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Abstract Enantioselective synthesis governed by chiral catalysts has been extensively developed, but that without any chiral auxiliaries or chiral catalysts is rare, particularly when remote stereogenic centers are involved. Here we report an enantioselectivity of heterochiral coupling in the one-pot reaction of racemic hydrazides with achiral 1,4-bis(isothiocyanine)benzene, yielding preferentially the heterochiral bilateral azapeptides over the homochiral ones. Despite bearing two hydrogen-bonded β-turn structures that allow intramolecular chiral transfer, the bilateral azapeptide products have two chiral centers separated by 14 atoms or 15 bonds, which prevent the direct intramolecular asymmetric communication between the two chiral centers. Interestingly, the heterochiral azapeptides feature intermolecular hydrogen bonding stacking between homochiral β-turns to form a superstructure of alternative M- and P-helices in the crystals. In contrast, the homochiral azapeptide counterparts adopt a β-sheet-like structure, which is less favorable compared to the helical-like superstructure from heterochiral azapeptides, accounting for the favored heterochiral coupling of the one-pot reaction. This work demonstrates enantioselective synthesis involving distant chiral centers through the formation of biomimetic superstructures, opening up new possibilities for the regulation of enantioselectivity.

Abstract Objective To characterize the retinal microvasculature and structure in subjective cognitive decline (SCD) and identify the potential biomarker for the early stage of the Alzheimer's disease (AD) spectrum. Methods In this study, 35 patients with SCD, 36 with cognitive impairment, and 29 with normal cognition (NC) were enrolled. Optical coherence tomography angiography was employed to assess retinal vascular density, fovea avascular zone area, and retinal thickness. The parameters reflecting retinal perfusion and structure were compared among the three groups. In addition, the association between retinal parameters, cerebral blood flow (CBF), and peripheral blood biomarkers in the SCD stage was analyzed. Results The superficial vascular complex (SVC) vascular density in the macula and retinal nerve fiber layer thickness in the peripapillary were significantly reduced in individuals with SCD compared to NC. Furthermore, there was a positive correlation between macular ganglion cell complex thickness and CBF in SCD. Interpretation The retinal microvasculature and structure exhibit alterations in individuals with SCD. Macular ganglion cell complex thickness demonstrates correlations with cerebral perfusion. The retina holds potential as a novel biomarker for early detection of AD.

Abstract Although septal myectomy is the preferred treatment for medication-refractory hypertrophic obstructive cardiomyopathy (HOCM), the procedure remains subjective. A preoperative planning procedure is proposed using computational fluid dynamics simulations and shape optimization to assist in the objective assessment of the adequacy of the resection. 3 patients with HOCM were chosen for the application of the proposed procedure. The geometries of the preoperative left ventricular outflow tract (LVOT) of patients in the systolic phase were reconstructed from medical images. Computaional fluid dynamics (CFD) simulations were performed to assess hemodynamics within LVOT. Sensitivity analysis was performed to determine the resection extent on the septal wall, and the depth of the resection was optimized to relieve LVOT obstruction while minimizing damage to the septum. The optimized resection was then transferred from systole to diastole to provide surgeons with instructive guidance for septal myectomy. Comparison between preoperative and postoperative hemodynamics showed an evident improvement with respect to the pressure gradient throughout the LVOT. The resected myocardium in the diastolic phase is more extended and thinner than its state in the systolic phase. The proposed preoperative planning procedure may be a viable addition to the current preoperative assessment of patients with HOCM.

Abstract Due to high computation complexity, traditional design methods for LLC converter usually consider limited kinds of performance, and the process for searching the optimal parameter scheme is discrete, which might cause the missing of real optimal solution. In order to solve these problems, a multi‐objectives optimization design method for the LLC converter is proposed in this paper. According to the numerical calculation method, a closed parameter space for resonant parameters is established under the constraints of operation mode, switching frequency, zero voltage switching (ZVS), and voltage stress of resonant capacitor. Besides, the root‐mean‐square (RMS) value of resonant current and secondary current, as well as the core loss of the transformer, are selected as the optimization objectives. Non‐dominated sorting genetic algorithm (NSGA‐II) is utilized to deal with these multi‐objective formulations. In order to reduce the computation complexity, a data‐driven method, called adaptive polynomial approximation (APA), is selected to obtain the explicit expressions of the parameter space and the optimization objectives. Then, by substituting this simplified surrogate model into the NSGA‐II algorithm, the optimal parameter scheme is obtained. The comprehensive comparison analysis is performed, and a 400 W/48 V experimental prototype was built to verify the theoretical analysis, which shows that the proposed method features the highest efficiency of 95%.

