Search

Abstract The Omicron subvariants of SARS-CoV-2, especially for BA.2.86 and JN.1, have rapidly spread across multiple countries, posing a significant threat in the ongoing COVID-19 pandemic. Distinguished by 34 additional mutations on the Spike (S) protein compared to its BA.2 predecessor, the implications of BA.2.86 and its evolved descendant, JN.1 with additional L455S mutation in receptor-binding domains (RBDs), are of paramount concern. In this work, we systematically examine the neutralization susceptibilities of SARS-CoV-2 Omicron subvariants and reveal the enhanced antibody evasion of BA.2.86 and JN.1. We also determine the cryo-EM structures of the trimeric S proteins from BA.2.86 and JN.1 in complex with the host receptor ACE2, respectively. The mutations within the RBDs of BA.2.86 and JN.1 induce a remodeling of the interaction network between the RBD and ACE2. The L455S mutation of JN.1 further induces a notable shift of the RBD–ACE2 interface, suggesting the notably reduced binding affinity of JN.1 than BA.2.86. An analysis of the broadly neutralizing antibodies possessing core neutralizing epitopes reveals the antibody evasion mechanism underlying the evolution of Omicron BA.2.86 subvariant. In general, we construct a landscape of evolution in virus-receptor of the circulating Omicron subvariants.

Abstract Ribosomal DNA (rDNA) encodes the ribosomal RNA genes and represents an intrinsically unstable genomic region. However, the underlying mechanisms and implications for genome integrity remain elusive. Here, we use Bloom syndrome (BS), a rare genetic disease characterized by DNA repair defects and hyper-unstable rDNA, as a model to investigate the mechanisms leading to rDNA instability. We find that in Bloom helicase (BLM) proficient cells, the homologous recombination (HR) pathway in rDNA resembles that in nuclear chromatin; it is initiated by resection, replication protein A (RPA) loading and BRCA2-dependent RAD51 filament formation. However, BLM deficiency compromises RPA-loading and BRCA1/2 recruitment to rDNA, but not RAD51 accumulation. RAD51 accumulates at rDNA despite depletion of long-range resection nucleases and rDNA damage results in micronuclei when BLM is absent. In summary, our findings indicate that rDNA is permissive to RAD51 accumulation in the absence of BLM, leading to micronucleation and potentially global genomic instability.

Abstract Meningitis induced by Pasteurella multocida has been substantially described in clinical practice in both human and veterinary medicine, but the underlying mechanisms have not been previously reported. In this study, we investigated the influence of P. multocida infection on the permeability of the blood–brain barrier (BBB) using different models. Our in vivo tests in a mouse model and in vitro tests using human brain microvascular endothelial cell (hBMEC) model showed that P. multocida infection increased murine BBB permeability in mice and hBMEC monolayer permeability. Furthermore, we observed that P. multocida infection resulted in decreased expression of tight junctions (ZO1, claudin-5, occludin) and adherens junctions (E-cadherin) between neighboring hBMECs. Subsequent experiments revealed that P. multocida infection promoted the activation of hypoxia inducible factor-1α (HIF-1α)/vascular endothelial growth factor A (VEGFA) signaling and NF-κB signaling, and suppressed the HIF-1α/VEGFA significantly remitted the decrease in ZO1/E-cadherin induced by P. multocida infection (P

ObjectivesA new Spar-type floating wind turbine platform design scheme is proposed for a 15 MW floating wind turbine, and its performance is analyzed. MethodsBased on potential flow theory, the frequency domain hydrodynamic calculation of the platform is carried out and the wave loads and motion response characteristics of the platform under different wave directions are analyzed. The blade element momentum method is applied to calculate the aerodynamic load of the impeller and make it equivalent to the wind coefficient in order to calculate the time-domain response of the platform under the combined effect of wind, waves and currents under different working conditions, while also analyzing the force situation of the mooring lines. ResultsThe results show that the heave, roll, and pitch of the platform have peak points at the natural frequency of its motion, and the positions of occurrence are all far from the main energy region of the waves. Under the action of wind, waves and currents, compared to the working conditions, the maximum pitch angle of the platform under extreme conditions is smaller, but the amplitude of maximum surge, heave and mooring tension are greater than the working conditions. ConclusionsThe newly designed Spar-type floating wind turbine platform has good stability and hydrodynamic performance. Under the designed environmental loads, its response and mooring force can meet the requirements of the specifications, ensuring the safety and stability of the wind turbine.

Abstract There is no effective and noninvasive solution for thrombolysis because the mechanism by which certain thrombi become tissue plasminogen activator (tPA)-resistant remains obscure. Endovascular thrombectomy is the last option for these tPA-resistant thrombi, thus a new noninvasive strategy is urgently needed. Through an examination of thrombi retrieved from stroke patients, we found that neutrophil extracellular traps (NETs), ε-(γ-glutamyl) lysine isopeptide bonds and fibrin scaffolds jointly comprise the key chain in tPA resistance. A theranostic platform is designed to combine sonodynamic and mechanical thrombolysis under the guidance of ultrasonic imaging. Breakdown of the key chain leads to a recanalization rate of more than 90% in male rat tPA-resistant occlusion model. Vascular reconstruction is observed one month after recanalization, during which there was no thrombosis recurrence. The system also demonstrates noninvasive theranostic capabilities in managing pigs’ long thrombi (>8 mm) and in revascularizing thrombosis-susceptible tissue-engineered vascular grafts, indicating its potential for clinical application. Overall, this noninvasive theranostic platform provides a new strategy for treating tPA-resistant thrombi.

Abstract Background Colorectal cancer (CRC) is a prevalent malignancy with high morbidity and mortality rates. Previous studies have demonstrated that interleukin (IL)-22 is involved in CRC progression; however, the exact mechanism remains unclear. This study aimed to investigate the effects of IL-22 on CRC cell proliferation and metastasis. Methods IL-22 levels in the serum and tissues of CRC patients were measured using enzyme-linked immunosorbent assay (ELISA). Cell counting kit-8 (CCK-8) assay was used to detect the viability of CRC (HCT116) cells treated with different IL-22 concentrations. Colony formation, Transwell invasion, and scratch assays were employed to assess the effects of IL-22 on cell proliferation, invasion, and migration. Western blotting was performed to measure the expression levels of phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), p-PI3K, p-AKT, E-cadherin, matrix metalloproteinase (MMP)-2, MMP-9, SNAI1, and TWIST1 in HCT116 cells treated with IL-22 or a PI3K inhibitor. Results ELISA results showed that the expression of IL-22 was significantly increased in the serum and tissues of CRC patients compared to controls. IL-22 treatment increased cell viability and colony formation in a concentration-dependent manner and enhanced cell invasion and migration. Western blotting analysis revealed that IL-22 stimulation upregulated p-PI3K and p-AKT expression, while total PI3K and AKT levels remained unchanged. Additionally, IL-22 also decreased E-cadherin expression and increased the expression of MMP-2, MMP-9, SNAI1, and TWIST1. Conclusions IL-22 activates the PI3K-AKT pathway and promotes HCT116 cell proliferation and metastasis. Targeting the regulation of the PI3K/AKT pathway may be a potential therapeutic strategy for CRC.

Abstract Background Non-syndromic tooth agenesis (NSTA) is a type of ectodermal dysplasia (ED) in which patients with non-syndromic oligodontia may only affect teeth. No pathological findings were found in other tissues of the ectodermal. Herein, we report a case of a NSTA patient with severe dental anxiety and poor oral health. Case presentation A 5-year-old boy without systemic diseases presented as a patient with oligodontia, extensive caries, and periapical periodontitis. Molecular genetic analysis found a mutation in the Ectodysplasin A (EDA) gene, confirming the diagnosis of NSTA. Conclusion Tooth agenesis (TA) is the most common ectodermal developmental abnormality in humans. Non-syndromic oligodontia patients often seek treatment in the department of stomatology. Because of their complex oral conditions, these patients should be provided with a systematic and personalized treatment plan.

