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Background Neurodevelopmental disorders (NDDs) are associated with altered development of the brain especially in childhood. Copy number variants (CNVs) play a crucial role in the genetic aetiology of NDDs by disturbing gene expression directly at linear sequence or remotely at three-dimensional genome level in a tissue-specific manner. Despite the substantial increase in NDD studies employing whole-genome sequencing, there is no specific tool for prioritising the pathogenicity of CNVs in the context of NDDs.Methods Using an XGBoost classifier, we integrated 189 features that represent genomic sequences, gene information and functional/genomic segments for evaluating genome-wide CNVs in a neuro/brain-specific manner, to develop a new tool, neuroCNVscore. We used Human Phenotype Ontology to construct an independent NDD-related set.Results Our neuroCNVscore framework (https://github.com/lxsbch/neuroCNVscore) achieved high predictive performance (precision recall=0.82; area under curve=0.85) and outperformed an existing reference method SVScore. Notably, the predicted pathogenic CNVs showed enrichment in known genes associated with autism.Conclusions NeuroCNVscore prioritises functional, deleterious and pathogenic CNVs in NDDs at whole genome-wide level, which is important for genetic studies and clinical genomic screening of NDDs as well as for providing novel biological insights into NDDs.

Abstract Background Limited data is available on retinal vessel morphology in the north China. The study aimed to evaluate the prevalence of retinal vascular abnormalities (RVAs) and investigate their associations with the self-reported diagnosis of cardiovascular and cerebrovascsular diseases (CCVds) in a rural adult population of northeast China. Methods A population-based, cross-sectional study was conducted, using the cluster random sampling method. One eye of each participant was photographed with a non-mydriatic fundus camera. RVAs including focal and general arteriolar narrowing (FAN and GAN), arteriovenous nicking (AVN), arteriolar sheathing (AS), and retinopathy were evaluated. Data on self-reported diagnosis of cardiovascular and cerebrovascular diseases and status of smoking and alcohol drinking were obtained from questionnaires. Results Among the 6267 participants with an age ≥ 50 years, photographs were obtained of 99.2%, with quality sufficient to perform retinal evaluations in 82.5%. The prevalence of FAN, AVN, AS, retinopathy and GAN were 9.1, 8.9, 5.0, 6.6 and 6.2%, respectively. All the retinal lesions were associated with hypertension (all P

Genome-wide association studies (GWAS) have contributed significantly to predisposing the disease etiology by associating single nucleotide polymorphisms (SNPs) with complex diseases. However, most GWAS-SNPs are in the noncoding regions that may affect distal genes via long range enhancer-promoter interactions. Thus, the common practice on GWAS discoveries cannot fully reveal the molecular mechanisms underpinning complex diseases. It is known that perturbations of topological associated domains (TADs) lead to long range interactions which underlie disease etiology. To identify the probable long range interactions in noncoding regions via GWAS and TADs perturbed by deletions, we integrated datasets from GWAS-SNPs, enhancers, TADs, and deletions. After ranking and clustering, we prioritized 201,132 high confident pairs of GWAS-SNPs and target genes. In this study, we performed a systematic inference on noncoding regions via GWAS-SNPs and deletion-perturbed TADs to boost GWAS discovery power. The high confident pairs of GWAS-SNPs and target genes (SE-Gs) provide the promising candidates to understand the molecular mechanisms underlying complex diseases with emphasis on the three-dimensional genome.

The hydrological regimes of many freshwater lakes have been dramatically changed by human activity. Nevertheless, few studies have reported the effects of human water management on the formation mechanisms of lakeshore plant communities. In this study, we investigated the effects of flooding and soil nutrients on the plant diversity of lakeshore Carex communities fringing a pristine lake (Poyang Lake) and a human managed lake (Shengjin Lake), two adjacent floodplain lakes in the middle and lower reaches of the Yangtze River. Over time, the Carex meadow at Shengjin Lake experienced a lower flooding frequency and a smaller amplitude of water level fluctuations in comparison with those obtained at Poyang Lake, but similar flooding durations were found for both sites. Soil total nitrogen (TN), total phosphorus (TP) and the ratio of TN to TP in study plots at Shengjin Lake tended to be higher than those in the plots at Poyang Lake at the 0–100 cm soil depth except for soil TP at the 0–10 cm soil depth. A total of 23 plant species were recorded in the Carex communities at the two lakes. Artificial water management increased plant diversity but had no effect on plant biomass in the Carex community. The primary factor in determining plant diversity changed from the flooding regime to the concentrations of soil nutrients as the water regime underwent management. Flooding regimes had strong direct impacts on the plant communities, while imposing few indirect effects on plants by changing soil nutrients in the pristine lake. Our results represent essential information for enhancing the robustness of management efforts for these large and important freshwater lakes.

