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Abstract Aims Surveys and research on the applications of the hepatic venous pressure gradient (HVPG) are important for understanding the current status and future development of this technology in China. This article aimed to investigate the status of hepatic venous pressure gradient measurement in China in 2022. Methods We investigated the overall status of HVPG technology in China—including hospital distribution, hospital level, annual number of cases, catheters used, average cost, indications, and current challenges by using online questionnaire. By counting the number and percentages of cases of these results, we hope to clarify the current status of HVPG measurements in China. Results According to the survey, 85 hospitals in China used HVPG technology in 2022 distributed across 29 provinces. A total of 4989 HVPG measurements were performed in all of the surveyed hospitals in 2022, of which 2813 cases (56.4%) were measured alone. The average cost of HVPG measurement was 5646.8 ± 2327.9 CNY. Of the clinical teams who performed the measurements (sometimes multiple per hospital), 94.3% (82/87) used the balloon method, and the majority of the teams (72.4%, 63/87) used embolectomy catheters. Conclusions This survey clarified the clinical application status of HVPG in China and confirmed that some medical institutions in China have established a foundation for this technology. It is still necessary to continue promoting and popularizing this technology in the future.

Abstract Coffin-Siris syndrome (CSS) is a rare autosomal dominant inheritance disorder characterized by distinctive facial features, hypoplasia of the distal phalanx or nail of the fifth and additional digits, developmental or cognitive delay of varying degree, hypotonia, hirsutism/hypertrichosis, sparse scalp hair and varying kind of congenital anomalies. CSS can easily be misdiagnosed as other syndromes or disorders with a similar clinical picture because of their genetic and phenotypic heterogeneity. We describde the genotype-phenotype correlation of one patient from a healthy Chinese family with a novel genotype underlying CSS, who was first diagnosed in the ophthalmology department as early-onset high myopia (eoHM). Comprehensive ophthalmic tests as well as other systemic examinations were performed on participants to confirm the phenotype. The genotype was identified using whole exome sequencing, and further verified the results among other family members by Sanger sequencing. Real-time quantitative PCR (RT-qPCR) technology was used to detect the relative mRNA expression levels of candidate genes between proband and normal family members. The pathogenicity of the identified variant was determined by The American College of Medical Genetics and Genomics (ACMG) guidelines. STRING protein-protein interactions (PPIs) network analysis was used to detect the interaction of candidate gene-related proteins with high myopia gene-related proteins. The patient had excessive eoHM, cone-rod dystrophy, coarse face, excessive hair growth on the face, sparse scalp hair, developmental delay, intellectual disability, moderate hearing loss, dental hypoplasia, patent foramen ovale, chronic non-atrophic gastritis, bilateral renal cysts, cisterna magna, and emotional outbursts with aggression. The genetic assessment revealed that the patient carries a de novo heterozygous frameshift insertion variant in the ARID1B c.3981dup (p.Glu1328ArgfsTer5), which are strongly associated with the typical clinical features of CSS patients. The test results of RT-qPCR showed that mRNA expression of the ARID1B gene in the proband was approximately 30% lower than that of the normal control in the family, suggesting that the variant had an impact on the gene function at the level of mRNA expression. The variant was pathogenic as assessed by ACMG guidelines. Analysis of protein interactions in the STRING online database revealed that the ARID1A protein interacts with the high myopia gene-related proteins FGFR3, ASXL1, ERBB3, and SOX4, whereas the ARID1A protein antagonizes the ARID1B protein. Therefore, in this paper, we are the first to report a de novo heterozygous frameshift insertion variant in the ARID1B gene causing CSS with excessive eoHM. Our study extends the genotypic and phenotypic spectrums for ARID1B-CSS and supplies evidence of significant association of eoHM with variant in ARID1B gene. As CSS has high genetic and phenotypic heterogeneity, our findings highlight the importance of molecular genetic testing and an interdisciplinary clinical diagnostic workup to avoid misdiagnosis as some disorders with similar manifestations of CSS.

Abstract Minimal hepatic encephalopathy (MHE) has a substantial impact on the clinical outcomes and quality of life (QOL) of patients with cirrhosis. However, timely diagnosis and intervention are challenging due to sophisticated diagnostic methods. In this study, 673 healthy controls and 905 patients with cirrhosis were screened, and 660 healthy controls and 757 patients with cirrhosis, divided into the test (292 patients) and validation (465 patients) cohort, were analyzed after screening. A diagnostic model of the Stroop test (Stroop‐CN) was constructed by multivariate linear regression based on the results of healthy controls. The prevalence of MHE and the comparison results with psychometric hepatic encephalopathy score through the Stroop‐CN model were stable in the test and validation cohorts. Moreover, the prevalence of MHE remained significantly higher in patients with worse disease conditions marked as high Child–Pugh grades and the Model for End‐stage Liver Disease and Sodium (MELD‐Na) scores in the test and validation cohort. The EuroQol 5‐D questionnaire revealed that patients with MHE had a worse QOL than those without MHE both in the test and validation cohort. In conclusion, an easy and practical Stroop‐CN model for MHE diagnosis based on the EncephalApp is established. It is found that a considerable number of Chinese patients with cirrhosis experience MHE, which significantly impacts their QOL.

PurposeNanophthalmos is a congenital ocular structural anomaly that can cause significant visual loss in children. The early diagnosis and then taking appropriate clinical and surgical treatment remains a challenge for many ophthalmologists because of genetic and phenotypic heterogeneity. The objective of this study is to identify the genetic cause of nanophthalmos in the affected families and analyze the clinical phenotype of nanophthalmos with MFRP gene variation (Microphthalmia, isolated; OMIM#611040 and Nanophthalmos 2; OMIM#609549, respectively).MethodsComprehensive ophthalmic examinations were performed on participants to confirm the phenotype. The genotype was identified using whole exome sequencing, and further verified the results among other family members by Sanger sequencing. The normal protein structure was constructed using Alphafold. Mutant proteins were visualized using pymol software. Pathogenicity of identified variant was determined by in silico analysis and the guidelines of American College of Medical Genetics and Genomics (ACMG). The relationship between genetic variants and clinical features was analyzed.ResultsFive nanophthalmos families were autosomal recessive, of which four families carried homozygous variants and one family had compound heterozygous variants in the MFRP gene. Both family one and family three carried the homozygous missense variant c.1486G>A (p.Glu496Lys) in the MFRP gene (Clinvar:SCV005060845), which is a novel variant and evaluated as likely pathogenic according to the ACMG guidelines and in silico analysis. The proband of family one presented papilloedema in both eyes, irregular borders, thickened retinas at the posterior pole, tortuous and dilated retinal vessels, and indistinguishable arteries and veins, while the proband of family three presented uveal effusion syndrome-like changes in the right eye. In families one and 3, despite carrying the same gene variant, the probands had completely different clinical phenotypes. The homozygous nonsense variant c.271C>T (p.Gln91Ter) (Clinvar:SCV005060846) of the MFRP gene was detected in family 2, presenting shallow anterior chamber in both eyes, pigmentation of peripheral retina 360° from the equator to the serrated rim showing a clear demarcation from the normal retina in the form of strips. Family four proband carried the homozygous missense variant c.1411G>A (p.Val471Met) in the MFRP gene (Clinvar:SCV005060847), family five proband carried compound heterozygous missense variants c.1486G>A (p.Glu496Lys) and c.602G>T (p.Arg201Leu) in the MFRP gene (Clinvar:SCV005060848), which is a novel variant and evaluated as likely pathogenic according to the ACMG guidelines and in silico analysis, and they all presented clinically with binocular angle-closure glaucoma, family four also had retinal vein occlusion in the right eye during the follow-up.ConclusionIn this study, pathogenic variants of the MFRP gene were detected in five nanophthalmos families, including two novel variants. It also revealed a distinct phenotypic diversity among five probands harboring variants in the MFRP gene. Our findings extend the phenotype associated with MFRP variants and is helpful for ophthalmologists in early diagnosis and making effective treatment and rehabilitation strategies.