Arsenic is commonly used in alloy materials and the semiconductor industry, and has promising applications. Arsenic and antimony have similar physicochemical properties, and their binding and separation mechanisms are unknown, thereby limiting the purification and preparation of arsenic. This study, from a microscopic perspective, reveals that arsenic and antimony covalently interact in alloys through a combination of thermodynamic analysis and molecular dynamics simulations. In addition, antimony as arsenic-antimony clusters enters the gas phase, and the diffusion coefficients of the clusters are in the order of As4>As3Sb > As2Sb2>AsSb3. A green and efficient vacuum sublimation-graded condensation process for arsenic purification is proposed based on the different diffusion coefficients to obtain the optimal process parameters. The coalescence of arsenic on a condenser was normally distributed. The removal rate of antimony in the most concentrated area of the condensate was 91.37% under the optimal conditions of 748 K, 60 min, and 10 Pa. Thus, the proposed method effectively solves the challenging problem of separating arsenic and antimony, and the study results provide theoretical support for purifying arsenic via vacuum sublimation.

ObjectiveTo investigate the risk factors associated with cognitive frailty among older adults in nursing homes using logistic regression and decision tree modeling, and to compare the predictive performance of these methods.MethodsA cross-sectional study was conducted involving 697 participants aged 60 and older residing in eight nursing homes in Sichuan province, China. Participants were recruited using convenience sampling. Data were collected through questionnaires administered to the older adults. Logistic regression and decision tree modeling were employed to construct models predicting cognitive frailty.ResultsLogistic regression analysis identified age, education degree, exercise, intellectual activities, number of chronic diseases, nutritional status, sleep quality, and depression as significant predictors of cognitive frailty (all p

Background and AimAmmoxetine, a novel chiral serotonin and norepinephrine reuptake inhibitor, holds promise for major depressive disorder treatment. This study aimed to thoroughly investigate its preclinical drug metabolism and pharmacokinetics (DMPK) profiles.MethodsThe preclinical DMPK profiles of ammoxetine were examined through in vitro, in vivo, and in silico methods.ResultsAssessment of blood-brain barrier penetration via MDCK-MDR1 cells revealed strong brain permeation by ammoxetine, despite being a probable P-glycoprotein (P-gp) substrate. Molecular docking indicated a robust binding interaction between ammoxetine and P-gp. Ammoxetine was well absorbed orally, with Tmax ranging from 0.75 to 3.83 h in rats and 0.75–1.40 h in beagle dogs. At a 2 mg/kg dose in beagle dogs, ammoxetine exhibited an absolute bioavailability of approximately 42%. Plasma protein binding rates were around 50%–60% in beagle dogs, rats, and humans, suggesting moderate binding. Tissue distribution studies displayed rapid and extensive ammoxetine spread in major rat tissues post-gavage, with notable brain exposure and no tissue accumulation. Cumulative excretion rates in rats’ urine, feces, and bile accounted for only 1.11% of the total administered drug, indicating extensive transformation into metabolites. Chiral inversion of ammoxetine was absent in vivo. Metabolic stability varied across species using liver microsomes, but beagle dogs showed clearance rates more akin to humans. Metabolic pathways unveiled two key metabolites, M1 and M2. M1, likely generated through methylenedioxyphenyl ring oxidation, involves CYP2C19 and CYP3A4, crucial human cytochrome P450 (CYP) enzymes for liver metabolism, while M2 is M1’s glucuronide conjugate. Ammoxetine may exhibit saturation elimination trends with increasing doses in rats and beagle dogs. A high-throughput assay using the cocktail-substrate method indicated weak CYP inhibition by ammoxetine on CYP2D6 and CYP1A2, with minimal effects on other CYP enzymes, suggesting a low likelihood of CYP inhibition-related drug-drug interactions.ConclusionThis study presents encouraging DMPK profiles of ammoxetine, backing its potential as a candidate compound for future clinical assessments.

