Search

Key Clinical Message Balanced reciprocal chromosomal translocation carriers will have greater risk to experience recurrent miscarriages, embryonic death, and infertility. We show the pedigree carrying a paternal karyotype which was reported first. This research helps to better understand the clinical manifestations and prognosis of patients with this rare chromosomal abnormality.

Objective: To provide prenatal diagnosis for a pregnant woman with genetic history of intellectual disability. Case report: A Chinese pedigree with intellectual disability was collected in this study. Cytogenetic analysis, chromosomal microarray analysis (CMA) and whole exome sequencing (WES) followed by Sanger validation were conducted to identify the genetic pathogenesis. A novel heterozygous deletion c.370_374delTTCCC in TBR1 gene was identified, leading to a frameshift mutation starting at Phe124 followed by a premature stop codon at position 141 (p.Phe124Valfs∗18). Segregation analysis identified that this novel mutation is co-segregated among the affected family members but absent in unaffected family members. Prenatal diagnosis indicated the absence of this mutation, and the family decided to continue the pregnancy after genetic counseling. Conclusion: Our findings demonstrated the significance of genetic testing in the diagnosis of intellectual disability. This work also confirmed the effectiveness of WES in prenatal diagnosis.

Abstract Background Down syndrome is characterized by trisomy 21 or partial duplication of chromosome 21. Extensive studies have focused on the identification of the Down Syndrome Critical Region (DSCR). We aim to provide evidence that duplication of 21q21.1-q21.2 should not be included in the DSCR and it has no clinical consequences on the phenotype. Case presentation Because serological screening was not performed at the appropriate gestational age, noninvasive prenatal testing (NIPT) analysis was performed for a pregnant woman with normal prenatal examinations at 22 weeks of gestation. The NIPT results revealed a 5.8 Mb maternally inherited duplication of 21q21.1-q21.2. To assess whether the fetus also carried this duplication, ultrasound-guided amniocentesis was conducted, and the result of chromosomal microarray analysis (CMA) with amniotic fluid showed a 6.7 Mb duplication of 21q21.1-q21.2 (ranging from position 18,981,715 to 25,707,009). This partial duplication of 21q21.1-q21.2 in the fetus was maternally inherited. After genetic counseling, the pregnant woman and her family decided to continue the pregnancy. Conclusion Our case clearly indicates that 21q21.1-q21.2 duplication is not included in the DSCR and most likely has no clinical consequences on phenotype.

Abstract Background Cleft lip with or without cleft palate (CL/P) is the most common craniofacial anomaly with a high incidence of live births. The specific pathogenesis of CL/P is still unclear, although plenty of studies have been conducted. Variations of tumor protein 63 (TP63) was reported to be related to the phenotype of CL/P. The case discussed in this report involves a pedigree with mutation at TP63 gene, and the variation was not reported before. Case presentation A Chinese pedigree with CL/P was collected in this study. The proband is a 3-year-old boy with the phenotype of CL/P, while his global development and intelligence are normal. After two CL/P repair operations, he looks almost normal. The proband's uncle and grandmother both have the phenotype of CL/P. Cytogenetic analysis and chromosomal microarray analysis (CMA) were performed, followed by whole exome sequencing (WES) and sanger validation. Analysis of WES revealed a variant of C>T at nucleotide position 1324 (1324C>T) of TP63 gene, possibly producing a truncated protein with a premature stop codon at amino acid position 442 (p.Q442*). This mutation was localized at the oligomerization domain (OD) of TP63 and might impair the capacity of p63 oligomerization. Conclusion The mutation in TP63 was recognized to be the possible cause of the phenotype of CL/P in this pedigree. This report provides some evidence for the clinical diagnosis of CL/P. And our study also provides clinical evidence for the molecular mechanism of TP63 gene causing nonsyndromic cleft lip with or without cleft palate (NSCL/P).

Abstract Background This meta-analysis aimed to compare the clinical outcomes and complications of minimally invasive plate osteosynthesis (MIPO) and open reduction–internal fixation (ORIF) in patients with proximal humeral fractures. Methods We searched PubMed, EMBASE, Ovid, and the Cochrane Library to identify all relevant studies from inception to April 2019. Cochrane Collaboration’s Review Manage 5.3 was used for meta-analysis. Results Sixteen studies involving 1050 patients (464 patients in the MIPO group and 586 patients in the ORIF group) were finally included. According to the meta-analysis, MIPO was superior to ORIF in operation time, blood loss, postoperative pain, fracture union time, and constant score. However, MIPO was associated with more exposure to radiation and axillary nerve injury. No significant differences were found in length of hospital stays and complication except for axillary nerve injury. Conclusion The present evidence indicates that compared to ORIF, MIPO had advantages in functional outcomes, operation time, blood loss, postoperative pain, and fracture union time for the treatment of PHFs. However, the MIPO technique had a higher rate of axillary nerve injury and longer radiation time compared to ORIF.