Introduction Patients with clinically significant portal hypertension (CSPH) are recommended to be treated with non-selective beta-blockers (ie, carvedilol) to prevent the first hepatic decompensation event by the renewing Baveno VII consensus. CSPH is defined by hepatic venous pressure gradient (HVPG)≥10 mm Hg; however, the HVPG measurement is not widely adopted due to its invasiveness. Liver stiffness (LS)≥25 kPa can be used as a surrogate of HVPG≥10 mm Hg to rule in CSPH with 90% of the positive predicting value in majority aetiologies of patients. A compelling argument is existing for using LS≥25 kPa to diagnose CSPH and then to initiate carvedilol in patients with compensated cirrhosis, and about 5%–6% of patients under this diagnosis criteria may not be benefited from carvedilol and are at risk of lower heart rate and mean arterial pressure. Randomised controlled trial on the use of carvedilol to prevent liver decompensation in CSPH diagnosed by LS remains to elucidate. Therefore, we aimed to investigate if compensated cirrhosis patients with LS≥25 kPa may benefit from carvedilol therapy.Methods and analysis This study is a randomised, double-blind, placebo-controlled, multicentre trial. We will randomly assign 446 adult compensated cirrhosis patients with LS≥25 kPa and without any previous decompensated event and without high-risk gastro-oesophageal varices. Patients are randomly divided into two groups, with 223 subjects in group A and 223 subjects in group B. Group A is a carvedilol intervention group, while group B is a placebo group. All patients in both groups will receive aetiology therapies and are followed up at an interval of 6 months. The 3-year incidences of decompensated events of cirrhosis-related and liver-related death are the primary outcome. The secondary outcomes include development of each complication of portal hypertension individually (ascites, variceal bleeding or overt hepatic encephalopathy), development of spontaneous bacterial peritonitis and other bacterial infections, development of new varices, growth of small varices to large varices, delta changes in LS and spleen stiffness, change in hepatic dysfunction assessed by Child-Pugh and model for end-stage liver disease score, change in platelet count, development of hepatocellular carcinoma, development of portal vein thrombosis and adverse events with a 3-year follow-up. A predefined interim analysis will be performed to ensure that the calculation is reasonable.Ethics and dissemination The study protocol has been approved by the ethics committees of the Sixth People’s Hospital of Shenyang (2023-05-003-01) and independent ethics committee for clinical research of Zhongda Hospital, affiliated to Southeast University (2023ZDSYLL433-P01). The results from this trial will be submitted for publication in peer-reviewed journals and will be presented at international conferences.Trial registration number ChiCTR2300073864.

Introduction and Objectives: Type 2 Diabetes Mellitus (T2DM), a prevalent metabolic disorder, often coexists with a range of complications, with retinopathy being particularly common. Recent studies have shed light on a potential connection between diabetic retinopathy (DR) and hepatic fibrosis, indicating a possible shared pathophysiological foundation in T2DM. This study investigates the correlation between retinopathy and hepatic fibrosis among individuals with T2DM, as well as evaluates the diagnostic value of DR for significant hepatic fibrosis. Materials and Methods: Our cross-sectional analysis incorporated 5413 participants from the National Health and Nutrition Examination Survey (NHANES) 2005-2008. The Fibrosis-4 score (FIB-4) classified hepatic fibrosis into different grades (F0-F4), with significant hepatic fibrosis marked as F2 or higher. Retinopathy severity was determined using retinal imaging and categorized into four levels. The analysis of variance or Chi-square tests facilitated group comparisons. Additionally, the receiver operating characteristic (ROC) analysis appraised the predictive accuracy of retinopathy for significant hepatic fibrosis in the T2DM population. Results: Among 5413 participants, the mean age was 59.56 ± 12.41, with 50.2% male. And 20.6% were diagnosed with T2DM. Hepatic fibrosis grading was positively associated with retinopathy severity (OR [odds ratio]: 1.521, 95%CI [confidence interval]: 1.152-2.008, P = 0.003) across the entire population. The association was amplified in the T2DM population according to Pearson's analysis results. The ROC curve demonstrated retinopathy's diagnostic capacity for significant hepatic fibrosis in the T2DM population (AUC [area under curve] = 0.72, 95%CI: 0.651-0.793, P < 0.001). Conclusions: Retinopathy could serve as an independent predictor of significant hepatic fibrosis in T2DM population. Ophthalmologists are advised to closely monitor T2DM patients with retinopathy.

Doubled haploid (DH) technology is an important tool in crop breeding because it can significantly accelerate the breeding process. ZmPLA1/MATL/NLD and ZmDMP are two key genes controlling haploid induction (HI) in maize, exhibiting a synergistic effect. However, it is unknown whether knock out of ZmDMP orthologs can stimulate HI in rice. In this study, a ZmPLA1 ortholog (OsPLA1) and two ZmDMP orthologs (OsDMP3 and OsDMP6) were identified in rice. All three genes encode plasma membrane-localized proteins and were highly expressed in mature anthers. Knockout of OsPLA1 in both Minghui 63 and Nipponbare resulted in reduced seed setting rate (SSR) and caused HI. The osdmp3, osdmp6 and the double mutant failed to trigger HI independently, nor increased the haploid induction rate (HIR) when combined with ospla1. Repeated pollinations operations of QX654A with the ospla1 mutant significantly improve SSR, while reducing HIR. RNA-seq profiling of mature ospla1 mutant anthers indicated that a large number of differentially expressed genes (DEGs) were enriched in redox homeostasis and lipid metabolic GO terms, plant hormone signal transduction, and MAPK signaling pathways. These findings provide important insights towards construction of an efficient DH breeding technology and study of the molecular mechanism of HI in rice.

This study aims to identify risk factors for secondary venous thromboembolism (VTE) in stroke patients and establish a nomogram, an accurate predictor of probability of VTE occurrence during hospitalization in stroke patients. Medical Information Mart for Intensive Care IV (MIMIC-IV) database of critical care medicine was utilized to retrieve information of stroke patients admitted to the hospital between 2008 and 2019. Patients were randomly allocated into train set and test set at 7:3. Univariate and multivariate logistic regression analyses were used to identify independent risk factors for secondary VTE in stroke patients. A predictive nomogram model was constructed, and the predictive ability of the nomogram was evaluated using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). This study included 266 stroke patients, with 26 patients suffering secondary VTE after stroke. A nomogram for predicting risk of secondary VTE in stroke patients was built according to pulmonary infection, partial thromboplastin time (PTT), log-formed D-dimer, and mean corpuscular hemoglobin (MCH). Area under the curve (AUC) of the predictive model nomogram was 0.880 and 0.878 in the train and test sets, respectively. The calibration curve was near the diagonal, and DCA curve presented positive net benefit. This indicates the model's good predictive performance and clinical utility. The nomogram effectively predicts the risk probability of secondary VTE in stroke patients, aiding clinicians in early identification and personalized treatment of stroke patients at risk of developing secondary VTE.

Abstract Background Familial exudative vitreoretinopathy (FEVR) is a genetic eye disorder that leads to abnormal development of retinal blood vessels, resulting in vision impairment. This study aims to identify pathogenic variants by targeted exome sequencing in 9 independent pedigrees with FEVR and characterize the novel pathogenic variants by molecular dynamics simulation. Methods Clinical data were collected from 9 families with FEVR. The causative genes were screened by targeted next-generation sequencing (TGS) and verified by Sanger sequencing. In silico analyses (SIFT, Polyphen2, Revel, MutationTaster, and GERP + +) were carried out to evaluate the pathogenicity of the variants. Molecular dynamics was simulated to predict protein conformation and flexibility transformation alterations on pathogenesis. Furthermore, molecular docking techniques were employed to explore the interactions and binding properties between LRP5 and DKK1 proteins relevant to the disease. Results A 44% overall detection rate was achieved with four variants including c.4289delC: p.Pro1431Argfs*8, c.2073G > T: p.Trp691Cys, c.1801G > A: p.Gly601Arg in LRP5 and c.633 T > A: p.Tyr211* in TSPAN12 in 4 unrelated probands. Based on in silico analysis and ACMG standard, two of them, c.4289delC: p.Pro1431Argfs*8 and c.2073G > T: p.Trp691Cys of LRP5 were identified as novel pathogenic variants. Based on computational predictions using molecular dynamics simulations and molecular docking, there are indications that these two variants might lead to alterations in the secondary structure and spatial conformation of the protein, potentially impacting its rigidity and flexibility. Furthermore, these pathogenic variants are speculated to potentially influence hydrogen bonding interactions and could result in an increased binding affinity with the DKK1 protein. Conclusions Two novel genetic variants of the LRP5 gene were identified, expanding the range of mutations associated with FEVR. Through molecular dynamics simulations and molecular docking, the potential impact of these variants on protein structure and their interactions with the DKK1 protein has been explored. These findings provide further support for the involvement of these variants in the pathogenesis of the disease.