Lytic bacteriophages (phages) are promising clinically viable therapeutic options against carbapenem-resistant Klebsiella pneumoniae (CRKP). In China, the predominant strains are those assigned to sequence type 11 and capsular type 64 (ST11-KL64). The emergence of phage resistance is a major bottleneck hindering effective phage therapy, requiring more new phages to provide the flexibility for creating different phage cocktails. However, the majority of phages against ST11-KL64 CRKP belong to the genus Przondovirus of the family Autographiviridae, which limits the options for constructing cocktails. We recovered a novel lytic phage of the genus Taipeivirus within the family Ackermannviridae against ST11-KL64 CRKP from a river in China. We phenotypically characterized this phage and obtained its genome sequence for analysis. This phage can inhibit the growth of ST11-KL64 CRKP for 6.5 h at a 0.1 multiplicity of infection and exhibits a narrow host range, being unable to attack CRKP strains of the other 30 capsular types. This phage carries no genes encoding antimicrobial resistance, virulence, or lysogeny. It is stable across a wide range of temperatures and pH values, making it suitable for phage therapy. Unlike other Taipeivirus phages, P01 has two tail spike proteins and a unique tail fiber protein. The distinct tail composition of this phage contributes to its activity against ST11-KL64 CRKP and its narrow host range. Taken together, we recovered a phage of a novel viral species with the potential for therapy, which expands the phage biobank against CRKP.

The utilization of ultrasonic guided wave technology for detecting cracks in railway tracks involves analyzing echo signals produced by the interaction of cracks with guided wave modes to achieve precise crack localization, which is extremely important in a real-time railway crack robotic detection system. Addressing the challenge of selecting the optimal detection mode for cracks in various regions of railway tracks, this paper presents a method for optimal crack detection mode selection. This method is based on the sensitivity of guided wave modes to cracks. By examining the frequency dispersion characteristics and mode shapes of guided wave modes, we establish indicators for crack zone energy and crack reflection intensity. Our focus is on the railhead of the railway track, selecting guided wave modes characterized by specific cracks for detection purposes. Experimental findings validate the accuracy of our proposed mode selection method in detecting cracks in railway tracks. This research not only enhances crack detection but also lays the groundwork for exploring advanced detection and localization techniques for cracks in railway tracks.

Magnesium (Mg) matrix composites (Mg-MMCs) with high strength and ductility properties are crucial for the development of lightweight automobiles. In this study, a novel method is proposed for fabricating Mg-MMCs by incorporating nanocopper (Cu) decorated titanium (Ti) particles (Cu@Ti) to reinforce AZ91 alloys. The in-situ generation of the AlCuMg phase at the interface between the Ti particles and the Mg matrix enhances interface integration and promotes the formation of massive twins. The 5.0 wt% Cu@Ti/AZ91 composite exhibits notable mechanical properties, with a yield strength of 238 MPa, ultimate tensile strength of 368 MPa, elongation of 12%, and modulus of elasticity of 46 GPa. These values represent increases of 8.9%, 5.3%, 50.0%, and 2.0%, respectively, compared to those of AZ91 alloys. The strengthening mechanism is mainly attributed to grain refinement strengthening, thermal expansion coefficient mismatch strengthening, Orowan strengthening, and load transfer strengthening. The plasticity improvement benefits from the optimization of the interface structure, grain refinement and twin formation.

Abstract The current first-line treatment for repairing cartilage defects in clinical practice is the creation of microfractures (MF) to stimulate the release of mesenchymal stem cells (MSCs); however, this method has many limitations. Recent studies have found that MSC-derived extracellular vesicles (MSC-EVs) play an important role in tissue regeneration. This study aimed to verify whether MSC-EVs promote cartilage damage repair mediated by MFs and to explore the repair mechanisms. In vitro experiments showed that human umbilical cord Wharton’s jelly MSC-EVs (hWJMSC-EVs) promoted the vitality of chondrocytes and the proliferation and differentiation ability of bone marrow-derived MSCs. This was mainly because hWJMSC-EVs carry integrin beta-1 (ITGB1), and cartilage and bone marrow-derived MSCs overexpress ITGB1 after absorbing EVs, thereby activating the transforming growth factor-β/Smad2/3 axis. In a rabbit knee joint model of osteochondral defect repair, the injection of different concentrations of hWJMSC-EVs into the joint cavity showed that a concentration of 50 µg/ml significantly improved the formation of transparent cartilage after MF surgery. Extraction of regenerated cartilage revealed that the changes in ITGB1, transforming growth factor-β, and Smad2/3 were directly proportional to the repair of regenerated cartilage. In summary, this study showed that hWJMSC-EVs promoted cartilage repair after MF surgery. Graphical abstract

For magnesium (Mg) matrix composites (MMCs), trade-off between strength and plasticity has long been an issue of puzzle. In this work, hot-press sintering and hot extrusion are used to prepare Ti particles (Tip) reinforced AZ31 (Tip/AZ31) composites. The strength, plasticity, and wear resistance of Tip/AZ31 composites are improved simultaneously. Ti particles refine the grains of composites and accelerate the precipitation of Mg17Al12 particles in Mg matrix. The best tensile properties and wear resistance are achieved in 6 wt%Tip/AZ31 composite, with ultimate tensile strength of 290 MPa, elongation of 15.5 %, and wear rate of 4.343 × 10−3 mm3/m, respectively. Especially, the wear rate of 6 wt%Tip/AZ31 is reduced by 54.6 % compared to the matrix alloy. The underlying strengthening mechanisms, toughness mechanisms, and wear mechanisms of Tip/AZ31 composites were discussed in detail.