Several viruses within the Coronaviridae family have been categorized as either emerging or re-emerging human pathogens, with Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) being the most well known. The NIAID-sponsored Virus Pathogen Database and Analysis Resource (ViPR, www.viprbrc.org) supports bioinformatics workflows for a broad range of human virus pathogens and other related viruses, including the entire Coronaviridae family. ViPR provides access to sequence records, gene and protein annotations, immune epitopes, 3D structures, host factor data, and other data types through an intuitive web-based search interface. Records returned from these queries can then be subjected to web-based analyses including: multiple sequence alignment, phylogenetic inference, sequence variation determination, BLAST comparison, and metadata-driven comparative genomics statistical analysis. Additional tools exist to display multiple sequence alignments, view phylogenetic trees, visualize 3D protein structures, transfer existing reference genome annotations to new genomes, and store or share results from any search or analysis within personal private ‘Workbench’ spaces for future access. All of the data and integrated analysis and visualization tools in ViPR are made available without charge as a service to the Coronaviridae research community to facilitate the research and development of diagnostics, prophylactics, vaccines and therapeutics against these human pathogens.

Abstract Background Alternative splicing (AS) is a process that facilitates the differential inclusion of exonic sequences from precursor messenger RNAs, significantly enhancing the diversity of the transcriptome and proteome. In cancer, pathogenic AS events are closely related to cancer progression. This study aims to investigate the role and regulatory mechanisms of AS in gastric cancer (GC). Methods We analyzed AS events in various tumor samples and identified hnRNPU as a key splicing factor in GC. The effects of hnRNPU on cancer progression were assessed through in vitro and in vivo experiments. Gene knockout models and the FTO inhibitor (meclofenamic acid) were used to validate the interaction between hnRNPU and FTO and their impact on AS. Results We found that hnRNPU serves as a key splicing factor in GC, and its high expression is associated with poor clinical prognosis. Genetic depletion of hnRNPU significantly reduced GC progression. Mechanistically, the m6A demethylase FTO interacts with hnRNPU transcripts, decreasing the m6A modification levels of hnRNPU, which leads to exon 14 skipping of the MET gene, thereby promoting GC progression. The FTO inhibitor meclofenamic acid effectively inhibited GC cell growth both in vitro and in vivo. Conclusion The FTO/hnRNPU axis induces aberrant exon skipping of MET, thereby promoting GC cell growth. Targeting the FTO/hnRNPU axis may interfere with abnormal AS events and provide a potential diagnostic and therapeutic strategy for GC. Graphical Abstract Schematic model for the findings of this work: Aberrant hnRNPU in GC binds FTO. The m6A-modified hnRNPU transcripts are recognized by m6A reader YTHDF3 and subsequently demethylated by FTO. This demethylation enhances the stability of hnRNPU mRNA, consequently promoting alternative splicing of MET. The altered splicing pattern ultimately contributes to the proliferation of GC cells.

Abstract Doxorubicin (DOX), a potent antineoplastic agent, is commonly associated with cardiotoxicity, necessitating the development of strategies to reduce its adverse effects on cardiac function. Previous research has demonstrated a strong correlation between DOX‐induced cardiotoxicity and the activation of oxidative stress pathways. This work introduces a novel antioxidant therapeutic approach, utilizing libraries of tannic acid and N‐acetyl‐L‐cysteine‐protected bimetallic cluster nanozymes. Through extensive screening for antioxidative enzyme‐like activity, an optimal bimetallic nanozyme (AuRu) is identified that possess remarkable antioxidant characteristics, mimicking catalase‐like enzymes. Theoretical calculations reveal the surface interactions of the prepared nanozymes that simulate the hydrogen peroxide decomposition process, showing that these bimetallic nanozymes readily undergo OH⁻ adsorption and O₂ desorption. To enhance cardiac targeting, the atrial natriuretic peptide is conjugated to the AuRu nanozyme. These cardiac‐targeted bimetallic cluster nanozymes, with their anchoring capability, effectively reduce DOX‐induced cardiomyocyte ferroptosis and PANoptosis without compromising tumor treatment efficacy. Thus, the therapeutic approach demonstrates significant reductions in chemotherapy‐induced cardiac cell death and improvements in cardiac function, accompanied by exceptional in vivo biocompatibility and stability. This study presents a promising avenue for preventing chemotherapy‐induced cardiotoxicity, offering potential clinical benefits for cancer patients.