Abstract: Optimizing feed efficiency through the feed conversion ratio (FCR) is paramount for economic viability and sustainability. In this study, we integrated RNA-seq, ATAC-seq, and genome-wide association study (GWAS) data to investigate key functional variants associated with feed efficiency in pigs. Identification of differentially expressed genes in the duodenal and muscle tissues of low- and high-FCR pigs revealed that pathways related to digestion of dietary carbohydrate are responsible for differences in feed efficiency between individuals. Differential open chromatin regions identified by ATAC-seq were linked to genes involved in glycolytic and fatty acid processes. GWAS identified 211 significant single-nucleotide polymorphisms associated with feed efficiency traits, with candidate genes PPP1R14C, TH, and CTSD. Integration of duodenal ATAC-seq data and GWAS data identified six key functional variants, particularly in the 1500985–1509676 region on chromosome 2. In those regions, CTSD was found to be highly expressed in the duodenal tissues of pigs with a high feed conversion ratio, suggesting its role as a potential target gene. Overall, the integration of multi-omics data provided insights into the genetic basis of feed efficiency, offering valuable information for breeding more efficient pig breeds.

Summary: Background: With increasingly prevalent coexistence of chronic hepatitis B (CHB) and hepatic steatosis (HS), simple, non-invasive diagnostic methods to accurately assess the severity of hepatic inflammation are needed. We aimed to build a machine learning (ML) based model to detect hepatic inflammation in patients with CHB and concurrent HS. Methods: We conducted a multicenter, retrospective cohort study in China. Treatment-naive CHB patients with biopsy-proven HS between April 2004 and September 2022 were included. The optimal features for model development were selected by SHapley Additive explanations, and an ML algorithm with the best accuracy to diagnose moderate to severe hepatic inflammation (Scheuer's system ≥ G3) was determined and assessed by decision curve analysis (DCA) and calibration curve. This study is registered with ClinicalTrials.gov (NCT05766449). Findings: From a pool of 1,787 treatment-naive patients with CHB and HS across eleven hospitals, 689 patients from nine of these hospitals were chosen for the development of the diagnostic model. The remaining two hospitals contributed to two independent external validation cohorts, comprising 509 patients in validation cohort 1 and 589 in validation cohort 2. Eleven features regarding inflammation, hepatic and metabolic functions were identified. The gradient boosting classifier (GBC) model showed the best performance in predicting moderate to severe hepatic inflammation, with an area under the receiver operating characteristic curve (AUROC) of 0.86 (95% CI 0.83–0.88) in the training cohort, and 0.89 (95% CI 0.86–0.92), 0.76 (95% CI 0.73–0.80) in the first and second external validation cohorts, respectively. A publicly accessible web tool was generated for the model. Interpretation: Using simple parameters, the GBC model predicted hepatic inflammation in CHB patients with concurrent HS. It holds promise for guiding clinical management and improving patient outcomes. Funding: This research was supported by the National Natural Science Foundation of China (No. 82170609, 81970545), Natural Science Foundation of Shandong Province (Major Project) (No. ZR2020KH006), Natural Science Foundation of Jiangsu Province (No.BK20231118), Tianjin Key Medical Discipline (Specialty), Construction Project, TJYXZDXK-059B, Tianjin Health Science and Technology Project key discipline special, TJWJ2022XK034, and Research project of Chinese traditional medicine and Chinese traditional medicine combined with Western medicine of Tianjin municipal health and Family Planning Commission (2021022).

Abstract Aim Patients with chronic liver disease (CLD), especially cirrhosis, are at a high risk of severe illness or death from coronavirus disease‐2019 (COVID‐19) and may have a suboptimal immune response to the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) vaccine. This study aimed to evaluate the safety and immunogenicity of the COVID‐19 booster vaccination in patients with CLD. Methods The study protocol was prospectively registered at ClinicalTrials.gov (No. NCT05204602) after approval by the Ethics Committee. Adult participants with CLD were enrolled in this multicenter prospective study. They completed two doses of the inactivated COVID‐19 vaccine and received booster doses at least 6 months later. Adverse reactions were recorded within 14 days after the booster dose. Serum samples of the enrolled patients were collected before and after booster vaccination and tested for SARS‐CoV‐2 receptor‐binding domain (RBD) immunoglobulin G and neutralizing antibodies. The chi‐squared or Fisher's exact test was used to compare categorical data, and the Mann–Whitney U test was used to compare continuous variables. Two‐sided p

An animal model harboring pathogenic mitochondrial DNA (mtDNA) mutations is important to understand the biological links between mtDNA variation and mitochondrial diseases. DdCBE, a DddA-derived cytosine base editor, has been utilized in zebrafish, mice, and rats for tC sequence-context targeting and human mitochondrial disease modeling. However, human pathogenic mtDNA mutations other than the tC context cannot be manipulated. Here, we screened the combination of different DdCBE pairs at pathogenic mtDNA mutation sites with nC (n for a, g, or c) context and identified that the left-G1333C (L1333C) + right G1333N (R1333N) pair could mediate C⋅G-to-T⋅A conversion effectively at aC sites in rat C6 cells. The editing efficiency at disease-associated mtDNA mutation sites within aC context was further confirmed to be up to 67.89% in vivo. Also, the installed disease-associated mtDNA mutations were germline transmittable. Moreover, the edited rats showed impaired cardiac function and mitochondrial function, resembling human mitochondrial disease symptoms. In summary, for the first time, we expanded the DdCBE targeting scope to an aC motif and installed the pathogenic mutation in rats to model human mitochondrial diseases.

Abstract Aims Patients with liver disease may exhibit higher infection rates and mortality rates from coronavirus disease 2019 (COVID‐19) than healthy individuals, and vaccination against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is an effective prevention strategy. This meta‐analysis aimed to assess the effectiveness and safety of SARS‐CoV‐2 vaccines in patients with chronic liver disease (CLD) and post‐liver transplantation (LT). Methods The PubMed, Embase, and Cochrane databases were searched. A random‐effects model meta‐analysis was used to determine the seropositivity rates of SARS‐CoV‐2 antibodies, odds ratio (OR) compared with healthy controls (HC), risk ratio (RR) between the booster and standard vaccination regimen, and the rate of adverse reactions (ADR). Results In the standard vaccination regimen analysis, 17 controlled articles were included for effectiveness analysis, and six articles for ADR analysis. The pooled seropositivity rates of SARS‐CoV‐2 antibodies in patients with CLD and post‐LT were 93.3% (95% confidence interval [CI]: 89.0%–97.6%) and 69.1% (95% CI: 63.0%–75.3%), respectively. Both rates were lower than those in HC (p

Abstract Background Multiple mitochondrial dysfunction syndromes (MMDS) are rare mitochondrial diseases caused by mutation of mitochondrial iron–sulfur cluster synthesis proteins. This study established a rat model simulating MMDS5 disease in the nervous system to investigate its pathological features and neuronal death. Methods We generated neuron‐specific Isca1 knockout rat (Isca1flox/flox ‐NeuN‐Cre) using CRISPR‐Cas9 technology. The brain structure changes of CKO rats were studied with MRI, and the behavior abnormalities were analyzed through gait analysis and open field tests, Y maze tests and food maze tests. The pathological changes of neurons were analyzed through H&E staining, Nissl staining, and Golgi staining. Mitochondrial damage was assessed by TEM, western blot and ATP assay, and the morphology of neurons was assessed by WGA immunofluorescence to detect the death of neurons. Results This study established the disease model of MMDS5 in the nervous system for the first time, and found that after Isca1 loss, the rats suffered from developmental retardation, epilepsy, memory impairment, massive neuronal death, reduced number of Nissl bodies and dendritic spines, mitochondrial fragmentation, cristae fracture, reduced content of respiratory chain complex protein, and reduced production of ATP. Isca1 knockout caused neuronal oncosis. Conclusions This rat model can be used to study the pathogenesis of MMDS. In addition, compared with human MMDS5, the rat model can survive up to 8 weeks of age, effectively extending the window of clinical treatment research, and can be used for the treatment of neurological symptoms in other mitochondrial diseases.