BackgroundPrevious studies have explored the role of plasma proteins on osteonecrosis. This Mendelian randomization (MR) study further assessed plasma proteins on osteonecrosis whether a causal relationship exists and provides some evidence of causality.MethodsSummary-level data of 4,907 circulating protein levels were extracted from a large-scale protein quantitative trait loci study including 35,559 individuals by the deCODE Genetics Consortium. The outcome data for osteonecrosis were sourced from the FinnGen study, comprising 1,543 cases and 391,037 controls. MR analysis was conducted to estimate the associations between protein and osteonecrosis risk. Additionally, Phenome-wide MR analysis, and candidate drug prediction were employed to identify potential causal circulating proteins and novel drug targets.ResultsWe totally assessed the effect of 1,676 plasma proteins on osteonecrosis risk, of which 71 plasma proteins had a suggestive association with outcome risk (P < 0.05). Notably, Heme-binding protein 1 (HEBP1) was significant positively associated with osteonecrosis risk with convening evidence (OR, 1.40, 95% CI, 1.19 to 1.65, P = 3.96 × 10−5, PFDR = 0.044). This association was further confirmed in other MR analysis methods and did not detect heterogeneity and pleiotropy (all P > 0.05). To comprehensively explore the health effect of HEBP1, the phenome-wide MR analysis found it was associated with 136 phenotypes excluding osteonecrosis (P < 0.05). However, no significant association was observed after the false discovery rate adjustment.ConclusionThis comprehensive MR study identifies 71 plasma proteins associated with osteonecrosis, with HEBP1, ITIH1, SMOC1, and CREG1 showing potential as biomarkers of osteonecrosis. Nonetheless, further studies are needed to validate this candidate plasma protein.

Daily experiences often involve the processing of multiple sequences, yet storing them challenges the limited capacity of working memory (WM). To achieve efficient memory storage, relational structures shared by sequences would be leveraged to reorganize and compress information. Here, participants memorized a sequence of items with different colors and spatial locations and later reproduced the full color and location sequences one after another. Crucially, we manipulated the consistency between location and color sequence trajectories. First, sequences with consistent trajectories demonstrate improved memory performance and a trajectory correlation between reproduced color and location sequences. Second, sequences with consistent trajectories show neural reactivation of common trajectories, and display spontaneous replay of color sequences when recalling locations. Finally, neural reactivation correlates with WM behavior. Our findings suggest that a shared common structure is leveraged for the storage of multiple sequences through compressed encoding and neural replay, together facilitating efficient information organization in WM.

Objectives: Research shows a close association between aberrant immune reactions in osteonecrotic tissues and immune cell infiltration. However, due to limitations in sample size and dataset comprehensiveness, the causal relationship between them is not fully established. This study aims to determine whether there is a causal relationship using a larger and more diverse dataset. Methods: We conducted a comprehensive Mendelian Randomization (MR) analysis to investigate the causal relationship between immune cell characteristics and osteonecrosis. Utilizing publicly available genetic data, we explored the causal relationships between 731 immune cell features and 604 cases from the FinnGen Finnish database, as well as 257 cases from the UK Biobank database with osteonecrosis data. The inverse-variance weighted (IVW) method was used for the primary analysis, and we employed sensitivity analyses to assess the robustness of the main results. In addition, considering data from the two databases used in this study, a meta-analysis was conducted on the significant immune cells associated with osteonecrosis (FDR

Objective This study was performed to explore the predictive value of the diaphragmatic thickness fraction (DTF) combined with the integrated pulmonary index (IPI) for the extubation outcome in patients with severe acute pancreatitis (SAP). Methods This prospective study involved 93 patients diagnosed with SAP and treated with mechanical ventilation in our hospital from October 2020 to September 2023. The patients were divided into a successful extubation group (61 patients) and an extubation failure group (32 patients) based on the extubation outcomes. The predictive value of the DTF, IPI, and their combination for extubation failure was analyzed. Results The DTF and IPI were independent risk factors for extubation failure in patients with SAP undergoing mechanical ventilation. In addition, the combination of the DTF and IPI showed predictive value for extubation failure in these patients. Conclusion The DTF and IPI hold predictive value for extubation failure in patients with SAP undergoing mechanical ventilation, and their combined use may improve the predictive efficiency.