AIM:To analyze the postoperative visual acuity, and preoperative and postoperative complications in cataract patients in Tibet Plateau area who received small incision cataract extraction without phacoemulsification as compared to in those who received phacoemulsification. METHODS:Four hundred and thirteen cataract patients admitted to ophthalmology departments in traditional Tibetan medicine hospital in Tibet Autonomic Region from October 2014 to January 2015 were collected. They were randomized into the group(200 patients with 200 eyes)receiving phacoemulsification combined with intraocular lens implantation as Phaco group and the group(213 patients with 213 eyes)receiving small incision cataract extraction combined with intraocular lens implantation as small incision group. The two groups were compared for uncorrected visual acuity at 1 and 5d postoperatively, and the preoperative and postoperative complications. RESULTS:At 1 and 5d postoperatively, there were 150 eyes(70.4%)and 196 eyes(92.0%)with visual acuity ≥0.5 in the small incision group, respectively. There were 156 eyes(78.0%)and 185 eyes(92.5%)in the Phaco group. The difference value of visual acuity before and at 1d after the operation of Phaco group was higher than that of small incision group(PP=0.33). According to Emery Standard, the number of eyes with visual acuity ≥0.5 showed no statistically significant differences between two groups in the patients with nuclear-grade I, Ⅳ and Ⅴ(P>0.05); however, it was statistically significant differences between two groups in the patients with nuclear-gradeⅡ and Ⅲ(PP>0.05).CONCLUSION:This study showed that age-relative cataract is still one of the most common pathogenesis in Tibet. Surgery is the only option for the best treatment effect so far. On postoperative 1d, the visual acuity of the patients with nuclear-gradeⅡ and Ⅲ in the Phaco group improved more than those in the small incision group. While, there was no significant difference in patients with nuclear-grade I, Ⅳ and Ⅴ. No differences were found on corneal edema, iris reaction or other complications. Therefore, small incision cataract extraction can achieve similar effect in the absence of condition for phacoemulsification.

The heat-tolerance mechanisms of (hyper)thermophilic proteins provide a unique opportunity to investigate the unsolved protein folding problem. In an attempt to determine whether the interval between residues in sequence might play a role in determining thermostability, we constructed a sequence interval-dependent value function to calculate the residue pair frequency. Additionally, we identified a new sequence arrangement pattern, where like-charged residues tend to be adjacently assembled, while unlike-charged residues are distributed over longer intervals, using statistical analysis of a large sequence database. This finding indicated that increasing the intervals between unlike-charged residues can increase protein thermostability, with the arrangement patterns of these charged residues serving as thermodynamically favorable nucleation points for protein folding. Additionally, we identified that the residue pairs K-E, R-E, L-V and V-V involving long sequence intervals play important roles involving increased protein thermostability. This work demonstrated a novel approach for considering sequence intervals as keys to understanding protein folding. Our findings of novel relationships between residue arrangement and protein thermostability can be used in industry and academia to aid the design of thermostable proteins.

Uveal melanoma is the most common intraocular malignant tumor in adults. For patients presenting with cataracts and glaucoma, it is recommended to assess whether an intraocular lesion is present as the primary cause. The present study describes the case of a 52-year-old man with primary intraocular malignant melanoma. The patient experienced painless vision loss in the right eye for 1 year, with recent onset of eye swelling and pain in the week prior to seeking medical attention. A slit-lamp examination revealed a shallow anterior chamber in the right eye, a visibly opaque lens and a faint reflection of the tumor surface in the vitreous humor. In addition, the intraocular pressure of this eye was >60 mmHg. Magnetic resonance imaging revealed a large tumor behind the lens measuring 16x18x14 mm. Pathological examination confirmed the diagnosis of malignant melanoma. No BRCA-associated protein-1 somatic mutation was detected, whereas germline mutations of MutL protein homolog 1, RAD54 like, and SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 were identified. Extensive systemic examination excluded the possibility that the tumors originated from another part of the body. The present case report highlights the crucial role of slit-lamp examination in the detection of ocular tumors. It is advocated that for patients presenting with cataracts, attention should be paid to the possibility of intraocular tumors. Meticulous slit-lamp microscopy may reveal a reflection of the surface of a malignant melanoma, preventing misdiagnosis. [ABSTRACT FROM AUTHOR]