Background/Aims: Low educational attainment is a well-established risk factor for nonalcoholic fatty liver disease (NAFLD) in developed areas. However, the association between educational attainment and the risk of NAFLD is less clear in China. Methods: A cross-sectional study including over 200,000 Chinese adults across mainland China was conducted. Information on education level and lifestyle factors were obtained through standard questionnaires, while NAFLD and advanced fibrosis were diagnosed using validated formulas. Outcomes included the risk of NAFLD in the general population and high probability of fibrosis among patients with NAFLD. Logistic regression analysis was employed to estimate the risk of NAFLD and fibrosis across education levels. A causal mediation model was used to explore the potential mediators. Results: Comparing with those receiving primary school education, the multi-adjusted odds ratios (95% confidence intervals) for NAFLD were 1.28 (1.16 to 1.41) for men and 0.94 (0.89 to 0.99) for women with college education after accounting for body mass index. When considering waist circumference, the odds ratios (95% CIs) were 0.94 (0.86 to 1.04) for men and 0.88 (0.80 to 0.97) for women, respectively. The proportions mediated by general and central obesity were 51.00% and 68.04% for men, while for women the proportions were 48.58% and 32.58%, respectively. Furthermore, NAFLD patients with lower educational attainment showed an incremental increased risk of advanced fibrosis in both genders. Conclusion : s: In China, a low education level was associated with a higher risk of prevalent NAFLD in women, as well as high probability of fibrosis in both genders.

Purpose: This study aimed to determine the therapeutic effectiveness of different machines in intense pulsed light (IPL) treatment of meibomian gland dysfunction (MGD). Methods: 213 subjects diagnosed with MGD underwent three sessions of IPL treatment in a control (M22) treatment group or experimental (OPL-I) treatment group and were followed up three to four weeks after each session. Tear breakup time (TBUT), meibomian gland secretion scores (MGSS), meibomian gland meibum scores (MGMS), corneal fluorescein staining (CFS) scores, and the Standard Patient Evaluation of Eye Dryness (SPEED) was used to assess eye dryness signs and symptoms at baseline and follow-up visits. Results: Two machines had the same working principles except that experimental (OPL-I) group consist of a dual filter system. Both groups showed significant improvements (P ​

Fueled by substantial advancements in deep learning, the domain of autonomous driving is swiftly advancing towards more robust and effective intelligent systems. One of the critical challenges in this field is achieving accurate 3D object detection, which is often hindered by data sparsity and occlusion. To address these issues, we propose a method centered around a multi-modal fusion strategy that leverages vehicle-road cooperation to enhance perception capabilities. Our approach integrates label information from roadside perception point clouds to harmonize and enrich the representation of image and LiDAR data. This comprehensive integration significantly improves detection accuracy by providing a fuller understanding of the surrounding environment. Rigorous evaluations of our proposed method on two benchmark datasets, KITTI and Waymo Open, demonstrate its superior performance, with our model achieving 87.52% 3D Average Precision (3D AP) and 93.71% Bird’s Eye View Average Precision (BEV AP) on the KITTI val set. These results highlight the effectiveness of our method in detecting sparse and distant objects, contributing to the development of safer and more efficient autonomous driving solutions.

Abstract Multichannel meta-imaging, inspired by the parallel-processing capability of neuromorphic computing, offers considerable advancements in resolution enhancement and edge discrimination in imaging systems, extending even into the mid- to far-infrared spectrum. Currently typical multichannel infrared imaging systems consist of separating optical gratings or merging multi-cameras, which require complex circuit design and heavy power consumption, hindering the implementation of advanced human-eye-like imagers. Here, we present printable graphene plasmonic photodetector arrays driven by a ferroelectric superdomain for multichannel meta-infrared imaging with enhanced edge discrimination. The fabricated photodetectors exhibited multiple spectral responses with zero-bias operation by directly rescaling the ferroelectric superdomain instead of reconstructing the separated gratings. We also demonstrated enhanced and faster shape classification (98.1%) and edge detection (98.2%) using our multichannel infrared images compared with single-channel detectors. Our proof-of-concept photodetector arrays simplify multichannel infrared imaging systems and offer potential solutions in efficient edge detection in human-brain-type machine vision.

Abstract Fetal adenocarcinoma of the lung (FLAC) is a rare form of lung adenocarcinoma and was divided into high-grade (H-FLAC) and low-grade (L-FLAC) subtypes. Despite the existence of some small case series studies, a comprehensive multi-omics study of FLAC has yet to be undertaken. In this study, we depicted the multi-omics landscapes of this rare lung cancer type by performing multi-regional sampling on 20 FLAC cases. A comparison of multi-omics profiles revealed significant differences between H-FLAC and L-FLAC in a multi-omic landscape. Two subtypes also showed distinct relationships between multi-layer intratumor heterogeneity (ITH). We discovered that a lower genetic ITH was significantly associated with worse recurrence-free survival and overall survival in FLAC patients, whereas higher methylation ITH in H-FLAC patients suggested a short survival. Our findings highlight the complex interplay between genetic and transcriptional heterogeneity in FLAC and suggest that different types of ITH may have distinct implications for patient prognosis.

The evolution of constituent particles and the precipitation behavior in a commercial 2024 alloy during various homogenization regimes and their effect on T4-state mechanical performance have been investigated quantitatively. A typical phase transformation of AlCuFeMn → Al7Cu2Fe + Al20Cu2Mn3 gradually occurred during homogenization was identified as the duration time increasing, resulting in a “composite-particle” configuration with flocculent morphology. Meanwhile, nano-sized T-Al20Cu2Mn3 continuously precipitate within the matrix as the homogenization proceeding. The H1 treatment (445 °C/18 h + 495 °C/2 h) produced the higher number density of T phase with a finer size, while H2 regime (445 °C/18 h + 495 °C/6 h) caused a more complete precipitation and thus increased the fraction of S-texture component after subsequent rolling and T4-treatment. At T4 state, the superior mechanical properties of the H1 plate were obtained compared with the H2 sample, owing to the better dispersion-strengthening effect from T phase. In addition, the higher ductility can be attributed to the less weak-bonding interfaces and less recrystallization resistance from inadequate AlCuFeMn phase transition and T-precipitation, respectively. This work will provide useful insights to regulate the homogenization regimes for 2024 alloys in industrial applications.

Abstract Background The key to enhancing the efficacy of antagonistic regimens in pregnancy is to better synchronize follicular growth during cycles of controlled ovarian stimulation (COS), especially in patients with diminished ovarian reserve (DOR). During in vitro fertilization-embryo transfer (IVF-ET) treatment, luteal phase estrogen pretreatment may enhance follicular development synchronization and yield of mature oocytes. However, the effect of estrogen pretreatment in DOR patients with elevated basal follicle-stimulating hormone (FSH) levels has not been well studied. Methods We retrospectively analyzed the clinical data of patients with elevated basal FSH levels and DOR (401 cycles) who underwent IVF/intracytoplasmic monosperm injection (ICSI)-assisted conception. Both groups were treated with a flexible gonadotropin-releasing hormone (GnRH) antagonist regimen and were further divided into two groups according to whether they received luteal estrogen pretreatment. There were 79 patients in the estrogen pretreatment group and 322 patients in the control group. On the second day of the menstrual cycle, gonadotropin (Gn) stimulation of the ovaries was initiated. The general characteristics, clinical, biological parameters and outcomes of the two groups were compared. Results The basic profiles of the two groups were similar (P > 0.05). More patients in the pretreatment group showed FSH rebound after gonadotropin (Gn) initiation, resulting in a significantly higher number of Gn days and total Gn than those in the control group (P 0.05). Conclusions The use of luteal phase estrogen pretreatment in patients with elevated basal FSH combined with DOR resulted in high FSH levels after the release of negative feedback, which was detrimental to early follicular growth, did not increase the follicular output rate, may have increased the use and duration of controlled ovarian stimulation drugs, and did not increase the number of eggs gained or improve clinical outcomes.