Abstract Background Rubinstein-Taybi syndrome (RSTS) is characterized by distinctive facial features, broad and often angulated thumbs and halluces, short stature, and moderate-to-severe intellectual disability, classified into two types RSTS1 (CREBBP-RSTS) and RSTS2 (EP300-RSTS). More often, the clinical features are inconclusive and the diagnosis of RSTS is established in a proband with identification of a heterozygous pathogenic variant in CREBBP or EP300 to confirm the diagnosis. Methods In this study, to describe an association between the clinical phenotype and the genotype of a RSTS2 patient who was initially diagnosed with severe early-onset high myopia (eoHM) from a healthy Chinese family, we tested the proband of this family by whole exome sequencing (WES) and further verified among other family members by Sanger sequencing. Real-time quantitative PCR was used to detect differences in the relative mRNA expression of candidate genes available in the proband and family members. Comprehensive ophthalmic tests as well as other systemic examinations were also performed on participants with various genotypes. Results Whole-exome sequencing revealed that the proband carried the heterozygous frameshift deletion variant c.3714_3715del (p.Leu1239Glyfs*3) in the EP300 gene, which was not carried by the normal parents and young sister as verified by Sanger sequencing, indicating that the variant was de novo. Real-time quantitative PCR showed that the mRNA expression of EP300 gene was lower in the proband than in other normal family members, indicating that such a variant caused an effect on gene function at the mRNA expression level. The variant was classified as pathogenic as assessed by the interpretation principles of HGMD sequence variants and ACMG guidelines. According to ACMG guidelines, the heterozygous frameshift deletion variant c.3714_3715del (p.Leu1239Glyfs*3) in the EP300 gene was more likely the pathogenic variant of this family with RSTS2. Conclusions Therefore, in this paper, we first report de novo heterozygous variation in EP300 causing eoHM-RSTS. Our study extends the genotypic spectrums for EP300-RSTS and better assists physicians in predicting, diagnosis, genetic counseling, eugenics guidance and gene therapy for EP300-RSTS.

ABSTRACT: Sperm motility is an important index for the evaluation of semen quality. Improving sperm motility is important to improve reproductive performance, promote breeding process, and reduce production cost. However, the molecular mechanisms regulating sperm motility in chickens remain unclear. In this study, histological observation and whole-transcriptome analysis were performed on testicular tissue of chickens with high and low sperm motility. Histological observations showed that roosters with high sperm motility exhibited better semen quality than those with low sperm motility. In addition, the germinal epithelial cells of roosters with low sperm motility were loosely arranged and contained many vacuoles. RNA-seq results revealed the expression of 23,033 mRNAs, 2,893 lncRNAs, and 515 miRNAs in chicken testes. Among them, there were 417 differentially expressed mRNAs (DEmRNAs), 106 differentially expressed lncRNAs (DElncRNAs), and 15 differentially expressed miRNAs (DEmiRNAs) between high and low sperm motility testes. These differentially expressed genes were involved in the G protein-coupled receptor signaling pathway, cilia structure, Wnt signaling, MAPK signaling, GnRH signaling, and mTOR signaling. By integrating the competitive relationships between DEmRNAs, DElncRNAs, and DEmiRNAs, we identified the regulatory pathway of MSTRG.3077.3/MSTRG.9085.1-gga-miR-138-5p-CADM1 and MSTRG.2290.1-gga-miR-142-3p-GNAQ/PPP3CA as crucial in the modulation of chicken sperm motility. This study provides new insights into the function and mechanism of ceRNAs in regulating sperm motility in chicken testes.

ABSTRACT: Intramuscular fat (IMF) is an important factor affecting chicken quality. However, the age-related mechanism of IMF deposition has not yet been elucidated. In this study, the IMF, phospholipids (PL), triglycerides (TG), and fatty acid (FA) content in the breast muscle of Beijing-You chicken (BJY) at 1, 56, 98, and 120 d of age was measured, and mRNA and miRNA sequencing was integrated to explore the regulatory genes of IMF deposition. The results showed that the IMF content of BJY at 1 d of age was significantly higher than that at later stage of birth (P < 0.05). The transcriptome sequencing results showed that 7, 225 differentially expressed genes (DEGs) and 243 differentially expressed miRNAs (DE-miRNAs) were identified. The cluster analysis showed that the expression of DEGs and DE-miRNAs at 1 d of age was significantly different from that at later stages of birth. Furthermore, a potential mRNA-miRNA regulatory network related to IMF deposition was established by weighted gene co-expression network analysis (WGCNA); gga-miR-29c-3p-PIK3R1, gga-miR-6701-3p-PTEN, gga-miR-363-3p-PTEN, gga-miR-1563-WWP1, gga-miR-449c/d-5p-TRAF6, and gga-miR-6701-3p-BMPR1B were identified as key mRNA-miRNA pairs for the regulation of IMF deposition. These results will help elucidate the mechanism of IMF formation mediated by miRNAs in chickens, and provide a theoretical foundation for the genetic improvement of broiler meat quality.

Abstract Aim The transjugular intrahepatic portosystemic shunt (TIPS) procedure has been performed in China for 30 years, but our understanding of the status and difficulties associated with the use of TIPS for portal hypertension is incomplete. This study aims to investigate the current situation of the use of TIPS for portal hypertension, which should aid the development of TIPS in China. Methods This study involved a questionnaire survey, initiated by the China Portal Hypertension Alliance (CHESS) to investigate the use of TIPS for portal hypertension in China. Questionnaires were released on the Internet between August 16, 2022 and September 16, 2022. Detailed information was collected from 545 hospitals contracted by the CHESS in China, which performed TIPS surgery in 2021. Results The 545 hospitals covers the majority of hospitals in China that conduct TIPS intervention. In the survey, a total of 13,527 TIPS interventions were carried out with 94.1% (498/545) of them had a system of routine follow‐up after TIPS. The majority (42.6% [232/545]) believed that the main indication of TIPS was the control of acute bleeding. Overall, 48.1% (262/545) carried out early or pre‐emptive TIPS, 53.0% (289/545) carried out TIPS for cavernous transformation of the portal vein, and 81.0% (441/545) chose routine embolization of collateral circulation during operation. Most used coils (97.0% [475/490]) and biological glue (72.0% [353/490]) as embolic materials, and 78.5% (428/545) routinely performed intraoperative portal pressure gradient measurements. When selecting TIPS stents, 57.1% (311/545) chose viator‐specific stents, and 57.2% (312/545) chose conventional anticoagulation after TIPS. Conventional anticoagulation after TIPS is over a time interval of 3–6 months (55.4% [173/312]). The limitation of TIPS surgery is mainly its cost (72.3% [394/545]) and insufficient understanding of the procedure by doctors in other related departments (77.4% [422/545]). Most of the hospital teams accept the use of domestic instruments in TIPS surgery (92.7% [505/545]). Conclusions This survey shows that TIPS is an essential part of the treatment of portal hypertension in China. TIPS is widely used in Chinese patients with portal hypertension, and this survey presents a more comprehensive picture of the options and difficulties encountered in the implementation of TIPS. In the future, it is necessary to promote TIPS technology and further standardize surgical indications, routine operations, and instrument application.

Background: Non-alcoholic fatty liver disease (NAFLD) has emerged as a significant health issue due to its association with a growing proportion of cirrhosis and other chronic liver diseases (CLDs). To obtain a profound understanding of the burden of cirrhosis and other CLDs due to NAFLD, we aim to present a comprehensive analysis from 1990 to 2019. Methods: The study utilized data from the Global Burden of Disease database. Results: From 1990 to 2019, the global incidence, prevalence, death, and disability-adjusted life year (DALY) numbers increased 93%, 120%, 77%, and 62%, respectively. Despite the age-standardized death rate (ASDR) and the age-standardized DALY decreased, the age-standardized incident rate (ASIR) and age-standardized prevalent rate (ASPR) increased from 1.50 to 1.63 and 12065.15 to 15022.90 per 100,000 people, respectively. A higher incidence rate was observed among middle-aged individuals, while a higher prevalence, death, and DALY rates were among the elderly. Males remained higher number of prevalence, death, DALY cases than females. The low-middle and high socio-demographic index (SDI) region had the highest increase of ASIR and ASPR, respectively. The low SDI region had the largest decrease in ASDR and age-standardized DALY. Conclusions: An increasing cases of cirrhosis and other CLDs due to NAFLD was observed. The ASIR and ASPR showed a worsening trend, while ASDR and age-standardized DALY showed an improving trend. Middle-aged and older people are more susceptible. Males experienced a higher burden than females.