Oxidative stress and apoptosis play vital role in diabetic rats suffering from renal ischemia reperfusion injury (IRI). As a dipeptidyl dipeptidase-4 (DPP-4) inhibitor, Saxagliptin(SAX)has been confirmed in the regulation of inflammation and apoptosis by targeting Nrf-2/HO-1signalling. The study was designed to explore the efficacy and potential mechanisms of SAX on inflammation and apoptosis for treating of IRI in diabetic rats. Through testing the expressions of Nrf-2, HO-1, Cleaved-Caspase9, Cleaved-Caspase3, Bax, BCL-2, Bak, Apaf-1, cytochrome C (Cytc), Cystatin C (Cyssingle bondC), β2-microglobulin (β2-MG), creatinine (Cr), urea nitrogen (BUN), TUNEL and pathological morphology, the effects of SAX on IRI diabetic rats have been investigatedg. The results has displayed SAX treatment significantly attenuate the cell apoptosis and pathological damage of kidney as well as lessening the expression of cleaved-caspase-9, cleaved-caspase3, Bax, cytoplasmic-Cytc, MDA, Bak, and Apaf-1 molecules, and the contents of ROS, Cr, Cyssingle bondC, β2-MG, and BUN. Furthermore, SAX therapy also increased the expression of Nrf-2, BCL-2, HO-1 and mitochondrial cytochrome Cytc, and enhanced the activity of SOD, CAT and GPx. Therefore, our study has indicated that SAX treatment alleviated IRI in diabetic rats by suppressing oxidative stress and mitochondrial apoptotic pathways by activating the Nrf-2/HO-1 signaling. [ABSTRACT FROM AUTHOR]

Background Endothelial dysfunction is associated with the risk of cardiovascular complications in diabetic patients. Endothelial progenitor cells (EPCs) and flow-mediated dilation (FMD) are common markers of endothelial function. In this study, we aim to investigate whether the DPP-4 inhibitor saxagliptin modulate EPCs number and FMD in newly diagnosed, treatment-naive type 2 diabetic patients. Methods This was a controlled, randomized, open-label clinical trial. Saxagliptin group and metformin group consumed either saxagliptin 5 mg per day or metformin 1 500 mg per day respectively for 12 weeks. Changes of FMD and EPCs number after 12-week intervention were the primary endpoints. Results 31 patients were initially enrolled and randomized to saxagliptin group (n = 16) and metformin group (n = 15). 27 patients completed the trial (saxagliptin group n = 14 and metformin group n = 13), and 4 patients dropped out during the study. FMD and EPCs number increased significantly in both saxagliptin group and metformin group, and there was no significant difference between groups. 2-h postprandial plasma glucose, HbA1c and diastolic blood pressure improved significantly in both groups, and there was no significant difference between groups. Conclusion Saxagliptin and metformin had comparable beneficial effects on endothelial function. [ABSTRACT FROM AUTHOR]

nti-apoptosis plays an important role in tumour formation and development. Survivin is a member of the inhibitor of apoptosis (IAP) family, which is a target for anti-cancer drug exploitation was replaced as development. We investigated the role of the homo dominant-negative mutant Survivin-T34A in suppressing human lung adenocarcinomas (A549). The anti-tumour activity of HSurvivinT34A plasmid was evaluated in the A549 cell line and nude mice bearing A549 subcutaneous tumours. Low-dose systemic administration was continuously used. The HSurvivinT34A plasmid (5 µg/one) complexed with a cationic liposome (DOTAP/Chol) significantly inhibited tumour growth in our model. We observed microvessel density degradation by CD31 immunohistochemistry and apoptotic cell increase by TUNEL assay, PI staining and flow cytometric analysis in the treated group. The present findings suggest that the HSurvivinT34A plasmid complexed with a cationic liposome may provide an effective approach to inhibit the growth of human lung adenocarcinomas in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Background: A high concentration of cisplatin (CDDP) induces apoptosis in many tumor cell lines. CDDP has been administered by infusion to avoid severe toxicity. Recently, it has been reported that changes in survivin expression or function may lead to tumor sensitization to chemical and physical agents. The aim of this study was to determine whether a dominant-negative mouse survivin mutant could enhance the anti-tumor activity of CDDP. Methods: A plasmid encoding the phosphorylation-defective dominant-negative mouse survivin threonine 34Talanine mutant (survivin T34A) complexed to a DOTAP-chol liposome (Lip-mS) was administered with or without CDDP in Lewis Lung Carcinoma (LLC) cells and in mice bearing LLC tumors, and the effects on apoptosis, tumor growth and angiogenesis were assessed. Data were analyzed using one-way analysis of variance(ANOVA), and a value of P < 0.05 was considered to be statistically significant. Results: LLC cells treated with a combination of Lip-mS and CDDP displayed increased apoptosis compared with those treated with Lip-mS or CDDP alone. In mice bearing LLC tumors and treated with intravenous injections of Lip-mS and/ or CDDP, combination treatment significantly reduced the mean tumor volume compared with either treatment alone. Moreover, the antitumor effect of Lip-mS combined with CDDP was greater than their anticipated additive effects. Conclusion: These data suggest that the dominant-negative survivin mutant, survivin T34A, sensitized LLC cells to chemotherapy of CDDP. The synergistic antitumor activity of the combination treatment may in part result from an increase in the apoptosis of tumor cells, inhibition of tumor angiogenesis and induction of a tumor-protective immune response. [ABSTRACT FROM AUTHOR]