Objective To investigate the association between preoperative nutritional scores and moderate-to-severe acute kidney injury (AKI) after coronary artery bypass graft (CABG) surgery and the predictive significance of nutritional indices for moderate to severe AKI.Methods This study retrospectively included older patients underwent CABG surgery from the Medical Information Mart for Intensive Care (MIMIC) database. Nutritional scores were calculated by the Geriatric Nutritional Risk Index (GNRI) and the Prognostic Nutritional Index (PNI), respectively. Moderate-to-severe injury was determined by KDIGO criteria. Logistic regression, subgroup analysis, and restricted cubic splines were utilized to investigate the association. The predictive value was also assessed by the area under the curve (AUC), net reclassification index (NRI), and integrated discrimination improvement (IDI).Results A total of 1,007 patients were retrospectively included, of which 100 (9.9%) and 380 (37.7%) had malnutrition calculated by GNRI and PNI scores. The incidence of moderate-to-severe AKI was 524 (52.0%). After adjustment for selected risk factors, worse nutritional scores were associated with a higher incidence of moderate-to-severe AKI (PGNRI

Purpose: Using regional homogeneity (ReHo) and functional connectivity (FC) to assess alterations in brain function and their potential relation to different Hoehn and Yahr (H&Y) stages in Parkinson's disease (PD). Materials and methods: 66 patients with PD and 57 age- and sex-matched healthy control (HC) participants were recruited. All subjects underwent clinical assessments and resting-state functional magnetic resonance imaging (rs-fMRI) scanning. We analyzed alterations in regional brain activity using ReHo analyses in all subjects and further explored their relationship to disease severity. Finally, the brain region significantly associated with disease severity was used as a seed point to analyze the FC changes between it and other brain regions in the whole brain. Results: Compared with HC participants, PD patients showed a significant decrease ReHo in the sensorimotor network (bilateral precentral and postcentral gyrus). The ReHo value of the left precentral gyrus in PD patients decreased with increasing H&Y stage and correlated negatively with Unified Parkinson’s Disease Rating Scale (UPDRS) III scores. Further, FC analysis of the left precentral gyrus as a region of interest showed that functional activity between the left precentral gyrus and sensorimotor network, default network, and visual network was decreased. Conclusion: The left precentral gyrus plays an important role in the pathophysiological mechanisms of PD patients, and this finding further highlights the potential of the primary motor cortex (M1) as a non-invasive therapeutic target for neuromodulation in PD patients.

Introduction:At different times, China has pursued different carbon emission reduction targets, so it is crucial to develop a reasonable and flexible allocation scheme for Chinese carbon emissions quotas, referred to as Chinese Emission Allowance (CEA), in order to achieve carbon reduction goals. As important responsible entities for carbon reduction, each province needs to rely on a well-designed CEA allocation scheme to help achieve their emission reduction goals.Methods:Therefore, based on the utility perspective, this paper constructs allocation principles and methods to formulate the inter-provincial CEA allocation scheme for China in 2030. Specifically, the entropy method, SBM model, improved variable weight function, and ARIMA time series model are sequentially adopted to simulate the re-allocation scheme, examine its rationality, and develop CEA allocation schemes under different principles.Results and Discussion:The following conclusions are drawn: 1) The allocation scheme formulated based on historical emission simulation methods, industry benchmark methods, and other current CEA allocation methods has certain irrationality, and future CEA allocation should not follow the original methods; 2) The improved variable weight function is better suited for allocation in CEA than the current original allocation method. The allocation scheme developed under this method, which balances fairness and efficiency principles, is more appropriate for the actual reduction of carbon emissions in China.