Abstract Pressure drifting is a troublesome error in invasive coronary function tests. This study aimed to evaluate the relationship between prolonged and short-time pressure equalizations in pressure drifting. Pressure drifting was defined as the pressure gradient between the mean pressure of the distal wire sensor (Pd) and aortic pressure (Pa) when the wire was withdrawn to the tip of the guiding catheter. Significant drifts 1 and 2 were defined as the absolute values of pressure gradients > 2 and > 3 mmHg, respectively. A logistic regression model was used to evaluate the associations between prolonged pressure equalization and each pressure drifting. The prolonged pressure equalization strategy was associated with a lower incidence of drift 1 than the short-time pressure equalization strategy (6.84% vs. 16.92%, p

Abstract Topologically associating domains (TADs), megabase-scale features of chromatin spatial architecture, are organized in a domain-within-domain TAD hierarchy. Within TADs, the inner and smaller subTADs not only manifest cell-to-cell variability, but also precisely regulate transcription and differentiation. Although over 20 TAD callers are able to detect TAD, their usability in biomedicine is confined by a disagreement of outputs and a limit in understanding TAD hierarchy. We compare 13 computational tools across various conditions and develop a metric to evaluate the similarity of TAD hierarchy. Although outputs of TAD hierarchy at each level vary among callers, data resolutions, sequencing depths, and matrices normalization, they are more consistent when they have a higher similarity of larger TADs. We present comprehensive benchmarking of TAD hierarchy callers and operational guidance to researchers of life science researchers. Moreover, by simulating the mixing of different types of cells, we confirm that TAD hierarchy is generated not simply from stacking Hi-C heatmaps of heterogeneous cells. Finally, we propose an air conditioner model to decipher the role of TAD hierarchy in transcription.

Education is recognised as an integral part of building the capacity of all ages to drive the transformation toward sustainable development. While the Hong Kong government aspires to achieve carbon neutrality by 2050 and has ramped up efforts to integrate sustainability into school curricula and raise public awareness through educational activities, this policy brief argues that Hong Kong’s existing measures failed to empower and motivate individuals and the community to keep pace with its climate action ambition. Drawing on Sterling's framework of education for sustainability (EFS), this paper presents a diagnosis of Hong Kong’s major problems in sustainability education policies and suggests that the Hong Kong government should learn from the Italian experience to take a more systemic, empowering, and democratic approach in advancing its EFS policies.

Abstract Background The triglyceride glucose-body mass index (TyG-BMI) is recognized as a reliable surrogate for evaluating insulin resistance and an effective predictor of cardiovascular disease. However, the link between TyG-BMI index and adverse outcomes in heart failure (HF) patients remains unclear. This study examines the correlation of the TyG-BMI index with long-term adverse outcomes in HF patients with coronary heart disease (CHD). Methods This single-center, prospective cohort study included 823 HF patients with CHD. The TyG-BMI index was calculated as follows: ln [fasting triglyceride (mg/dL) × fasting blood glucose (mg/dL)/2] × BMI. To explore the association between the TyG-BMI index and the occurrences of all-cause mortality and HF rehospitalization, we utilized multivariate Cox regression models and restricted cubic splines with threshold analysis. Results Over a follow-up period of 9.4 years, 425 patients died, and 484 were rehospitalized due to HF. Threshold analysis revealed a significant reverse “J”-shaped relationship between the TyG-BMI index and all-cause mortality, indicating a decreased risk of all-cause mortality with higher TyG-BMI index values below 240.0 (adjusted model: HR 0.90, 95% CI 0.86–0.93; Log-likelihood ratio p = 0.003). A distinct “U”-shaped nonlinear relationship was observed with HF rehospitalization, with the inflection point at 228.56 (adjusted model: below: HR 0.95, 95% CI 0.91–0.98; above: HR 1.08, 95% CI 1.03–1.13; Log-likelihood ratio p

Abstract Background Hepatic encephalopathy (HE) is closely associated with inflammatory responses. However, as a crucial regulator of the immune and inflammatory responses, the role of leucine-rich repeat kinase 2 (LRRK2) in the pathogenesis of HE remains unraveled. Herein, we investigated this issue in thioacetamide (TAA)-induced HE following acute liver failure (ALF). Methods TAA-induced HE mouse models of LRRK2 wild type (WT), LRRK2 G2019S mutation (Lrrk2 G2019S) and LRRK2 knockout (Lrrk2 −/−) were established. A battery of neurobehavioral experiments was conducted. The biochemical indexes and pro-inflammatory cytokines were detected. The prefrontal cortex (PFC), striatum (STR), hippocampus (HIP), and liver were examined by pathology and electron microscopy. The changes of autophagy-lysosomal pathway and activity of critical Rab GTPases were analyzed. Results The Lrrk2 −/−-HE model reported a significantly lower survival rate than the other two models (24% vs. 48%, respectively, p

Abstract Leukemias and their bone marrow microenvironments undergo dynamic changes over the course of disease. However, little is known about the circulation kinetics of leukemia cells, nor the impact of specific factors on the clearance of circulating leukemia cells (CLCs) from the blood. To gain a basic understanding of CLC dynamics over the course of disease progression and therapeutic response, we apply a blood exchange method to mouse models of acute leukemia. We find that CLCs circulate in the blood for 1–2 orders of magnitude longer than solid tumor circulating tumor cells. We further observe that: (i) leukemia presence in the marrow can limit the clearance of CLCs in a model of acute lymphocytic leukemia (ALL), and (ii) CLCs in a model of relapsed acute myeloid leukemia (AML) can clear faster than their untreated counterparts. Our approach can also directly quantify the impact of microenvironmental factors on CLC clearance properties. For example, data from two leukemia models suggest that E-selectin, a vascular adhesion molecule, alters CLC clearance. Our research highlights that clearance rates of CLCs can vary in response to tumor and treatment status and provides a strategy for identifying basic processes and factors that govern the kinetics of circulating cells.

Abstract The rapid emergence and spread of colistin-resistant gram-negative bacteria has raised worldwide public health concerns, and phosphoethanolamine (PEtn) transferase modification-mediated colistin resistance has been widely documented in multiple gram-negative bacterial species. However, whether such a mechanism exists in the zoonotic pathogen Pasteurella multocida is still unknown. Recently, a novel PEtn transferase, PetL, was identified in P. multocida, but whether it is associated with colistin resistance remains to be elucidated. In this study, we found that PetL in P. multocida (PetLPM) exhibited structural characteristics similar to those of the mobile-colistin-resistant (MCR) protein and the PEtn transferase characterized in Neisseria meningitidis. The transformation of petL PM into E. coli or K. pneumoniae changed the phenotype of several tested strains from colistin sensitive to colistin resistant. Deletion of this gene decreased the colistin minimum inhibitory concentration (MIC) of P. multocida by 64-fold. Our extensive analysis by MALDI-TOF–MS demonstrated that PetLPM participated in the modification of bacterial lipopolysaccharide (LPS)-lipid A. Deletion of petL PM led to an increase in membrane charge but a decrease in cell-surface hydrophobicity and cell permeability in P. multocida. The present study is the first to report the presence of PEtn transferase-mediated colistin resistance in the zoonotic pathogen P. multocida.