The persistently low pay-performance sensitivity between executive compensation and firm performance has puzzled both practitioners and academics. We propose a hybrid model that incorporates both moral hazard and adverse selection problems to explain this puzzle. We argue that the managerial labor market is heterogeneous in nature, not homogeneous as assumed by the pure moral hazard model and empirical work based on this model. We demonstrate that the optimal pay-performance sensitivity derived from the hybrid model is lower than that derived from the pure moral hazard model. Furthermore, we also show that pay-performance sensitivity is a function of the mix of types in the market. The more capable managers there are in the market, the more likely the market's average pay-performance sensitivity is high. We then conduct an empirical test and find evidence that is consistent with the prediction of our model. [ABSTRACT FROM AUTHOR]

Wheat is one of the major food crops in the world. Functional validation of the genes in increasing the grain yield of wheat by genetic engineering is essential for feeding the ever-growing global population. This study investigated the role of ABP7, a bHLH transcription factor from maize involved in kernel development, in regulating grain yield-related traits in transgenic wheat. Molecular characterization showed that transgenic lines HB123 and HB287 contained multicopy integration of ABP7 in the genome with higher transgene expression. At the same time, QB205 was a transgenic event of single copy insertion with no significant difference in ABP7 expression compared to wild-type (WT) plants. Phenotyping under field conditions showed that ABP7 over-expressing transgenic lines HB123 and HB287 exhibited improved grain yield-related traits (e.g., grain number per spike, grain weight per spike, thousand-grain weight, grain length, and grain width) and increased grain yield per plot, compared to WT plants, whereas line QB205 did not. In addition, total chlorophyll, chlorophyll a, chlorophyll b, and total soluble sugars were largely increased in the flag leaves of both HB123 and HB287 transgenic lines compared to the WT. These results strongly suggest that ABP7 positively regulates yield-related traits and plot grain yield in transgenic wheat. Consequently, ABP7 can be utilized in wheat breeding for grain yield improvement.

Increasing the planting density is one way to enhance grain production in maize. However, high planting density brings about growth and developmental defects such as barrenness, which is the major factor limiting grain yield. In this study, the barrenness was characterized in an association panel comprising 280 inbred lines under normal (67 500 plants ha–1, ND) and high (120 000 plants ha–1, HD) planting densities in 2017 and 2018. The population was genotyped using 776 254 single nucleotide polymorphism (SNP) markers with criteria of minor allele frequency >5% and

Background. There is a significant role for peroxisome proliferator-activated receptors (PPARs) in the development of cancer. Nevertheless, the role of PPARs-related genes in ovarian cancer (OC) remains unclear. Methods. The open-accessed data used for analysis were downloaded from The Cancer Genome Atlas database, which was analyzed using the R software. Results. In our study, we comprehensively investigated the PPAR target genes in OC, including their biological role. Meanwhile, a prognosis signature consisting of eight PPAR target genes was established, including apolipoprotein A-V, UDP glucuronosyltransferase 2 family, polypeptide B4, TSC22 domain family, member 1, growth hormone inducible transmembrane protein, renin, dedicator of cytokinesis 4, enoyl CoA hydratase 1, peroxisomal (ECH1), and angiopoietin-like 4, which showed a good prediction efficiency. A nomogram was constructed by combining the clinical feature and risk score. Immune infiltration and biological enrichment analysis were applied to investigate the difference between high- and low-risk patients. Immunotherapy analysis indicated that low-risk patients might respond better to immunotherapy. Drug sensitivity analysis indicated that high-risk patients might respond better to bleomycin, nilotinib, pazopanib, pyrimethamine, and vinorelbine, yet worse to cisplatin and gefitinib. Furthermore, the gene ECH1 was selected for further analysis. Conclusions. Our study identified a prognosis signature that could effectively indicates patients survival. Meanwhile, our study can provide the direction for future studies focused on the PPARs in OC.