This study aimed to investigate whether a dietary 25-OHD3 addition improved the performance, egg quality, blood indexes, antioxidant status, jejunal morphology, and tibia quality of aged laying hens compared to a dietary VD3 addition. A total of 270 Hy-Line Brown laying hens at 55 wk of age were randomly assigned to three dietary treatments with six replicates (15 birds per replicate with 3 birds per cage). Chickens were fed a corn–soybean meal diet supplementation of 4000 IU/kg VD3 (control group), 50 μg/kg 25-OHD3 and 2000 IU/kg VD3 (experimental group 1), or 50 μg/kg 25-OHD3 and 4000 IU/kg VD3 (experimental group 2) for 12 weeks. The results demonstrated that 25-OHD3 caused a significant increase in the laying rate, especially in the 50 μg/kg 25-OHD3 + 2000 IU/kg VD3 group; the laying rate reached the maximum compared with other groups after 12 weeks (p < 0.05). However, there were no significant effects on the average egg weight, average daily feed intake, or feed-to-egg ratio (p > 0.05). A dietary supplementation of 50 μg/kg 25-OHD3 and 2000 IU/kg VD3 provided an improved eggshell strength, thick albumen height, and Haugh unit after 12 weeks (p < 0.05). Further analysis of the blood indexes showed that alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, calcium, and phosphorus were enhanced significantly in the 50 μg/kg 25-OHD3 + 2000 IU/kg VD3 group, while the content of total bilirubin decreased significantly (p < 0.05). In addition, the 25-OHD3 addition in diets improved the calcium and phosphorus contents in the serum (p < 0.05). The concentrations of 25-OHD3, parathyroid hormones, follicle-stimulating hormone, and progesterone were increased in the 50 μg/kg 25-OHD3 + 2000 IU/kg VD3 group, and the levels of cortisol, calcitonin, bone gla protein, and endotoxin in the serum reached a minimum in the 50 μg/kg 25-OHD3 + 4000 IU/kg VD3 group (p < 0.05), which constitutes an advantage for the aged laying hens. The antioxidant enzyme activities and free radical scavenging abilities in the 50 μg/kg 25-OHD3 + 2000 IU/kg VD3 group increased markedly, and the MDA level decreased significantly in the 50 μg/kg 25-OHD3 + 4000 IU/kg VD3 group (p < 0.05). Improvements in jejunal morphology and intestinal integrity resulted in an increased villi-length-to-crypt-depth ratio in the 50 μg/kg 25-OHD3 + 2000 IU/kg VD3 group (p < 0.05). Dietary 50 μg/kg 25-OHD3 and 2000 IU/kg VD3 additions improved the tibia quality, including fresh tibia weight, strength, mineral content (Ca), and trabeculae area (p < 0.05). Taken together, compared with the dietary VD3 addition, dietary supplementation of 25-OHD3 supported a stable physiological status for sustained egg production, egg quality, and bone quality in late-phase laying hens, and the addition levels of 50 μg/kg 25-OHD3 and 2000 IU/kg VD3 had the best effect. Therefore, this could provide a theoretical basis for the use of 25-OHD3 as a substitute forVD3.

As a pivotal player in spermatogenesis, the blood-testis barrier (BTB) made from junction apparatus coexisting in Sertoli cells (SCs) is impaired with an increase in age and ultimately induces spermatogenic dysfunction or even infertility. It has been corroborated that bone marrow mesenchymal stem cell (BMSC) transplantation can efficiently repair and regenerate the testicular function. As vital mediators of cell-to-cell communication, MSC-derived exosomes (Exos) can directly serve as therapeutic agents for tissue repair and regeneration. However, the therapeutic value of BMSC-Exos in aging-induced BTB damage remains to be confirmed. In this study, we explored that the old porcine testes had defective autophagy, which aggravated BTB disruption in SCs. BMSC-Exos could decrease ROS production and NLRP3 inflammasome activation but enhanced autophagy and tight junction (TJ) function in D-gal-triggered aging porcine SCs and mouse model testes, according to in vitro and in vivo experiments. Furthermore, rapamycin, NAC, MCC950, and IL-1Ra restored the TJ function in D-gal-stimulated aging porcine SCs, while BMSC-Exos’ stimulatory effect on TJ function was inhibited by chloroquine. Moreover, the treatment with BMSC-Exos enhanced autophagy in D-gal-induced aging porcine SCs by means of the AMPK/mTOR signal transduction pathway. These findings uncovered through the present study that BMSC-Exos can enhance the BTB function in aging testes by improving autophagy via the AMPK/mTOR signaling pathway, thereby suppressing ROS production and NLRP3 inflammasome activation.

Abstract Few studies have reported on acoustic radiation force impulse (ARFI) for varices screening. Our study aimed to identify a strategy based on liver stiffness measurement (LSM) and spleen stiffness measurement (SSM) by ARFI combined with platelet count (PLT), named the ARP strategy, for ruling out high‐risk varices (HRV) and avoiding unnecessary esophagogastroduodenoscopy (EGD) in patients with compensated cirrhosis. We retrospectively reviewed patients who underwent ARFI from a previous cohort (NCT04307264). Of them, patients between 2017 and 2019 composed the training cohort to develop the ARP strategy. The validation cohort consisted of others between 2015 and 2016 to validate and compare it with Baveno VI criteria about the performance for varices screening. Primary outcomes were the rates of spared EGDs and HRV missed. A total of 741 consecutive patients were included in the final analysis. Of them, 576 patients were included in the training cohort and 165 patients in the validation cohort. In the training cohort, ARP strategy was defined as LSM 110 × 109/L. ARP strategy could spare 234 (40.6%) EGDs with a missed HRV rate of 3.4% (8 of 234). In the validation cohort, compared with Baveno VI criteria, the ARP strategy improved the proportion of avoided EGDs (49.7% vs. 34.5%; p

Abstract Tissue engineering (TE) is promising for the regeneration of failed organs. However, immune rejection, shortage of seed cells, and unintegrated blood vessels restrict the development and clinical application of TE. The last factor is the most challenging and intractable. Harnessing the mature blood vessel network in existing dispensable organs could be a powerful approach to effectively overcome the obstacles. After being remodeled to harbor an immunosuppressive and proregenerative niche, these potential target organs can be transformed into other organs with specific physiological functions, compensating the latter's failed native functions. Organ transformation, such as a hepatized spleen, represents an effective and encouraging TE strategy. In this review, we discuss the current development and obstacles of TE and its feasibility and superiority in organ transformation.

Abstract Purpose This study aimed to explore circular RNA (circRNA) hsa_circ_0000690 as a potential biomarker for diagnosis and prognosis of intracranial aneurysm (IA) and its relationship with clinical factors and complications of IA. Material/methods 216 IA patients admitted to the neurosurgery department of our hospital from January 2019 to December 2020 were selected as the experimental group, and 186 healthy volunteers were selected as the control group. The expression of hsa_circ_0000690 in peripheral blood was detected by quantitative real‐time PCR, and its diagnostic value was assessed by receiver operating characteristic curve. Relationship between hsa_circ_0000690 and clinical factors of IA was assessed by chi‐square test. Nonparametric test was used in univariate analysis, and regression analysis was used in multivariate analysis. Multivariate Cox proportional hazards regression analysis was used to analyze the survival time. Results CircRNA hsa_circ_0000690 of IA patients was relatively lower than that in the control group (p

Abstract Aim To determine the tolerance and acceptance of hepatic venous pressure gradient (HVPG) measurements in patients with liver cirrhosis. Methods This prospective international multicenter study included 271 patients with cirrhosis who were scheduled to undergo HVPG measurement between October 2019 and June 2020. Data related to the tolerance and acceptance of HVPG measurements were collected using descriptive questionnaires. Results HVPG measurements were technically successful in all 271 patients, with 141 (52.0%) undergoing HVPG measurement alone. The complication rate was 0.4%. Postoperative pain was significantly lower than preoperative expected pain (p

Abstract Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. NAFLD‐related cirrhosis is often complicated by portal hypertension (PHT). Recent evidence showed that portal venous pressure (PVP) starts to rise in the early stages of NAFLD, even in absence of advanced fibrosis or cirrhosis. However, the precise pathological mechanisms of this process are still poorly understood. Lipid accumulation, hepatocellular ballooning, sinusoidal endothelial cell dysfunction, capillarization, microthrombosis, increased angiogenesis, and pericellular fibrosis may all be involved in the early development of increased PVP in NAFLD. Direct measurement of PHT is invasive and impractical in noncirrhotic NAFLD individuals and may also underestimate its severity. Thus, the development and validation of noninvasive and more accurate measurements, including new serum biomarkers, scoring models, and imaging techniques (such as ultrasonography, elastography, and magnetic resonance imaging), are urgently needed. Owing to the increasing morbidity, challenges in the prevention and management of PHT in NAFLD are unprecedented. This review article aims to briefly discuss these challenges and summarizes the mechanisms, diagnosis, and emerging therapies for PHT in people with NAFLD.