The air quality in children's living spaces has a significant impact on their health, and ultrafine particulate matter (PM2.5), as one of the main pollutants in the air, poses a particularly prominent threat to children's respiratory and immune systems. Therefore, it important to conduct health risk assessment on ultrafine particle exercise in children's living spaces. In this article, an intelligent risk assessment model of ultrafine atmospheric particles in children's sports space in residential areas based on probabilistic neural network (PNN) is studied. This model utilizes probabilistic neural networks to monitor and predict ultrafine particles in residential spaces, evaluating their potential risks to children's health. By collecting relevant data such as particulate matter concentration and air quality index in residential spaces, and using probabilistic neural networks for training and prediction, accurate assessment of the health risks of ultrafine particulate matter during exercise can be achieved. This model can be applied to densely populated places such as families and schools, providing parents and relevant institutions with scientific risk warning and prevention measures to ensure the health and safety of children. Probabilistic neural networks can learn and simulate complex nonlinear relationships, making the model more accurate in predicting the concentration of ultrafine particles and health risks. So as to construct a method system of health risk assessment of atmospheric particles, and the model is heavy metal elements in atmospheric fine particles, and corresponding improvement measures are put forward according to the assessment results. For circulatory system diseases, the degree of harm of atmospheric temperature and fine particles to children's health is basically close, and with the continuous decline of temperature, the synergistic effect of the two is more obvious. The concentration of atmospheric ultrafine particles significantly affects the health risk of children's sports activities space. All the experiments in this article are quite good. Among them, the average accuracy of the PNN health risk identification model is 0.840, and the average recall rate is 0.837. The health risk assessment model in this article strengthens the correlation of data information through scientific methods, grasps the basic information of children's sports activity spaces in residential areas, and formulates targeted sports health risk assessments for children's sports activity spaces in residential areas. Compared with the comparison method, the response speed is significantly improved, with an accuracy rate of over 90%.

Background: Chemotherapy remains the standard-of-care for many patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC), but acquired resistance presents challenges. The aim of this open-label, multicenter phase 2 clinical trial was to determine the efficacy and safety of utidelone, a novel genetically engineered epothilone analog and microtubule-stabilizing agent, as a third- or later-line treatment for locally advanced or metastatic NSCLC. Methods: Patients who had failed standard second-line treatment (including platinum-containing chemotherapy or targeted therapy) received utidelone (40 mg/m2 via intravenous injection daily, day 1–5) every 21 days. The primary endpoint was the objective response rate (ORR). Secondary endpoints were the duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Results: From March 12, 2019 to January 18, 2021, 26 pretreated patients with locally advanced or metastatic NSCLC (100% of patients had received prior platinum and 65.4% patients had received prior taxane treatment) were enrolled (80.8% of patients had adenocarcinoma). At baseline, nine (34.6%) patients had received second-line treatment, 10 (38.5%) patients had received third-line treatment, and seven (26.9%) patients had received fourth- or later-line treatment. By the data cut-off date of August 10, 2021, the median follow-up was 7.49 months (range, 1.4–26.7 months). The ORR was 15.4% (95% confidence interval [CI], 4.4%–34.9%) in the intention-to-treat (ITT) cohort (N = 26) and 19.0% (95% CI, 5.4%–41.9%) in the per-protocol (PP) cohort (N = 21). The disease control rate was 69.2% (95% CI, 48.2%–85.7%) and 81.0% (95% CI, 58.1%–94.6%) in the ITT and PP cohorts, respectively. The median DoR was 4.1 months (95% CI, 3.1–5.1 months) in the ITT cohort. The median PFS was 4.37 months (95% CI, 2.50–5.29 months) in the ITT cohort and 4.37 months (95% CI, 2.50–9.76 months) in the PP cohort. The median OS was not reached, and the 12-month OS rate was 69% (95% CI, 45.1%–84.1%). Grade 3/4 treatment-emergent adverse events occurred in 38.5% of patients, and the most common was peripheral neuropathy (23.1%, all Grade 3), which was manageable with dose modifications. Conclusions: In this clinical trial, utidelone showed promising efficacy and had a manageable safety profile. Further clinical studies are warranted to confirm its role in NSCLC treatment. Trial registration: No.NCT03693547; https://classic.clinicaltrials.gov.

Previous studies reported that hemoprotein CYP450 catalyzed triclosan coupling is an “uncommon” metabolic pathway that may enhance toxicity, raising concerns about its environmental and health impacts. Hemoglobin, a notable hemoprotein, can catalyze endogenous phenolic amino acid tyrosine coupling reactions. Our study explored the feasibility of these coupling reactions for exogenous phenolic pollutants in plasma. Both hemoglobin and hemin were found to catalyze triclosan coupling in the presence of H₂O₂. This resulted in the formation of five diTCS-2 H, two diTCS-Cl-3 H, and twelve triTCS-4 H in phosphate buffer, with a total of nineteen triclosan coupling products monitored using LC-QTOF. In plasma, five diTCS-2 H, two diTCS-Cl-3 H, and two triTCS-4 H were detected in hemoglobin-catalyzed reactions. Hemin showed a weaker catalytic effect on triclosan transformation compared to hemoglobin, likely due to hemin dimerization and oxidative degradation by H₂O₂, which limits its catalytic efficiency. Triclosan transformation in the human plasma-like medium still occurs with high H₂O₂, despite the presence of antioxidant proteins that typically inhibit such transformations. In plasma, free H₂O₂ was depleted within 40 minutes when 800 µM H₂O₂ was added, suggesting a rapid consumption of H₂O₂ in these reactions. Antioxidative species, or hemoglobin/hemin scavengers such as bovine serum albumin, may inhibit but not completely terminate the triclosan coupling reactions. Previous studies reported that diTCS-2 H showed higher hydrophobicity and greater endocrine-disrupting effects compared to triclosan, which further underscores the potential health risks. This study indicates that hemoglobin and heme in human plasma might significantly contribute to phenolic coupling reactions, potentially increasing health risks.

ABSTRACT Interaction between viruses and bacteria during the development of infectious diseases is a complex question that requires continuous study. In this study, we explored the interactions between pseudorabies virus (PRV) and Pasteurella multocida (PM), which are recognized as the primary and secondary agents of porcine respiratory disease complex (PRDC), respectively. In vivo tests using mouse models demonstrated that intranasal inoculation with PRV at a sublethal dose induced disruption of murine respiratory barrier and promoted the invasion and damages caused by PM through respiratory infection. Inoculation with PRV also disrupted the barrier function of murine and porcine respiratory epithelial cells, and accelerated the adherence and invasion of PM to the cells. In mechanism, PRV infection resulted in decreased expression of tight junction proteins (ZO-1, occludin) and adherens junction proteins (β-catenin, E-cadherin) between neighboring respiratory epithelial cells. Additionally, PRV inoculation at an early stage downregulated multiple biological processes contributing to epithelial adhesion and barrier functions while upregulating signals beneficial for respiratory barrier disruption (e.g., the HIF-1α signaling). Furthermore, PRV infection also stimulated the upregulation of cellular receptors (CAM5, ICAM2, ACAN, and DSCAM) that promote bacterial adherence. The data presented in this study provide insights into the understanding of virus-bacteria interactions in PRDC and may also contribute to understanding the mechanisms of secondary infections caused by different respiratory viruses (e.g., influenza virus and SARS-CoV-2) in both medical and veterinary medicine.IMPORTANCECo-infections caused by viral and bacterial agents are common in both medical and veterinary medicine, but the related mechanisms are not fully understood. This study investigated the interactions between the zoonotic pathogens PRV and PM during the development of respiratory infections in both cell and mouse models, and reported the possible mechanisms which included: (i) the primary infection of PRV may induce the disruption and/or damage of mammal respiratory barrier, thereby contributing to the invasion of PM; (ii) PRV infection at early stage accelerates the transcription and/or expression of several cellular receptors that are beneficial for bacterial adherence. This study may shed a light on understanding the mechanisms on the secondary infection of PM promoted by different respiratory viruses (e.g., influenza virus and SARS-CoV-2) in both medical and veterinary medicine.