Introduction Rheumatoid arthritis (RA) has a huge societal impact due to the high prevalence, irreversible joint damage and systemic complications. Gut microbiota plays an important role in the pathogenesis and progression of RA by regulating the host immune system. Restoring intestinal homeostasis by altering the microbiota could be an attractive strategy for the prevention and treatment of RA. However, the signature features of microbial dysbiosis in RA are still controversial. Therefore, we aim to elucidate the characteristic change in the diversity and composition of gut microbiota in RA.Methods and analysis We will systematically search through PubMed, EMBASE, Web of Science and Cochrane Library, as well as dissertations and conference proceedings. The reference lists of all included studies will be also reviewed to retrieve additional relevant studies. The case-control studies that reported either the relative abundance of bacteria at the phylum or genus level or at least one of the alpha-diversity, beta-diversity indexes in both RA and healthy controls will be included. Eligible studies will be screened independently by two reviewers according to the inclusion criteria. The Newcastle-Ottawa Quality Assessment Scale will be used to assess the quality of the included studies. Data extraction, qualitative and quantitative analysis will be performed within the gut microbial dysbiosis in RA. The expected outcomes will be the identification of the specific changes in composition and diversity of the gut microbiota in patients with RA. The quality of evidence will be assessed by the Grading of Recommendations Assessment, Development and Evaluation framework.Ethics and dissemination Ethical approval is unnecessary as this review does not address the data and privacy of patients. The results will be published in a peer-reviewed scientific journal and conference presentations.PROSPERO registration number CRD42021225229.

Food shortages arise more frequently owing to unpredictable crop yield losses caused by biotic and abiotic stresses. With advances in molecular biology and marker technology, a new era of molecular breeding has emerged that has greatly accelerated the pace of plant breeding. High-throughput genotyping technology and phenotyping platforms have enabled large-scale marker-trait association analysis, such as genome-wide association studies, to precisely dissect the genetic architecture of plant traits. Large-scale mapping of agronomically important quantitative trait loci, gene cloning and characterization, mining of elite alleles/haplotypes, exploitation of natural variations, and genomic selection have paved the way towards genomics-assisted breeding (GAB). With the availability of more and more informative genomic datasets, GAB would become a promising technique to expedite the breeding cycle for crop improvement.

Ethnopharmacological relevance YiQiFuMai Powder Injection (YQFM), a traditional Chinese medicine prescription re-developed based on Sheng-Mai-San, is a classical and traditional therapeutic for clinical heart failure (HF) and angina. However, its potential mechanism against HF remains unclear. Aim of the study The present study observes the therapeutic role of YQFM and mechanisms underlying its effects on coronary artery ligation (CAL)-induced myocardial remodeling (MR) and HF. Methods MR and HF were induced by permanent CAL for 2 weeks in ICR mice. Then mice were treated with YQFM (0.13 g/kg, 0.26 g/kg and 0.53 g/kg) once a day until 2 weeks later. Cardiac structure and function were evaluated by echocardiography. Serum lactate dehydrogenase (LDH), creatine kinase (CK) and malondialdehyde (MDA) were measured by biochemical kits and cardiomyocyte morphology was assessed by hematoxylin-eosin (HE) staining. Myocardial hydroxyproline (HYP), serum amino-terminal pro-peptide of pro-collagen type III (PIIINP), and Masson's trichrome staining were employed to evaluate cardiac fibrosis. Circulating level of N-terminal pro-B-type natriuretic peptide (NT-proBNP) was tested by ELISA kit to predict prognosis of CAL-induced HF. Effects of YQFM on the mitogen-activated protein kinases (MAPKs) pathway after CAL operation was evaluated by Western blotting and immunohistochemistry assay. Results YQFM (0.53 g/kg) improved the left ventricular (LV) function and structure impairment after 2 weeks in CAL mice. YQFM administration also decreased LDH and CK activities, circulating levels of MDA, PIIINP, NT-proBNP, and HYP contents. Moreover, YQFM ameliorated cardiac injury and fibrosis. Furthermore, YQFM (0.53 g/kg) inhibited the myocardial phosphorylation of MAPKs in HF mice. Conclusion Our findings suggest that YQFM attenuates CAL-induced HF via improving cardiac function, attenuating structure damage, oxidative stress, necrosis, collagen deposition, and fibrosis. In addition, YQFM ameliorates cardiac remodeling and HF, partially through inhibiting the MAPKs signaling pathways. These data provide insights and mechanisms into the widely application of YQFM in patients with HF, MI and other ischemic heart diseases. [ABSTRACT FROM AUTHOR]