Abstract Background Gene expression programs are intimately linked to the interplay of active cis regulatory elements mediated by chromatin contacts and associated RNAs. Genome-wide association studies (GWAS) have identified many variants in these regulatory elements that can contribute to phenotypic diversity. However, the functional interpretation of these variants remains nontrivial due to the lack of chromatin contact information or limited contact resolution. Furthermore, the distribution and role of chromatin-associated RNAs in gene expression and chromatin conformation remain poorly understood. To address this, we first present a comprehensive interaction map of nuclear dynamics of 3D chromatin-chromatin interactions (H3K27ac BL-HiChIP) and RNA-chromatin interactions (GRID-seq) to reveal genomic variants that contribute to complex skeletal muscle traits. Results In a genome-wide scan, we provide systematic fine mapping and gene prioritization from GWAS leading signals that underlie phenotypic variability of growth rate, meat quality, and carcass performance. A set of candidate functional variants and 54 target genes previously not detected were identified, with 71% of these candidate functional variants choosing to skip over their nearest gene to regulate the target gene in a long-range manner. The effects of three functional variants regulating KLF6 (related to days to 100 kg), MXRA8 (related to lean meat percentage), and TAF11 (related to loin muscle depth) were observed in two pig populations. Moreover, we find that this multi-omics interaction map consists of functional communities that are enriched in specific biological functions, and GWAS target genes can serve as core genes for exploring peripheral trait-relevant genes. Conclusions Our results provide a valuable resource of candidate functional variants for complex skeletal muscle-related traits and establish an integrated approach to complement existing 3D genomics by exploiting RNA-chromatin and chromatin-chromatin interactions for future association studies.

Abstract Background Inflammation is a complex physiological and pathological process. Although many types of inflammation are well characterized, their physiological functions are largely unknown. tRNA aspartic acid methyltransferase 1 (TRDMT1) has been implicated as a stress‐related protein, but its intrinsic biological role is unclear. Methods We constructed a Trdmt1 knockout rat and adopted the LPS‐induced sepsis model. Survival curve, histopathological examination, expression of inflammatory factors, and protein level of TLR4 pathway were analyzed. Results Trdmt1 deletion had no obvious impact on development and growth. Trdmt1 deletion slightly increased the mortality during aging. Our data showed that Trdmt1 strongly responded in LPS‐treated rats, and Trdmt1 knockout rats were vulnerable to LPS treatment with declined survival rate. We also observed more aggravated tissue damage and more cumulative functional cell degeneration in LPS‐treated knockout rats compared with control rats. Further studies showed upregulated TNF‐α level in liver, spleen, lung, and serum tissues, which may be explained by enhanced p65 and p38 phosphorylation. Conclusions Our data demonstrated that Trdmt1 plays a protective role in inflammation by regulating the TLR4‐NF‐κB/MAPK‐TNF‐α pathway. This work provides useful information to understand the TRDMT1 function in inflammation.

Chicken meat quality and flavor are determined by abundant metabolites. In this study, HPLC-QTRAP-MS-based metabolomic analysis was used to evaluate the characteristic metabolites in the breast muscle of Beijing You chickens aged 56, 98, and 120 days. A total of 544 metabolites in 32 categories were identified, among which amino acids and organic acids were the most abundant. 60 and 55 differential metabolites were identified between 56 and 98 days of age, 98 and 120 days of age, respectively. The content of l-carnitine, l-methionine and 3-hydroxybutyrate increased significantly at 98 or 120 days of age. Arginine biosynthesis, purine metabolism, alanine, aspartic acid, and glutamic acid metabolism were important metabolic pathways that affect chicken meat flavor. This study can help to elucidate the metabolic mechanism of breast muscle during Beijing You chicken development and provide a theoretical reference for the improvement of chicken meat quality and flavor.

Donnai-Barrow syndrome (DBS) is a rare autosomal recessive disorder caused by mutation in the low density lipoprotein receptor-related protein 2 gene (LRP2). Defects in this protein may lead to clinical multiple organ malformations by affecting the development of organs such as the nervous system, eyes, ears, and kidneys. Although some variations on LRP2 have been found to be associated with DBS, early diagnosis and prevention of patients with atypical DBS remains a challenge for many physicians because of their clinical heterogeneity. The objective of this study is to explore the association between the clinical presentation and the genotype of a DBS patient who was initially diagnosed with early-onset high myopia (eoHM) from a healthy Chinese family. To this end, we tested the patient of this family via whole exome sequencing and further verified the results among other family members by Sanger sequencing. Comprehensive ophthalmic tests as well as other systemic examinations were also performed on participants with various genotypes. Genetic assessment revealed that two novel variations in LRP2, a de novo missense variation (c.9032G>A; p.Arg3011Lys) and a novel splicing variation (c.2909-2A>T) inherited from the father, were both carried by the proband in this family, and they are strongly associated with the typical clinical features of DBS patients. Therefore, in this paper we are the first to report two novel compound heterozygous variations in LPR2 causing DBS. Our study extends the genotypic spectrums for LPR2-DBS and better assists physicians in predicting, diagnosing, and conducting gene therapy for DBS.

Southern corn rust (SCR), caused by Puccinia polysora Underw, is a destructive disease that can severely reduce grain yield in maize (Zea mays L.). Owing to P. polysora being multi-racial, it is very important to explore more resistance genes and develop more efficient selection approaches in maize breeding programs. Here, four Doubled Haploid (DH) populations with 384 accessions originated from selected parents and their 903 testcross hybrids were used to perform genome-wide association (GWAS). Three GWAS processes included the additive model in the DH panel, additive and dominant models in the hybrid panel. As a result, five loci were detected on chromosomes 1, 7, 8, 8, and 10, with P-values ranging from 4.83×10-7 to 2.46×10-41. In all association analyses, a highly significant locus on chromosome 10 was detected, which was tight chained with the known SCR resistance gene RPPC and RPPK. Genomic prediction (GP), has been proven to be effective in plant breeding. In our study, several models were performed to explore predictive ability in hybrid populations for SCR resistance, including extended GBLUP with different genetic matrices, maker based prediction models, and mixed models with QTL as fixed factors. For GBLUP models, the prediction accuracies ranged from 0.56-0.60. Compared with traditional prediction only with additive effect, prediction ability was significantly improved by adding additive-by-additive effect (P-value< 0.05). For maker based models, the accuracy of BayesA and BayesB was 0.65, 8% higher than other models (i.e., RRBLUP, BRR, BL, BayesC). Finally, by adding QTL into the mixed linear prediction model, the accuracy can be further improved to 0.67, especially for the G_A model, the prediction performance can be increased by 11.67%. The prediction accuracy of the BayesB model can be further improved significantly by adding QTL information (P-value< 0.05). This study will provide important valuable information for understanding the genetic architecture and the application of GP for SCR in maize breeding.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive neurodegeneration and cognitive decline. Evodiamine, a main component in Chinese medicine, was found to improve cognitive impairment in AD model mice based on several intensive studies. However, evodiamine has high cytotoxicity and poor bioactivity. In this study, several evodiamine derivatives were synthesized via heterocyclic substitution and amide introduction and screened for cytotoxicity and antioxidant capacity. Under the same concentrations, compound 4c was found to exhibit lower cytotoxicity and higher activity against H2O2 and amyloid β oligomers (AβOs) than evodiamine in vitro and significantly improve the working memory and spatial memory of 3 x Tg and APP/PS1 AD mice. Subsequent RNA sequencing and pathway enrichment analysis showed that 4c affected AD-related genes and the AMPK and insulin signaling pathways. Furthermore, we confirmed that 4c recovered PI3K/AKT/GSK3β/Tau dysfunction in vivo and in vitro. In conclusion, 4c represents a potential lead compound for AD therapy based on the recovery of PI3K/AKT/GSK3β pathway dysfunction.