BackgroundThere is a consensus that both nonsuicidal self-injury (NSSI) and suicidal ideation as risk factors for suicidal behavior have a strong connection. However, a lack of longitudinal information has limited the clarification of the concrete relationship between them.AimsThis study aimed to examine the specific mechanism between NSSI and suicidal ideation over time, during adolescence.MethodA longitudinal study was conducted with 193 Chinese adolescents. NSSI and suicidal ideations were examined over the course of a 1year followed-up, and three waves of data were collected.ResultsThe NSSI at time T1 significantly positively predicted suicidal ideation at time T2; Suicidal ideation at time T2 also significantly positively predicted NSSI at time T3.LimitationsGiven that the small number of participants with suicidal ideation and NSSI, the findings of the study should be interpreted with caution and a lager sample is needed in the future.ConclusionIt was suggested that NSSI may occur before suicidal ideation, which in turn would strengthen NSSI, so interventions should be carried out from two aspects (behaviors and thoughts) to improve adolescents’ mental health.

The mitochondrial unfolded protein response (UPRmt) is a cytoprotective response in response to cellular stress that is activated in response to mitochondrial stress to maintain intra-protein homeostasis, thereby protecting the cell from a variety of stimuli. The activation of this response has been linked to cardiovascular diseases. Here, we reviewed the current understanding of UPRmt and discussed its specific molecular mechanism, mainly in mammals, as well as addressing its protective role against cardiovascular diseases, so as to provide direction for further research on UPRmt and therapies targeting cardiovascular diseases in the future.

A cruise was conducted in the summer of 2023 from the Pearl River Estuary (PRE) to the adjacent waters of the Xisha Islands in the northern South China Sea (NSCS) to investigate the distribution, community structure, and assembly patterns of eukaryotic and prokaryotic phytoplankton using high-throughput sequencing (HTS) and microscopic observation. Dinophyta were the most abundant phylum in the eukaryotic phytoplankton community based on HTS, accounting for 92.17% of the total amplicon sequence variants (ASVs). Syndiniales was the most abundant order among eukaryotic phytoplankton, whereas Prochlorococcus was the most abundant genus within cyanobacteria. The alpha diversity showed the lowest values in the PRE area and decreased gradually with depth, while cyanobacteria exhibited higher alpha diversity indices in the PRE and at depths ranging from 75 m to 750 m. The morphological results were different from the data based on HTS. Diatoms (37 species) dominated the phytoplankton community, with an average abundance of 3.01 × 104 cells L−1, but only six species of dinoflagellate were observed. Spearman correlation analysis and redundancy analysis (RDA) showed that the distribution and community structure of phytoplankton were largely influenced by geographical location and environmental parameters in the NSCS. The neutral community model (NCM) and null model indicated that deterministic processes played a significant role in the assembly of eukaryotic phytoplankton, with heterogeneous selection and homogeneous selection accounting for 47.27 and 29.95%, respectively. However, stochastic processes (over 60%) dominated the assembly of cyanobacteria and undominated processes accounted for 63.44%. In summary, the formation of eukaryotic phytoplankton was mainly influenced by environmental factors and geographic location, but the assembly of cyanobacteria was shaped by both stochastic processes, which accounted for over 60%, and environmental selection in the NSCS.

BackgroundMinimal change disease (MCD) is a common cause of adult nephrotic syndrome. Most adults with MCD achieve complete remission (CR) after initial steroid therapy. However, approximately 30% of adults who respond to steroids experience frequent relapses, becoming steroid-dependent and potentially developing refractory MCD. Treating refractory MCD in adults poses a significant challenge.Main bodyA 37-year-old woman presented to the nephrology department with a 6-year history of MCD. The diagnosis of MCD was confirmed via renal biopsy. She initially achieved CR with steroid treatment but experienced relapse during steroid tapering. Subsequent CR was achieved with a regimen of steroids and tacrolimus although multiple relapses occurred. Rituximab led to another CR, but its maintenance lasted only 6 months. The response to subsequent rituximab treatments was unsatisfactory. Ultimately, obinutuzumab was selected, resulting in the induction and maintenance of CR for 12 months.ConclusionsThis case demonstrates the successful treatment of frequently relapsed, steroid-dependent, and rituximab-resistant MCD with obinutuzumab. Obinutuzumab is a promising therapeutic option for rituximab-resistant MCD.

ObjectiveSeveral studies have investigated the correlation between blood lipids and homocysteine, but no clear conclusions have been defined yet. Therefore, we utilized data from National Health and Nutrition Examination Survey (NHANES) to explore the correlation between serum homocysteine (Hcy) levels and hyperlipidemia, which is determined by the levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG). We believe this study can provide a scientific basis for the prevention and treatment of lipid abnormalities.MethodsThe data used in this study were sourced from NHANES 1999–2006, linked with National Death Index mortality data from January 1999 to December 2019. We employed logistic regression to assess the associations between Hcy levels and the presence of hyperlipidemia. Additionally, survival analysis using Kaplan-Meier estimate and Cox proportional hazards regression model was conducted to evaluate the associations between Hcy levels and all-cause mortality in the hyperlipidemia population.Results(1) A total of 13,661 subjects were included in the study. There were statistically significant differences in Hcy levels across different groups based on gender, age, race, marital status, education level, hypertension status, diabetes status, and Body Mass Index (BMI) (P

BackgroundGlobally, the incidence rates of obesity and its related diseases, such as cardiovascular diseases and type 2 diabetes, are continuously rising, posing a significant public health challenge. Studies have indicated a potential correlation between vitamin D deficiency and obesity. However, a quantitative analysis of the studies related vitamin D and obesity is lacking. This investigation aims to fill this gap by providing a comprehensive bibliometric analysis to uncover the collaborative networks, research hotspots, and evolutionary trends within the field of vitamin D and obesity research.MethodsThis study retrieved literature related to vitamin D and obesity from the Web of Science database spanning from 2000 to 2023. Bibliometric analysis was conducted using tools such as HistCite, VOSviewer, and CiteSpace to excavate multi-dimensional information including countries, institutions, authors, journals, citations, and keywords.ResultsA total of 6,144 records were retrieved, involving 123 countries, 6,726 institutions, and 28,156 authors, published in 1,551 journals. The number of published papers and citations showed a generally increasing trend. The United States led in terms of publication volume and influence, with journals such as Nutrients and Obesity Surgery having the highest publication counts. Nasser M. Al-Daghri was the most prolific and influential author. Keyword clustering revealed that research topics covered metabolic health, nutrition, immunity, and bariatric surgery. Citation burst analysis indicated a shift in research focus from the relationship between dietary calcium and obesity to the preventive effects of vitamin D supplementation on metabolic diseases.ConclusionThe application of bibliometric methods to analyze the research literature in the fields of obesity and vitamin D has provided a comprehensive understanding of the collaborative networks, key research focus, and evolutionary trends in this field, offering insights for guiding future research directions.

