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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.

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

The combustion characteristics of micro-combustors significantly impact the performance of micro-thermophotovoltaic (MTPV) systems. This study aims to investigate the effects of sinusoidal-shaped walls and catalyst segmentation on flame stability and combustion performance in a micro-combustor by using numerical methods. The numerical simulation with detailed gas-phase and surface reaction mechanisms is reliable, as the results of numerical simulation align with experimental data. The results show that the interplay between flame stability and sinusoidal-shaped walls is crucial, particularly because of the cavities formed by the sinusoidal-shaped walls of the micro-combustor. The gas-phase ignition position of the sinusoidal-shaped wall combustor moves upstream by 0.050 m compared to the planar-wall combustor, but the flame is stretched. The catalyst segments coated on the crest can shorten the flame length and increase the average temperature by a maximum 62 K, but delay the gas-phase ignition. Conversely, catalyst segments coated on the trough can advance ignition, but this results in flame elongation and a decrease in the average temperature. The rational combination of catalyst segmentation and sinusoidal-shaped walls facilitates moving the ignition position upstream by a maximum of 0.065 m while substantially reducing the length of the combustor required for complete fuel conversion by more than 60%. These attributes are highly beneficial for improving efficiency and minimizing the length of the micro-combustor for MTPV application.

The effects of Helicobacter pylori eradication on gastric mucosa-colonizing microbes in patients with functional dyspepsia (FD) remain unclear. Here, we explored microbial variation induced by H. pylori infection and eradication treatment in FD patients. Gastric microbial abundance and diversity were significantly reduced in the H. pylori-infected FD patients. Eradication treatment increased alpha and beta diversity of gastric mucosa-colonizing microbes, and promoted the expansion of several probiotic microbes, such as Leuconostoc mesenteroides, which exhibited a matched antagonistic performance against H. pylori. Significant variation was observed in gastric mucosa-colonizing microbes between H. pylori-positive and H. pylori-negative FD patients. Eradication treatment induced microbial diversity recovery and may provide sufficient nutrition and space for probiotic microbes, such as Leuconostoc mesenteroides.

Abstract Esophageal squamous cell carcinoma (ESCC) is an upper gastrointestinal cancer with high morbidity and mortality. New strategies are urgently needed to prolong patients’ survival. Through screening FDA-approved drugs, we found dasabuvir, a drug approved for hepatitis C virus (HCV) treatment, suppressed ESCC proliferation. Dasabuvir could inhibit the growth of ESCC cells in a time and dose-dependent manner and arrested cell cycle at the G0/G1 phase. The antitumor activity was further validated in vivo using patient-derived xenograft tumor models. In terms of mechanism, we unveil that dasabuvir is a Rho-associated protein kinase 1 (ROCK1) inhibitor. Dasabuvir can bind to ROCK1 and suppress its kinase activity, thus downregulating the phosphorylation of ERK1/2 by ROCK1 and the expression of cyclin-dependent kinase 4 (CDK4) and cyclin D1. These results provide evidence that dasabuvir suppresses ESCC growth in vivo and in vitro through blocking ROCK1/ERK signaling pathway.

Abstract Objective To explore the characteristics of peripheral blood, high resolution computed tomography (HRCT) imaging and the radiomics signature (RadScore) in patients infected with delta variant virus under different coronavirus disease (COVID-19) vaccination status. Methods 123 patients with delta variant virus infection collected from November 1, 2021 to March 1, 2022 were analyzed retrospectively. According to COVID-19 vaccination Status, they were divided into three groups: Unvaccinated group, partially vaccinated group and full vaccination group. The peripheral blood, chest HRCT manifestations and RadScore of each group were analyzed and compared. Results The mean lymphocyte count 1.22 ± 0.49 × 10^9/L, CT score 7.29 ± 3.48, RadScore 0.75 ± 0.63 in the unvaccinated group; The mean lymphocyte count 1.55 ± 0.70 × 10^9/L, CT score 5.27 ± 2.72, RadScore 1.03 ± 0.46 in the partially vaccinated group; The mean lymphocyte count 1.87 ± 0.70 × 10^9/L, CT score 3.59 ± 3.14, RadScore 1.23 ± 0.29 in the fully vaccinated group. There were significant differences in lymphocyte count, CT score and RadScore among the three groups (all p