Although shape memory alloy/Polyvinyl alcohol (SMA/PVA) hybrid fiber reinforced cementitious composites, (SMA/PVA-ECC) exhibit excellent crack closure and deformation recovery capabilities, however, the research on their fundamental mechanical properties is still limited. This study investigates the tensile mechanical properties of SMA/PVA-ECC materials by conducting uniaxial tensile tests, analyzing the failure behavior, stress–strain curves, and characteristic parameters of the specimens, comparing the influence of SMA fiber content and diameter, and establishing a tensile constitutive model. The results show that the residual crack width of SMA/PVA-ECC specimens significantly decreases after unloading, and SMA fiber content and diameter have a significant impact on the tensile properties of the specimens. The comprehensive tensile properties of specimens with a fiber diameter of 0.2 mm and content of 0.2% are the best, with their initial cracking strength, ultimate strength, and strain increasing by 56.4%, 23.6%, and 13.4%, respectively, compared to ECC specimens. The proposed bilinear tensile constitutive model has high accuracy. This study provides a theoretical basis for further research on SMA/PVA-ECC materials.

Abstract Background Multiple mitochondrial dysfunction syndromes (MMDS) presents as complex mitochondrial damage, thus impairing a variety of metabolic pathways. Heart dysplasia has been reported in MMDS patients; however, the specific clinical symptoms and pathogenesis remain unclear. More urgently, there is a lack of an animal model to aid research. Therefore, we selected a reported MMDS causal gene, Isca1, and established an animal model of MMDS complicated with cardiac dysplasia. Methods The myocardium‐specific Isca1 knockout heterozygote (Isca1 HET) rat was obtained by crossing the Isca1 conditional knockout (Isca1 cKO) rat with the α myosin heavy chain Cre (α‐MHC‐Cre) rat. Cardiac development characteristics were determined by ECG, blood pressure measurement, echocardiography and histopathological analysis. The responsiveness to pathological stimuli were observed through adriamycin treatment. Mitochondria and metabolism disorder were determined by activity analysis of mitochondrial respiratory chain complex and ATP production in myocardium. Results ISCA1 expression in myocardium exhibited a semizygous effect. Isca1 HET rats exhibited dilated cardiomyopathy characteristics, including thin‐walled ventricles, larger chambers, cardiac dysfunction and myocardium fibrosis. Downregulated ISCA1 led to deteriorating cardiac pathological processes at the global and organizational levels. Meanwhile, HET rats exhibited typical MMDS characteristics, including damaged mitochondrial morphology and enzyme activity for mitochondrial respiratory chain complexes Ⅰ, Ⅱ and Ⅳ, and impaired ATP production. Conclusion We have established a rat model of MMDS complicated with cardiomyopathy, it can also be used as model of myocardial energy metabolism dysfunction and mitochondrial cardiomyopathy. This model can be applied to the study of the mechanism of energy metabolism in cardiovascular diseases, as well as research and development of drugs.

Abstract Background With the development of minimally invasive surgery technology, patients with bladder cancer are increasingly receiving laparoscopic radical cystectomy (LRC) or robotic-assisted radical cystectomy (RARC) treatment. The main purpose of this study was to compare the long-term outcomes of bladder cancer patients treated with LRC versus RARC. Methods A retrospective study to identify patients with clinical stage Ta/T1/Tis to T3 bladder cancer who underwent RARC or LRC has been performed. The perioperative outcome, recurrence, and overall survival (OS) of the two surgical methods were compared. Results 218 patients were identified from March 2010 to December 2019 in our department, which including 82 (38%) patients who received LRC and 136 (62%) patients who received RARC. There was no significant difference between the two groups in terms of lymph node collection, lymph node positive rate, resection margin positive rate, and postoperative pathological staging. Compared with the LRC group, patients in the RARC group had a median estimated blood loss (180 vs. 250 ml; P = 0.02) and reduced complications at 90 days postoperatively (30.8% vs. 46.3%; P = 0.01). Recurrence, all-cause death, and cancer-specific death occurred in 77 (35%), 55 (25%), and 39 (18%) patients, respectively. The 5-year OS rate was 54.63% and 54.65% in the RARC and LRC group (P > 0.05). The 5-year cancer-specific survival (CSS) rate was 73.32% and 61.55% in RARC and LRC group (P > 0.05). There was no significant difference in OS [hazard ratio (HR) 1.083, 95% confidence interval (CI) 0.626–1.874; P = 0.78], and CSS (HR 0.789, 95%CI 0.411–1.515; P = 0.61) between two groups. Conclusions Both RARC and LRC were safe and effective with a similar long-term clinical outcomes. Moreover, RARC had significantly lower median estimated blood loss and reduced postoperative complications.

Abstract Background Natural astaxanthin (ASTA) has strong antioxidant properties and has been widely used as a health product to improve human health. However, the effects of ASTA on the reproductive performance of aging roosters have been poorly studied. We aimed to investigate the effects of dietary ASTA on semen quality and antioxidant capacity in aging roosters and to explore the potential mechanism of semen quality change via anti-oxidation defense system. Methods In the present study, 96 53-week-old Jinghong No. 1 layer breeder roosters were fed a corn-soybean meal basal diet containing 0, 25, 50, or 100 mg/kg ASTA for 6 weeks. Results Semen quality in the ASTA groups remarkably improved than that in the control group, and antioxidant activities, the abilities to scavenge hydroxyl radicals and superoxide anions, increased gradually with ASTA addition (P

IntroductionPost-hepatectomy liver failure (PHLF) is one of the most serious complications and causes of death in patients with hepatocellular carcinoma (HCC) after hepatectomy. This study aimed to develop a novel machine learning (ML) model based on the light gradient boosting machines (LightGBM) algorithm for predicting PHLF.MethodsA total of 875 patients with HCC who underwent hepatectomy were randomized into a training cohort (n=612), a validation cohort (n=88), and a testing cohort (n=175). Shapley additive explanation (SHAP) was performed to determine the importance of individual variables. By combining these independent risk factors, an ML model for predicting PHLF was established. The area under the receiver operating characteristic curve (AUC), sensitivity, specificity, positive predictive value, negative predictive value, and decision curve analyses (DCA) were used to evaluate the accuracy of the ML model and compare it to that of other noninvasive models.ResultsThe AUCs of the ML model for predicting PHLF in the training cohort, validation cohort, and testing cohort were 0.944, 0.870, and 0.822, respectively. The ML model had a higher AUC for predicting PHLF than did other non-invasive models. The ML model for predicting PHLF was found to be more valuable than other noninvasive models.ConclusionA novel ML model for the prediction of PHLF using common clinical parameters was constructed and validated. The novel ML model performed better than did existing noninvasive models for the prediction of PHLF.

IntroductionDespite the widespread use of the unilateral striatal 6-hydroxydopamine (6-OHDA) lesion model in mice in recent years, the stability of behavioral deficits in the 6-OHDA striatal mouse model over time is not yet clear, raising concerns about using this model to evaluate a compound’s long-term therapeutic effects.Materials and methodsIn the current study, mice were tested at regular intervals in the cylinder test and gait analysis beginning 3 days after 6-OHDA injection of 4 and 8 μg and lasting until 56 days post-lesion. Apomorphine-induced rotational test and rotarod test were also performed on Day 23 and 43 post-lesion, respectively. Immunohistochemistry for dopaminergic neurons stained by tyrosine hydroxylase (TH) was also performed.ResultsOur results showed that both the 4 and 8 μg 6-OHDA lesion groups exhibited forelimb use asymmetry with a preference for the ipsilateral (injection) side on Day 3 and until Day 21 post-lesion, but did not show forelimb asymmetry on Day 28 to 56 post-lesion. The 8 μg 6-OHDA lesion group still exhibited forelimb asymmetry on Day 28 and 42 post-lesion, but not on Day 56. The gait analysis showed that the contralateral front and hind step cycles increased from Day 3 to 42 post-lesion and recovered on Day 56 post-lesion. In addition, our results displayed a dose-dependent reduction in TH+ cells and TH+ fibers, as well as dose-dependent apomorphine-induced rotations. In the rotarod test, the 8 μg 6-OHDA lesion group, but not the 4 μg group, decreased the latency to fall on the rotarod on Day 43 post-lesion.ConclusionIn summary, unilateral striatal 6-OHDA injections of 4 and 8 μg induced spontaneous motor impairment in mice, which partially recovered starting on Day 28 post-lesion. Forced motor deficits were observed in the 8 g 6-OHDA lesion group, which remained stable on Day 43 post-lesion. In addition, the rotarod test and apomorphine-induced rotational test can distinguish between lesions of different extents and are useful tools for the assessment of functional recovery in studies screening novel potential therapies.