ObjectiveThis study aims to investigate the Knowledge, Attitude, and Practice (KAP) pertaining to constipation during pregnancy among pregnant women in Shanghai.MethodsDemographic data and KAP scores were collected using a questionnaire. Differences across groups were analyzed using either Wilcoxon-Mann–Whitney tests or Kruskal-Wallis analysis of variance. Spearman’s correlation analysis was utilized to evaluate the relationships between KAP scores. Multivariable logistic regression analyses were conducted to identify factors that influence KAP scores.ResultsEncompassing 241 individuals (46.6%) aged between 30 and 34 years, with 349 participants (67.5%) being nulliparous. The median scores for knowledge (possible range: 0–26), attitude (possible range: 7–35), and practice (possible range: 14–70) were 22 (18, 24), 26 (23, 29), and 51 (46, 56), respectively. Multivariate analysis indicated that being a medical professional (OR = 2.222, p = 0.043) and receiving education on constipation during pregnancy (OR = 0.432, p

Introduction: Hexavalent chromium [Cr (VI)] has been identified as a human carcinogen and environmental pollutant capable of affecting multiple systems in the human body. However, the specific mechanisms by which Cr (VI) affects the human nervous system remain unclear.Objective: Following confirmation of Cr (VI)’s toxic effects on rat astrocytes, this study explores the metabolites and associated metabolic pathways of rat astrocytes under different doses of Cr (VI) exposure.Methods: Cell viability was assessed using CCK8 assays, intracellular reactive oxygen species (ROS) levels were measured using DCFH-DA fluorescent probes, intracellular 8-hydroxydeoxyguanosine (8-OHdG) content was determined by Elisa, mitochondrial membrane potential was observed using JC-1 probes, and key metabolites were identified through untargeted metabolomics analysis.Results: With increasing Cr (VI) doses, significant decreases in cell viability were observed in the 4, 8, and 16 mg/L dose groups (p < 0.05). Elevated levels of ROS and 8-OHdG, increased caspase-3 activity, and significant reductions in mitochondrial membrane potential were observed in the 2 and 4 mg/L dose groups (p < 0.05). Untargeted metabolomics analysis revealed Cr (VI)’s impact on key metabolites such as sphingosine and methionine. Enrichment analysis of KEGG pathways highlighted the critical roles of sphingolipid metabolism and the methionine-cysteine cycle in the effects of Cr (VI) on rat astrocytes.Conclusion: Our study underscores the potential neuro-health risks associated with environmental and occupational exposure to Cr (VI) and provides new perspectives and directions for investigating neurotoxic mechanisms.

ABSTRACT: Pigeons infected with aviadenoviruses have been found worldwide. Recently, pigeon adenovirus 2 (PiAdV-2) has been widely distributed in racing pigeons in Germany. However, the epidemiology of this virus remains unclear due to the lack of a specific detection platform for PiAdV-2. In this study, we first detected PiAdV-2 positivity in racing pigeons (designated FJ21125 and FJ21128, which share 100% nucleotide identity with each other based on the fiber 2 gene) in Fujian, Southeast China. These genes shared 99.8% nucleotide identity with PiAdV-2 (GenBank No. NC_031501) but only 54.1% nucleotide identity with PiAdV-1 (GenBank No. NC024474). Then, the TaqMan-qPCR assay for the detection of PiAdV-2 was established based on fiber 2 gene characterization. The established assay had a correlation coefficient of 1.00, with an amplification efficiency of 99.0%. The minimum detection limit was 34.6 copies/μL. Only PiAdV-2 exhibited a positive fluorescent signal, and no signal was detected for other pathogens (including PiCV, FAdV-4, FAdV-8a, EDSV, PPMV-1, RVA and PiHV). The assay has good reproducibility, with a coefficient of variation less than 2.42% both intragroup and intergroup. The distributions of PiAdV-2 in fecal samples from YPDS (35 samples) and healthy (43 samples) racing pigeons from different geographical areas were investigated and were 37.14% (YPDS) and 20.93% (healthy), respectively. In summary, we developed a TaqMan-qPCR platform for the detection of PiAdV-2 infection with high sensitivity, specificity, and reproducibility. We confirmed the presence of PiAdV-2 in China, and our data suggested that there is no indication of a correlation between YPDS and PiAdV-2. This study provides more information on the pathogenesis mechanism and epidemiological surveillance of PiAdV-2.

Abstract Background It is unclear whether short-term blood pressure variability (BPV) is associated with target organ damage in patients with non-dialysis chronic kidney disease (CKD). Methods A cross-sectional, single-center study was conducted among 3442 non-dialysis CKD patients hospitalized in the department of Nephrology of the Fifth Affiliated Hospital of Sun Yat-sen University from November 2017 to July 2022 and collected the demographic, laboratory, clinic blood pressure, ambulatory blood pressure data, and short-term BPV assessed by the weighted standard deviation (wSD) derived from ambulatory blood pressure monitoring (ABPM). Multivariate logistic analyses were used to evaluate the independent effects between short-term BPV and subclinical target organ damage, including left ventricular hypertrophy (LVH), abnormal carotid intima-media thickness (CIMT), low estimated glomerular filtration rate (eGFR), and albuminuria. Results The average age of the participants was 47.53 ± 14.06 years and 56% of participants were male. The baseline eGFR was 69 mL/min/1.73 m2. Based on the tertile distribution of wSD according to equal numbers, patients were divided into three categories with T1( 12.23 mmHg) of SBPV; T1( 9.93 mmHg) of DBPV. The participants with the higher wSD group had a higher prevalence of target organ damage than their counterparts (P-trend

Abstract Numerous studies have indicated a connection between psychiatric symptoms, specifically anxiety and depression, and gastroesophageal reflux. However, the precise nature of the link between the severity of gastroesophageal reflux disease and the severity of anxiety and depression remains uncertain. Here, we gathered 24-h pH monitoring data and baseline patient information from a cohort of 518 individuals. Additionally, we evaluated their psychological well-being using the Hospital Anxiety and Depression Scale. The relationship between baseline characteristics and varying degrees of anxiety, depression, and gastroesophageal reflux disease (GERD) was assessed using R software version 4.1.3 and logistic regression models. The findings indicate a statistically significant variation in anxiety levels based on gender, as well as a significant disparity in depression groups when considering age and literacy levels. Kruskal–Wallis test analysis revealed a significant positive correlation between the severity of anxiety and depression and the 24-h pH monitoring results in our patient cohort. As the anxiety and depression levels increased, the rank mean for each examination result also increased. Logistic regression modeling analysis showed that a higher anxiety level was associated with a higher level of GERD. In the presence of mild anxiety, there is a statistically significant association with a higher incidence of GERD with an odds ratio (OR) of 2.64 (95% CI 1.50, 4.64). Similarly, the moderately severe anxiety group also exhibits a causal relationship with an increased GERD incidence, with an OR of 6.84 (95% CI 3.92, 12.17). Additionally, moderate to severe depression is associated with a higher incidence of GERD, with an OR of 2.32 (95% CI 1.23, 4.37). The prevalence of GERD was greater among males compared to females (OR 2.29, 95% CI 1.51–3.49). Additionally, an elevated body mass index (BMI) demonstrated a positive correlation with the susceptibility to GERD (OR 1.07, 95% CI 1.01–1.14). Increasing age may promote the occurrence of GERD in patients. These findings may help to provide a better basis for psychological or pharmacological interventions for GERD patients with psychosomatic symptoms in the future, and provide a reference basis for clinical treatment of the disease.

Abstract The genetic basis of human facial variation and craniofacial birth defects remains poorly understood. Distant-acting transcriptional enhancers control the fine-tuned spatiotemporal expression of genes during critical stages of craniofacial development. However, a lack of accurate maps of the genomic locations and cell type-resolved activities of craniofacial enhancers prevents their systematic exploration in human genetics studies. Here, we combine histone modification, chromatin accessibility, and gene expression profiling of human craniofacial development with single-cell analyses of the developing mouse face to define the regulatory landscape of facial development at tissue- and single cell-resolution. We provide temporal activity profiles for 14,000 human developmental craniofacial enhancers. We find that 56% of human craniofacial enhancers share chromatin accessibility in the mouse and we provide cell population- and embryonic stage-resolved predictions of their in vivo activity. Taken together, our data provide an expansive resource for genetic and developmental studies of human craniofacial development.

