitination is critical in this process. Using the NOD/SCID/γ-c KO mouse model, we confirmed the induction of myeloid progenitor cells by IMiD compounds at the expense of common lymphoid progenitors. These results demonstrate a novel mechanism of action of IMiD compounds in hematopoietic progenitor cells, leading to selective degradation of transcription factors critical for myeloid maturation, and explain the occurrence of neutropenia associated with treatment by IMiD compounds.

Background/Aim: We studied the expression of interleukin-17 and interleukin-22 in the serum and the lower esophageal sphincter (LES) in healthy individuals and in patients diagnosed with achalasia (AC) to gain a better understanding of the etiopathogenesis of AC. Patients and Methods: Our study comprised 14 randomly selected patients with AC who underwent peroral endoscopic myotomy and 14 randomly selected healthy individuals who served as controls. Venous blood samples were evaluated in all study subjects to detect the expression of interleukin-17 and interleukin-22 in the serum using an enzyme-linked immunosorbent assay. Immunohistochemistry studies were performed to evaluate LES myofilaments obtained from both groups, as well as from 12 patients diagnosed with a subendothelial non-invasive tumor and who had undergone submucosal tunneling endoscopic resection, to assess the expression of interleukin-17 and interleukin-22 in LES myofilaments. Results: Compared with that in the control group, the expression of interleukin-17 and interleukin-22 in the serum and LES, in patients with AC, was significantly increased and was positively correlated. Conclusion: Interleukin-17 and interleukin-22 are upregulated in the serum and LES in patients with AC, suggesting that both interleukin-17 and interleukin-22 are involved in the pathogenesis of AC, and that AC may be an immune-mediated inflammatory disease.

Abstract Background Th1, Th2, Th17, Treg and Tfh cells play important roles in schistosomiasis. Th9 cells secrete IL-9 as a signature cytokine and contribute to several classes of inflammatory disease. However, the effects of Th9 cells in schistosomiasis are unknown. We aimed to explore the dynamic changes and potential roles of Th9 cells in the pathogenesis of hepatic egg granulomatous inflammation in mice infected with Schistosoma japonicum. Methods Twenty mice with S. japonicum infection and five normal controls (NC) were used as models. The average areas of egg granulomas were estimated by hematoxylin-eosin (H & E) staining. Hepatic IL-9 and transcription factor PU.1 levels were detected by immunohistochemistry. Flow cytometry techniques were used to analyze the proportions of Th9 cells. With the help of ELISA, serum levels of IL-9 were examined. Results The egg granulomas began to form from four weeks after infection and continued to develop. In parallel with the development of egg granulomas, the hepatic levels of IL-9 and PU.1 increased very slowly during the first four weeks post-infection and increased rapidly thereafter. Moreover, the proportions of splenic Th9 cells and levels of serum IL-9 had similar developmental trends with the egg granulomas. Conclusion The proliferation of Th9 cells and levels of IL-9 were significantly higher in S. japonicum-infected mice compared to NC. In addition, dynamic changes of Th9 and IL-9 were synchronous with the developmental trend of hepatic egg granulomatous inflammation, suggesting that Th9 cells might be a new subset in the pathogenesis of schistosomiasis.

The immunomodulatory drugs, lenalidomide and pomalidomide yield high response rates in multiple myeloma patients, but are associated with a high rate of thrombocytopenia and increased risk of secondary hematologic malignancies. Here, we demonstrate that the immunomodulatory drugs induce self-renewal of hematopoietic progenitors and upregulate megakaryocytic colonies by inhibiting apoptosis and increasing proliferation of early megakaryocytic progenitors via down-regulation of IKZF1. In this process, the immunomodulatory drugs degrade IKZF1 and subsequently down-regulate its binding partner, GATA1. This results in the decrease of GATA1 targets such as ZFPM1 and NFE2, leading to expansion of megakaryocytic progenitors with concomitant inhibition of maturation of megakaryocytes. The down-regulation of GATA1 further decreases CCND1 and increases CDKN2A expression. Overexpression of GATA1 abrogated the effects of the immunomodulatory drugs and restored maturation of megakaryocytic progenitors. Our data not only provide the mechanism for the immunomodulatory drugs induced thrombocytopenia but also help to explain the higher risk of secondary malignancies and long-term cytopenia induced by enhanced cell cycling and subsequent exhaustion of the stem cell pool.

Agropyron cristatum, which is a wild grass of the tribe Triticeae, grows widely in harsh environments and provides many desirable genetic resources for wheat improvement. However, unclear interspecific phylogeny and genome-wide variation has limited the utilization of A. cristatum in the production of superior wheat varieties. In this study, by sequencing the transcriptome of the representative tetraploid A. cristatum Z559 and the common wheat variety Fukuhokomugi (Fukuho), which are often used as parents in a wide cross, their phylogenetic relationship and interspecific variation were dissected. First, 214,854 transcript sequences were assembled, and 3,457 orthologous genes related to traits of interest were identified in A. cristatum. Second, a total of 72 putative orthologous gene clusters were used to construct phylogenetic relationships among A. cristatum, Triticeae and other genomes. A clear division between A. cristatum and the other Triticeae species was revealed. Third, the sequence similarity of most genes related to traits of interest is greater than 95% between A. cristatum and wheat. Therefore, using the 5% mismatch parameter for A. cristatum, we mapped the transcriptome sequencing data to wheat reference sequences to discover the variations between A. cristatum and wheat and 862,340 high-quality variants were identified. Additionally, compared with the wheat A and B genomes, the P and D genomes displayed an obviously larger variant density and a longer evolutionary distance, suggesting that A. cristatum is more distantly related to the wheat D genome. Finally, by using Kompetitive Allele Specific PCR array (KASPar) technology, 37 of 53 (69.8%) SNPs were shown to be genuine in Z559, Fukuho, and additional lines with seven different P chromosomes, and function of the genes in which these SNPs are located were also determined. This study provides not only the first insights into the phylogenetic relationships between the P genome and Triticeae but also genetic resources for gene discovery and specific marker development in A. cristatum, and this information will be vital for future wheat-breeding efforts. The sequence data have been deposited in the Sequence Read Archive (SRA) database at the NCBI under accession number SRP090613.

Based on density functional theory calculations, systematic calculations of the structural properties, elastic anisotropy and mechanical properties of boron alloying aluminum phosphide (BxAl1-xP) ternary mixed crystal have been presented. The results of the lattice parameters, band gaps, elastic constants and elastic modulus accord with the experimental and others published data well. The band structure which is described by CASTEP method indicates they are direct gap semiconductors for the composition x = 0.25, 0.50 and 0.75. Beyond that, we studied the Debye temperatures together with the acoustic velocities for all the BxAl1-xP alloys using the obtained elastic modulus. Finally, we depicted the three dimensional surface constructions to explain the elastic anisotropy using several calculated different anisotropic indexes in our work.