Introduction and objectives The present study aimed to investigate different peripheral lymphocyte subsets in patients with severe hemophilia A (HA) and factor VIII (FVIII) inhibitor production. For this, age-matched cases of 19 FVIII inhibitor-positive (IP), 21 FVIII inhibitor-negative (IN) and 45 healthy controls were selected for study. Methods Flow cytometry was used to analyze the peripheral lymphocyte subsets, including T, B, natural killer (NK) and NKT cells. The T cell subsets included CD3 + CD4-CD8- [double negative T (DNT)], CD3 + CD4 + CD8+ [double-positive T (DPT)], CD3 + CD4 + CD8- and CD3 + CD4-CD8+ T cells. Pairwise comparisons of absolute lymphocyte subset values were conducted among the three groups. The cut-off value for absolute lymphocyte counts was determined using receiver operating characteristic curve analysis. Results The results demonstrated that the absolute values of DPT cells in the IN and IP groups were significantly lower than those in the healthy control group ( P = 0.007). The DNT values were also lower in severe HA patients with or without inhibitor than those in healthy subjects, but these differences were not statistically significant ( P = 0.053). In addition, the absolute value of CD4+ Th cells in the IP group was lower than that in the healthy controls ( P = 0.013). Although not statistically significant ( P = 0.064), the absolute values of NKT cells were higher in the IN group compared with the IP group, and higher in the IP group compared with the healthy control group. There were no statistically significant differences in total T, B, CD8 + and NK cells among the IN, IP and healthy control groups. The cut-off value for absolute CD4+ Th cells in the IN group was 598/µl, clinicians should be vigilant for possible FVIII inhibitor production, especially on days prior to FVIII exposure.

Abstract Background Healthy lifestyle behaviors (LBs) have been widely recommended for the prevention and management of cardiovascular disease (CVD). Despite a large number of studies exploring the association between combined LBs and CVD, a notable gap exists in integration of relevant literatures. We conducted a systematic review and meta-analysis of prospective cohort studies to analyze the correlation between combined LBs and the occurrence of CVD, as well as to estimate the risk of various health complications in individuals already diagnosed with CVD. Methods Articles published up to February 10, 2023 were sourced through PubMed, EMBASE and Web of Science. Eligible prospective cohort studies that reported the relations of combined LBs with pre-determined outcomes were included. Summary relative risks (RRs) and 95% confidence intervals (CIs) were estimated using either a fixed or random-effects model. Subgroup analysis, meta-regression, publication bias, and sensitivity analysis were as well performed. Results In the general population, individuals with the healthiest combination of LBs exhibited a significant risk reduction of 58% for CVD and 55% for CVD mortality. For individuals diagnosed with CVD, adherence to the healthiest combination of LBs corresponded to a significant risk reduction of 62% for CVD recurrence and 67% for all-cause mortality, when compared to those with the least-healthy combination of LBs. In the analysis of dose-response relationship, for each increment of 1 healthy LB, there was a corresponding decrease in risk of 17% for CVD and 19% for CVD mortality within the general population. Similarly, among individuals diagnosed with CVD, each additional healthy LB was associated with a risk reduction of 27% for CVD recurrence and 27% for all-cause mortality. Conclusions Adopting healthy LBs is associated with substantial risk reduction in CVD, CVD mortality, and adverse outcomes among individuals diagnosed with CVD. Rather than focusing solely on individual healthy LB, it is advisable to advocate for the adoption of multiple LBs for the prevention and management of CVD. Trial registration PROSPERO: CRD42023431731.

Background Despite substantial progress in reducing the global burden of chronic obstructive pulmonary disease (COPD), traditional methods to promote understanding and management of COPD are insufficient. We developed an innovative model based on the internet of things (IoT) for screening and management of COPD in primary healthcare (PHC).Methods Electronic questionnaire and IoT-based spirometer were used to screen residents. We defined individuals with a questionnaire score of 16 or higher as high-risk population, COPD was diagnosed according to 2021 Global Initiative for COPD (Global Initiative for Chronic Obstructive Lung Disease) criteria. High-risk individuals and COPD identified through the screening were included in the COPD PHC cohort study, which is a prospective, longitudinal observational study. We provide an overall description of the study’s design framework and baseline data of participants.Results Between November 2021 and March 2023, 162 263 individuals aged over 18 from 18 cities in China were screened, of those 43 279 high-risk individuals and 6902 patients with COPD were enrolled in the cohort study. In the high-risk population, the proportion of smokers was higher than that in the screened population (57.6% vs 31.4%), the proportion of males was higher than females (71.1% vs 28.9%) and in people underweight than normal weight (57.1% vs 32.0%). The number of high-risk individuals increased with age, particularly after 50 years old (χ2=37 239.9, p