In this study, the interaction evolution between the α precipitates that are thermally actived and deformation-induced α′ martensite in a metastable β-Zr alloy during tensile deformation was investigated. Following a two-step heat treatment, it results in the simultaneous precipitation of the thermally activated α phase in both within the β grain (αIN) and at the grain boundaries (αGB). The microstructure after deformation demonstrates that the α′ martensite induced by deformation initially nucleates and subsequently develops into elongated plates that are parallel with each other in the spaces between the αIN. As deformation continues, the α′ martensite grows rapidly in the length direction, firstly facing initial obstruction from αIN, but finally penetrating it and persisting to develop further. However, the growing α′ martensite encounters αGB, it is prevented completely from growing in length direction and instead grows quickly in width direction. Furthermore, α′ martensite plates further thicken and merge with each other, ultimately enveloping the complete β grain, including αIN, to construct an α′ martensite domain featuring an unusual shell-core arrangement. The shell layer is αGB and the core layer is α′ martensite surrounding αIN. Meanwhile, the secondary deformation product, namely {101‾1} twins, will form within α′ martensite domain in subsequent deformation process.

Abstract Currently, the classification of bone mineral density (BMD) in many research studies remains rather broad, often neglecting localized changes in BMD. This study aims to explore the correlation between peri-implant BMD and primary implant stability using a new artificial intelligence (AI)-based BMD grading system. 49 patients who received dental implant treatment at the Affiliated Hospital of Stomatology of Fujian Medical University were included. Recorded the implant stability quotient (ISQ) after implantation and the insertion torque value (ITV). A new AI-based BMD grading system was used to obtain the distribution of BMD in implant site, and the bone mineral density coefficients (BMDC) of the coronal, middle, apical, and total of the 1 mm site outside the implant were calculated by model overlap and image overlap technology. Our objective was to investigate the relationship between primary implant stability and BMDC values obtained from the new AI-based BMD grading system. There was a significant positive correlation between BMDC and ISQ value in the coronal, middle, and total of the implant (P 0.05). Furthermore, BMDC was notably higher at implant sites with greater ITV (P

Abstract PCOS is a widespread disease that primarily caused in-pregnancy in pregnant-age women. Normoandrogen (NA) and Hyperandrogen (HA) PCOS are distinct subtypes of PCOS, while bio-markers and expression patterns for NA PCOS and HA PCOS have not been disclosed. We performed microarray analysis on granusola cells from NA PCOS, HA PCOS and normal tissue from 12 individuals. Afterwards, microarray data were processed and specific genes for NA PCOS and HA PCOS were identified. Further functional analysis selected IL6R and CD274 as new NA PCOS functional markers, and meanwhile selected CASR as new HA PCOS functional marker. IL6R, CD274 and CASR were afterwards experimentally validated on mRNA and protein level. Subsequent causal relationship analysis based on Apriori Rules Algorithm and co-occurrence methods identified classification markers for NA PCOS and HA PCOS. According to classification markers, downloaded transcriptome datasets were merged with our microarray data. Based on merged data, causal knowledge graph was constructed for NA PCOS or HA PCOS and female infertility on NA PCOS and HA PCOS. Gene-drug interaction analysis was then performed and drugs for HA PCOS and NA PCOS were predicted. Our work was among the first to indicate the NA PCOS and HA PCOS functional and classification markers and using markers to construct knowledge graphs and afterwards predict drugs for NA PCOS and HA PCOS based on transcriptome data. Thus, our study possessed biological and clinical value on further understanding the inner mechanism on the difference between NA PCOS and HA PCOS.

Abstract Epidemiological studies suggested an association between omega-3 fatty acids and cognitive function. However, the causal role of the fatty acid desaturase (FADS) gene, which play a key role in regulating omega-3 fatty acids biosynthesis, on cognitive function is unclear. Hence, we used two-sample Mendelian randomization (MR) to estimate the gene-specific causal effect of omega-3 fatty acids (N = 114,999) on cognitive function (N = 300,486). Tissue- and cell type-specific effects of FADS1/FADS2 expression on cognitive function were estimated using brain tissue cis-expression quantitative trait loci (cis-eQTL) datasets (GTEx, N ≤ 209; MetaBrain, N ≤ 8,613) and single cell cis-eQTL data (N = 373), respectively. These causal effects were further evaluated in whole blood cis-eQTL data (N ≤ 31,684). A series of sensitivity analyses were conducted to validate MR assumptions. Leave-one-out MR showed a FADS gene-specific effect of omega-3 fatty acids on cognitive function [β = −1.3 × 10−2, 95% confidence interval (CI) (−2.2 × 10−2, −5 × 10−3), P = 2 × 10−3]. Tissue-specific MR showed an effect of increased FADS1 expression in cerebellar hemisphere and FADS2 expression in nucleus accumbens basal ganglia on maintaining cognitive function, while decreased FADS1 expression in nine brain tissues on maintaining cognitive function [colocalization probability (PP.H4) ranged from 71.7% to 100.0%]. Cell type-specific MR showed decreased FADS1/FADS2 expression in oligodendrocyte was associated with maintaining cognitive function (PP.H4 = 82.3%, respectively). Increased FADS1/FADS2 expression in whole blood showed an effect on cognitive function maintenance (PP.H4 = 86.6% and 88.4%, respectively). This study revealed putative causal effect of FADS1/FADS2 expression in brain tissues and blood on cognitive function. These findings provided evidence to prioritize FADS gene as potential target gene for maintenance of cognitive function.

Abstract. Background:. To perform anatomical anterior cruciate ligament reconstruction (ACLR), tunnels should be placed relatively higher in the femoral anterior cruciate ligament (ACL) footprint based on the findings of direct and indirect femoral insertion. But the clinical results of higher femoral tunnels (HFT) in double-bundle ACLR (DB-ACLR) remain unclear. The purpose was to investigate the clinical results of HFT and lower femoral tunnels (LFT) in DB-ACLR. Methods:. From September 2014 to February 2016, 83 patients who underwent DB-ACLR and met the inclusion and exclusion criteria were divided into HFT-ACLR (group 1, n = 37) and LFT-ACLR (group 2, n = 46) according to the position of femoral tunnels. Preoperatively and at the final follow-up, clinical scores were evaluated with International Knee Documentation Committee (IKDC), Tegner activity, and Lysholm score. The stability of the knee was evaluated with KT-2000, Lachman test, and pivot-shift test. Cartilage degeneration grades of the International Cartilage Repair Society (ICRS) were evaluated on magnetic resonance imaging (MRI). Graft tension, continuity, and synovialization were evaluated by second-look arthroscopy. Return-to-sports was assessed at the final follow-up. Results:. Significantly better improvement were found for KT-2000, Lachman test, and pivot-shift test postoperatively in group 1 (P >0.05). Posterolateral bundles (PL) showed significantly better results in second-look arthroscopy regarding graft tension, continuity, and synovialization (P 0.05). No statistically significant differences were found in IKDC subjective score, Tegner activity, and Lysholm score between the two groups. Higher return-to-sports rate was found in group 1 with 86.8% (32/37) vs. 65.2% (30/46) in group 2 (P = 0.027). Conclusion:. The HFT-ACLR group showed better stability results, better PL, and higher return-to-sports rate compared to the LFT-ACLR group.

We use actual pavement disease data, pavement performance data and pavement maintenance data to develop a data envelopment analysis (DEA) model to evaluate the effectiveness of repairing each type of pavement disease. Next, an optimization model is proposed to improve the pavement maintenance performance while reducing the pavement maintenance cost. Results indicate that repairing transverse cracking and rutting pavement diseases is more effective in improving the pavement maintenance performance. We also find that the pavement maintenance performance is enhanced prominently if the cost constraint increases from 0.1 to 0.2, while only slight improvements are observed if the maintenance cost keeps increasing. When the cost constraint is set to 0.2, the number of expressway sections with excellent condition increases by 71 and the average pavement condition index (PCI) increases by 0.27, implying that the generated pavement maintenance strategy can achieve a good performance while using much lower maintenance cost.