Background & Aims: Non-invasive stratification of the liver decompensation risk remains unmet in people with compensated cirrhosis. This study aimed to develop a non-invasive tool (NIT) to predict hepatic decompensation. Methods: This retrospective study recruited 689 people with compensated cirrhosis (median age, 54 years; 441 men) from 5 centres from January 2016 to June 2020. Baseline abdominal computed tomography (CT), clinical features, and liver stiffness were collected, and then the first decompensation was registered during the follow-up. The spleen-based model was designed for predicting decompensation based on a deep learning segmentation network to generate the spleen volume and least absolute shrinkage and selection operator (LASSO)-Cox. The spleen-based model was trained on the training cohort of 282 individuals (Institutions I–III) and was validated in 2 external validation cohorts (97 and 310 individuals from Institutions IV and V, respectively) and compared with the conventional serum-based models and the Baveno VII criteria. Results: The decompensation rate at 3 years was 23%, with a 37.6-month median (IQR 21.1–52.1 months) follow-up. The proposed model showed good performance in predicting decompensation (C-index ≥0.84) and outperformed the serum-based models (C-index comparison test p

The objective of this review was to summarize the most pertinent CT imaging findings in patients with coronavirus disease 2019 (COVID-19). A literature search retrieved eligible studies in PubMed, EMBASE, Cochrane Library and Web of Science up to June 1, 2020. A comprehensive review of publications of the Chinese Medical Association about COVID-19 was also performed. A total of 84 articles with more than 5340 participants were included and reviewed. Chest CT comprised 92.61% of abnormal CT findings overall. Compared with real-time polymerase chain reaction result, CT findings has a sensitivity of 96.14% but a low specificity of 40.48% in diagnosing COVID-19. Ground glass opacity (GGO), pure (57.31%) or mixed with consolidation (41.51%) were the most common CT features with a majority of bilateral (80.32%) and peripheral (66.21%) lung involvement. The opacity might associate with other imaging features, including air bronchogram (41.07%), vascular enlargement (54.33%), bronchial wall thickening (19.12%), crazy-paving pattern (27.55%), interlobular septal thickening (42.48%), halo sign (25.48%), reverse halo sign (12.29%), bronchiectasis (32.44%), and pulmonary fibrosis (26.22%). Other accompanying signs including pleural effusion, lymphadenopathy and pericardial effusion were rare, but pleural thickening was common. The younger or early stage patients tended to have more GGOs, while extensive/multilobar involvement with consolidation was prevalent in the older or severe population. Children with COVID-19 showed significantly lower incidences of some ancillary findings than those of adults and showed a better performance on CT during follow up. Follow-up CT showed GGO lesions gradually decreased, and the consolidation lesions first increased and then remained relatively stable at 6–13 days, and then absorbed and fibrosis increased after 14 days. Chest CT imaging is an important component in the diagnosis, staging, disease progression and follow-up of patients with COVID-19.

PurposeTo determine the predictive value of portal hypertension (PH) for the development of post-hepatectomy liver failure (PHLF) in patients with hepatocellular carcinoma (HCC).Patients and methodsThis study enrolled a total of 659 patients with HCC that received hepatectomy as a first-line therapy. PH was classified as grade 0, 1, and 2 according to whether the indirect criteria for PH were met: 1) patients had obvious varicose veins and 2) splenomegaly was present and platelet count < 100 × 109/L. The effects of each variable on the occurrence of PHLF were assessed using univariate and multivariate analyses.ResultsPH grade 2 (odds ratio [OR] = 2.222, p = 0.011), higher age (OR = 1.031, p = 0.003), hepatitis C infection (OR = 3.711, p = 0.012), open surgery (OR = 2.336, p < 0.001), portal flow blockage (OR = 1.626, p = 0.023), major hepatectomy (OR = 2.919, p = 0.001), hyperbilirubinemia (≥ 17.2 μmol/L, OR = 2.113, p = 0.002), and high levels of alpha-fetoprotein (> 400n g/ml, OR = 1.799, p = 0.008) were significantly associated with PHLF occurrence. We performed a subgroup analysis of liver resection and found that the extent of liver resection and PH grade were good at distinguishing patients at high risk for PHLF, and we developed an easy-to-view roadmap.ConclusionPH is significantly related to the occurrence of PHLF in patients who underwent hepatectomy. Noninvasively assessing PH grade can predict PHLF risk.

To date, little is known about the regulatory landscape of the pig genome. Here, the authors characterize cis-regulatory elements in the pig genome using RNA-seq, ChIP-Seq and ATAC-seq, finding a higher degree of usage conservation between pig and human than mouse and human.

ABSTRACT: As the antioxidant capacity of sperm declines with age in roosters, the objective of the present study was to determine the effects of different levels of pyrroloquinoline quinone disodium (PQQ.Na2) on antioxidative and sperm quality parameters of aging layer breeder roosters. A total of ninety-six 63-wk-old Jinghong No. 1 layer breeder roosters were randomly assigned to 4 treatments (0, 0.5, 1, 2 mg/kg PQQ.Na2) for 6 wk. Antioxidant activity and semen parameters were assessed biweekly. The dietary administration of PQQ.Na2 significantly increased semen quality (semen volume, sperm motility, straightness, progressive motility, curvilinear velocity, straight-line velocity, and amplitude of lateral head displacement) and antioxidant capacity (T-SOD, GSH-Px, hydroxyl radical scavenging ability, and/or superoxide scavenging capacity) in seminal plasma in aging layer breeder roosters. Whereas, PQQ.Na2 supplementations significantly decreased malondialdehyde (MDA) concentration in seminal plasma in aging layer breeder roosters. Supplementation with 1 mg/kg dietary PQQ.Na2 as an antioxidant supplement could increase sperm quality and antioxidant activity of aging layer breeder roosters, while a higher dose (2 mg/kg) did not result in further increment.

Background and AimsEmergency endoscopy is recommended for patients with acute esophageal variceal bleeding (EVB) and their prognosis has improved markedly over past decades due to the increased specialization of endoscopic practice. The study aimed to compare outcomes following emergency endoscopic injection sclerotherapy (EIS) and endoscopic variceal ligation (EVL) in cirrhotic patients with acute EVB.MethodsCirrhotic patients with acute EVB who underwent emergency endoscopy were retrospectively enrolled from 2013 to 2020 across 34 university hospitals from 30 cities. The primary outcome was the incidence of 5-day rebleeding after emergency endoscopy. Subgroup analysis was stratified by Child-Pugh class and bleeding history. A 1:1 propensity score matching (PSM) analysis was performed.ResultsA total of 1,017 and 382 patients were included in EIS group and EVL group, respectively. The 5-day rebleeding incidence was similar between EIS group and EVL group (4% vs. 5%, P = 0.45). The result remained the same after PSM (P = 1.00). Among Child-Pugh class A, B and C patients, there were no differences in the 5-day rebleeding incidence between the two groups after PSM (P = 0.25, 0.82, and 0.21, respectively). As for the patients with or without bleeding history, the differences between EIS group and EVL group were not significant after PSM (P = 1.00 and 0.26, respectively).ConclusionThe nationwide cohort study indicates that EIS and EVL are both efficient emergency endoscopic treatment strategies for acute EVB. EIS should not be dismissed as an economical and effective emergency endoscopic treatment strategy of acute EVB. ClincialTrials.gov number NCT04307264.

Abstract Background Cardiovascular diseases (CVDs) and diabetes mellitus (DM) are top two chronic comorbidities that increase the severity and mortality of COVID‐19. However, how SARS‐CoV‐2 alters the progression of chronic diseases remain unclear. Methods We used adenovirus to deliver h‐ACE2 to lung to enable SARS‐CoV‐2 infection in mice. SARS‐CoV‐2’s impacts on pathogenesis of chronic diseases were studied through histopathological, virologic and molecular biology analysis. Results Pre‐existing CVDs resulted in viral invasion, ROS elevation and activation of apoptosis pathways contribute myocardial injury during SARS‐CoV‐2 infection. Viral infection increased fasting blood glucose and reduced insulin response in DM model. Bone mineral density decreased shortly after infection, which associated with impaired PI3K/AKT/mTOR signaling. Conclusion We established mouse models mimicked the complex pathological symptoms of COVID‐19 patients with chronic diseases. Pre‐existing diseases could impair the inflammatory responses to SARS‐CoV‐2 infection, which further aggravated the pre‐existing diseases. This work provided valuable information to better understand the interplay between the primary diseases and SARS‐CoV‐2 infection.