Cancer is widely regarded as a leading cause of death in humans, with colon adenocarcinoma (COAD) ranking among the most prevalent types. Cuproptosis is a novel form of cell death mediated by protein lipoylation. Cuproptosis-related genes (CRGs) participate in tumourigenesis and development. Their role in pan-cancer and COAD require further investigation. This study comprehensively evaluated the relationship among CRGs, pan-cancer, and COAD. Our research revealed the differential expression of CRGs and the cuproptosis potential index (CPI) between normal and tumour tissues, and further explored the correlation of CRGs or CPI with prognosis, immune infiltration, tumor mutant burden(TMB), microsatellite instability (MSI), and drug sensitivity in pan-cancer. Gene set enrichment analysis (GSEA) revealed that oxidative phosphorylation and fatty acid metabolism pathways were significantly enriched in the high CPI group of most tumours. FDX1 and CDKN2A were chosen for further exploration, and we found an independent association between FDX1 and CDKN2A and prognosis, immune infiltration, TMB, and MSI in pan-cancer. Furthermore, a prognostic risk model based on the association between CRGs and COAD was built, and the correlations between the risk score and prognosis, immune-related characteristics, and drug sensitivity were analysed. COAD was then divided into three subtypes using cluster analysis, and the differences among the subtypes in prognosis, CPI, immune-related characteristics, and drug sensitivity were determined. Due to the level of LIPT1 was notably positive related with the risk score, the cytological identification was carried out to identify the association of LIPT1 with proliferation and migration of colon cancer cells. In summary, CRGs can be used as potential prognostic biomarkers to predict immune infiltration levels in patients with pan-cancer. In addition, the risk model could more accurately predict the prognosis and immune infiltration levels of COAD and better guide the direction of clinical medication. Thus, FDX1, CDKN2A, and LIPT1 may serve as prospective new targets for cancer therapy.

The age-hardening behavior and precipitation evolution of an isothermal aged Mg−5Sm−0.6Zn−0.5Zr (wt.%) alloy have been systematically investigated by means of transmission electron microscopy (TEM) and atomic-resolution high-angle annular dark field scanning transmission electron microscopy (HAADF-STEM). The Vickers hardness of the present alloy increases first and then decreases with ageing time. The sample aged at 200 °C for 10 h exhibits a peak-hardness of 90.5 HV. In addition to the dominant β0′ precipitate (orthorhombic, a = 0.642 nm, b = 3.336 nm and c = 0.521 nm) formed on {11-20}α planes, a certain number of γ” precipitate (hexagonal, a = 0.556 nm and c = 0.431 nm) formed on basal planes are also observed in the peak-aged alloy. Significantly, the basal γ” precipitate is more thermostable than prismatic β0′ precipitate in the present alloy. β0′ precipitates gradually coarsened and were even likely to transform into β1 phase (face centered cubic, a = 0.73 nm) with the increase of ageing time, which accordingly led to a gradual decrease in number density of precipitates and finally resulted in the decreased hardness and mechanical property in the over-aged alloys.

Abstract Background Mechanism underlying the malignant progression of precancer to early-stage lung adenocarcinoma (LUAD) as well as their indolence nature remains elusive. Methods Single-cell RNA sequencing (scRNA) with simultaneous T cell receptor (TCR) sequencing on 5 normal lung tissues, 3 precancerous and 4 early-stage LUAD manifested as pulmonary ground-glass nodules (GGNs) were performed. Results Through this integrated analysis, we have delineated five key modules that drive the malignant progression of early-stage LUAD in a disease stage-dependent manner. These modules are related to cell proliferation and metabolism, immune response, mitochondria, cilia, and cell adhesion. We also find that the tumor micro-environment (TME) of early-stage LUAD manifested as GGN are featured with regulatory T (Tregs) cells accumulation with three possible origins, and loss-functional state (decreased clonal expansion and cytotoxicity) of CD8 + T cells. Instead of exhaustion, the CD8 + T cells are featured with a shift to memory phenotype, which is significantly different from the late stage LUAD. Furthermore, we have identified monocyte-derived macrophages that undergo a lipid-phenotype transition and may contribute to the suppressive TME. Intense interaction between stromal cells, myeloid cells including lipid associated macrophages and LAMP3 + DCs, and lymphocytes were also characterized. Conclusions Our work provides new insight into the molecular and cellular mechanism underlying malignant progression of LUAD manifested as GGN, and pave way for novel immunotherapies for GGN. Video Abstract