Abstract Background Prostate cancer (PCa) is the second leading cause of cancer-related mortality among men worldwide, and its incidence has risen substantially in recent years. Therefore, there is an urgent need to identify novel biomarkers and precise therapeutic targets for managing PCa progression and recurrence. Methods We investigated the clinical significance of NCAPG2 in PCa by exploring public datasets and our tissue microarray. Receiver operating characteristic (ROC) curve and survival analyses were performed to evaluate the correlation between NCAPG2 and PCa progression. Cell proliferation, wound healing, transwell, flow cytometry, cell cycle, tumor sphere formation, immunofluorescence (IF), co-immunoprecipitation (co-IP), and chromatin immunoprecipitation (ChIP) assays were conducted to further elucidate the molecular mechanism of NCAPG2 in PCa. Subcutaneous and orthotopic xenograft models were applied to investigate the effects of NCAPG2 on PCa proliferation in vivo. Tandem mass tag (TMT) quantitative proteomics was utilized to detect proteomic changes under NCAPG2 overexpression. Results NCAPG2 was significantly upregulated in PCa, and its overexpression was associated with PCa progression and unfavorable prognosis. Knockdown of NCAPG2 inhibited the malignant behavior of PCa cells, whereas its overexpression promoted PCa aggressiveness. NCAPG2 depletion attenuated the development and growth of PCa in vivo. TMT quantitative proteomics analyses indicated that c-MYC activity was strongly correlated with NCAPG2 expression. The malignancy-promoting effect of NCAPG2 in PCa was mediated via c-MYC. NCAPG2 could directly bind to STAT3 and induce STAT3 occupancy on the MYC promoter, thus to transcriptionally activate c-MYC expression. Finally, we identified that NCAPG2 was positively correlated with cancer stem cell (CSC) markers and enhanced self-renewal capacity of PCa cells. Conclusions NCAPG2 is highly expressed in PCa, and its level is significantly associated with PCa prognosis. NCAPG2 promotes PCa malignancy and drives cancer stemness via the STAT3/c-MYC signaling axis, highlighting its potential as a therapeutic target for PCa.

Abstract A comprehensive investigation of ovarian cancer (OC) progression at the single-cell level is crucial for enhancing our understanding of the disease, as well as for the development of better diagnoses and treatments. Here, over half a million single-cell transcriptome data were collected from 84 OC patients across all clinical stages. Through integrative analysis, we identified heterogeneous epithelial-immune-stromal cellular compartments and their interactions in the OC microenvironment. The epithelial cells displayed clinical subtype features with functional variance. A significant increase in distinct T cell subtypes was identified including Tregs and CD8+ exhausted T cells from stage IC2. Additionally, we discovered antigen-presenting cancer-associated fibroblasts (CAFs), with myofibroblastic CAFs (myCAFs) exhibiting enriched extracellular matrix (ECM) functionality linked to tumor progression at stage IC2. Furthermore, the NECTIN2-TIGIT ligand-receptor pair was identified to mediate T cells communicating with epithelial, fibroblast, endothelial, and other cell types. Knock-out of NECTIN2 using CRISPR/Cas9 inhibited ovarian cancer cell (SKOV3) proliferation, and increased T cell proliferation when co-cultured. These findings shed light on the cellular compartments and functional aspects of OC, providing insights into the molecular mechanisms underlying stage IC2 and potential therapeutic strategies for OC.

Abstract During myocardial infarction, microcirculation disturbance in the ischemic area can cause necrosis and formation of fibrotic tissue, potentially leading to malignant arrhythmia and myocardial remodeling. Here, we report a microchanneled hydrogel suture for two-way signal communication, pumping drugs on demand, and cardiac repair. After myocardial infarction, our hydrogel suture monitors abnormal electrocardiogram through the mobile device and triggers nitric oxide on demand via the hydrogel sutures’ microchannels, thereby inhibiting inflammation, promoting microvascular remodeling, and improving the left ventricular ejection fraction in rats and minipigs by more than 60% and 50%, respectively. This work proposes a suture for bidirectional communication that acts as a cardio-patch to repair myocardial infarction, that remotely monitors the heart, and can deliver drugs on demand.

The advanced technology microwave sounder (ATMS) is an important satellite instrument that provides vital data on atmosphere temperature and moisture for weather forecasting and climate research, and helps us plan for extreme weather. However, its coarse resolution and angular dependence have long been a challenge for improving image visualization. This article proposes a method to enhance the imagery visualization for ATMS, combining limb correction (LC) with artificial intelligence (AI) resolution enhancement (RE). Measurement data from the ATMS onboard NOAA-20 were utilized to train the LC method, which were then validated using newly acquired NOAA-21 ATMS data. The AI RE was performed using enhanced super-resolution generative adversarial networks, which increased the pixel resolution by a factor of four. The high-resolution (HR) Advanced Microwave Scanning Radiometer 2 data served as a reference to initially and quantitatively evaluate the RE method. The combined method of LC and AI RE produced an angular-dependence-free and HR ATMS image, resulting in a significant improvement in image visualization, including surface and atmosphere information, and allows for clear identification of severe weather events. For the swift identification and analysis of tropical cyclones in the upcoming season, as of this writing, this proposed method has been routinely employed to produce high-quality global ATMS images, and these images are showcased and tested in the NOAA internal HR imagery visualization system—JSTAR Mapper. Moreover, concentrated efforts are being made to further enhance these images in preparation for an official release.

In order to explore the effects of house warehouse storage on fungal community diversity of imported soybean, Illumina MiSeq high-throughput sequencing was employed to analyze the fungal community structure and diversity of newly harvested imported high oil soybean for 3 months with periodic sampling for moisture determination. The result demonstrated that the fungal communities in different storage periods in the high oil soybean belonged to 4 phyla, 9 classes, 14 orders, 15 families, 21 genera and 19 species in accordance with the 97% sequence similarity level. The four dominant phyla of soybean in different storage periods were Ascomycota, Basidiomycota, Mortierellomyco and Mucoromycota. At the species level, classification statistical analysis showed that the 10 strains with relatively high abundance presented an increasing trend with the extension of storage time (C47>B47>A47). In addition, quarantine pathogenic fungus gibberella were found. Through the analysis of Ven map and Beta diversity, it was found that the fungal community structure of soybean samples in the first two storage periods was relatively similar. The fungal community structure of soybean samples in the third storage period was significantly different from that in the first two storage periods with the storage of house warehouse. It could be concluded that the fungal community diversity of soybean samples in the third storage period not only increased significantly, but also experienced obvious succession of fungal community structure.

Abstract Background Cardiovascular diseases (CVD) is the leading cause of death among maintenance hemodialysis patients, with dyslipidemia being a prevalent complication. The paradoxical relationship between cardiovascular outcomes and established lipid risk markers, such as low-density lipoprotein cholesterol (LDL-C), complicates lipid management in this population. This study investigated Lipoprotein-associated phospholipase A2 (Lp-PLA2), an emerging biomarker known for its proinflammatory and proatherogenic properties, as a potential cardiovascular prognostic marker in this cohort. In this context, the association between Lp-PLA2 levels and cardiovascular outcomes was evaluated, with the aim to facilitate more accurate stratification and identification of high-risk individuals. Methods From August 2013 to January 2014, 361 hemodialysis patients were prospectively enrolled. Lp-PLA2 activity and laboratory measures at baseline were quantified. Comorbidities and medications were recorded. All patients were followed until the end of April, 2022. The individual and combined effects of Lp-PLA2 activity and LDL-C on patient outcomes were examined. The association between Lp-PLA2 activity and all-cause mortality, cardiovascular mortality, and major adverse cardiovascular events (MACEs) was analyzed. Results The median Lp-PLA2 activity was 481.2 U/L. In subjects with Lp-PLA2 activity over 481.2 U/L, significantly higher total cholesterol (4.89 vs. 3.98 mmol/L; P