The micro-radial inflow turbine (MRIT) is not only an important component of a micro-gas turbine but also the core part of a vehicle exhaust gas turbocharger and a small-scale organic Rankine circulatory system. Therefore, designing an MRIT with good performance is of great importance. The values of some main turbine design parameters can significantly influence its aerodynamic performance and structural size. In accordance with the structural characteristics of an MRIT, the relationships between the aerodynamic performance of a turbine and the absolute flow angle at the rotor inlet, the relative flow angle at the rotor outlet, the nozzle and rotor blade velocity coefficients, the ratio of the wheel diameter, velocity ratios, and the degree of reaction were examined. This was done through theoretical analysis combined with experience in the design of a conventional radial inflow turbine. On this basis, the influencing laws and degrees of the seven main design parameters on the aerodynamic performance of an MRIT during aerodynamic design were analyzed. The selection principles of these main design parameters were also summarized. The reasonableness of the above-mentioned selection principles was verified through an aerodynamic design case study of an MRIT combined with a 3D numerical simulation. It was found that the 3D numerical simulation results agreed well with the 1D aerodynamic design. The summarized selection principles of the main design parameters can provide a reference for the successful aerodynamic design of an MRIT.

The Zero-P spacer was primarily developed aiming to reduce the morbidity associated with the traditional anterior cervical plate. During the past decade, many authors have reported the use of Zero-P spacers for anterior cervical discectomy and fusion (ACDF) of one or two segments. Nevertheless, there is still a paucity of knowledge on the safety and feasibility of using Zero-P spacers for 3-level fixation. The objective of this study was to investigate the clinical and radiological outcomes, with a focus on the sagittal alignment reconstruction of 3-level ACDF surgery using Zero-P spacers versus those using a traditional plate and cage system. From Sep 2013 to Aug 2016, a total of 44 patients who received 3-level ACDF surgery due to cervical spondylotic myelopathy were recruited. The Zero-P spacer was used in 23 patients (group ZP) and the traditional plate and cage system in 21 (group PC). Clinical outcomes were analyzed by Neck Disability Index (NDI) and Japanese Orthopedic Association (JOA) scores, and dysphagia was evaluated using the Bazaz score. Radiological outcomes, including fusion rate, adjacent segment degeneration (ASD), and especially changes in cervical sagittal alignment, were analyzed. The NDI and JOA scores did not differ significantly between the two groups postoperatively (p > 0.05); however, there was significantly less dysphagia in patients using Zero-P spacers at the 3- and 6-month follow-up (p < 0.05). At the 24-month follow-up, the fusion rate and ASD were similar between the two groups (p > 0.05). Interestingly, patients using Zero-P spacers had a significantly lower postoperative C2-7 Cobb angle and fused segment Cobb angle, compared to those using a traditional plate and cage system (p < 0.05); meanwhile, the fused segment disc wedge was also found to be significantly smaller in patients using Zero-P spacers after surgery (p < 0.05). Moreover, we further divided patients into subgroups according to their cervical lordosis. In patients with a preoperative C2-7 Cobb angle ≤ 10°, significantly less cervical and local lordosis, as well as disc wedge, were seen in group ZP after surgery (p < 0.05), while in others with a preoperative C2-7 Cobb angle > 10°, no significant difference in postoperative changes of the cervical sagittal alignment was seen between group ZP and group PC (p > 0.05). Zero-P spacers used in 3-level ACDF surgery could provide equivalent clinical outcomes and a lower rate of postoperative dysphagia, compared to the traditional plate and cage system. However, our results showed that it was inferior to the cervical plate in terms of sagittal alignment reconstruction for 3-level fixation. We recommend applying Zero-P spacers for 3-level ACDF in patients with good preoperative cervical lordosis (C2-7 Cobb angle > 10°), in order to restore and maintain physiological curvature of the cervical spine postoperatively.