With the rapid development of the global construction industry, not only a large amount of construction waste has been derived, but also a growing shortage of natural sand resources emerges. Aiming at the above problems, this study uses waste concrete and artificial sand as recycled coarse and fine aggregates to form a new type of recycled concrete. 135 standard cubes and prismatic test blocks were produced. Concrete mixtures were prepared with recycled concrete aggregate and artificial sand to fully replace natural aggregates. This study investigates the mechanical properties of recycled concrete containing artificial sand and polypropylene fibers. Polypropylene fiber content varied from 0-1.5% by mass. Experimental results showed the addition of fibers enhanced the compressive strength and ductility. The optimum fiber dosage was 0.6% for strength gain. However, elastic modulus decreased with increasing fiber content due to increased porosity. The findings demonstrate the feasibility of recycled concrete with artificial sand and polypropylene fibers as an environmentally-friendly construction material.

Abstract Background Previous studies on the biomarkers of pathologic myopia choroidal neovascularization (pmCNV) development merely detected limited types of proteins and provide a meagre illustration of the underlying pathways. Hence, a landscape of protein changes in the aqueous humor (AH) of pmCNV patients is lacking. Here, to explore the potential mechanisms and biomarkers of pmCNV, we analyzed the clinical data and protein profile among atrophic (A) lesions, tractional lesions (T) and neovascular (N) lesions in myopic patients based on the ATN grading system for myopic maculopathy (MM). Results After investigating demographic data of our patients, a correlation was found between A and N lesions (R = 0.5753, P

Abstract Mounting attention has been focused on defects of the autophagy-lysosomal pathway in sepsis, however, the precise mechanisms governing the autophagy-lysosomal process in sepsis are poorly known. We have previously reported that Erbin deficiency aggravated the inflammatory response and organ injuries caused by sepsis. In the present study, we found that Erbin knockout impaired the autophagy process in both muramyl dipeptide (MDP)-induced bone marrow-derived macrophages (BMDMs) and sepsis mouse liver and lung, as detected by the accumulation of LC3-II and SQSTM1/p62, and autophagosomes. Pretreatment with autophagy inhibitor chloroquine (CQ) further aggravated inflammatory response and organ injuries in vivo and in vitro sepsis model. We also observed that the impaired lysosomal function mediated autophagic blockade, as detected by the decreased expression of ATP6V, cathepsin B (CTSB) and LAMP2 protein. Immunoprecipitation revealed that the C-terminal of Erbin (aa 391–964) interacts with the N-terminal of transcription factor EB (TFEB) (aa 1–247), and affects the stability of TFEB-14-3-3 and TFEB-PPP3CB complexes and the phosphorylation status of TFEB, thereby promote the nucleus translocation of TFEB and the TFEB target genes transcription. Thus, our study suggested that Erbin alleviated sepsis-induced inflammatory responses and organ injuries by rescuing dysfunction of the autophagy-lysosomal pathway through TFEB-14-3-3 and TFEB-PPP3CB pathway.

AimsTo evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of cetagliptin (CAS number:2243737-33-7) in Chinese patients with type 2 diabetes mellitus (T2DM). A population PK/PD model was developed to quantify the PK and PD characteristics of cetagliptin in patients.Materials and methods32 Chinese adults with T2DM were enrolled in this study. The subjects were randomly assigned to receive either cetagliptin (50 mg or 100 mg), placebo, or sitagliptin (100 mg) once daily for 14 days. Blood samples were collected for PK and PD analysis. Effects on glucose, insulin, C-peptide, and glucagon were evaluated following an oral glucose tolerance test (OGTT) (day15). Effects on HbA1c and glycated albumin (GA), and safety assessments were also conducted. Meanwhile, a population PK/PD model was developed by a sequential two-step analysis approach using Phoenix.ResultsFollowing multiple oral doses, cetagliptin was rapidly absorbed and the mean half-life were 34.9-41.9 h. Steady-state conditions were achieved after 1 week of daily dosing and the accumulation was modest. The intensity and duration of DPP-4 inhibition induced by 50 mg cetagliptin were comparable with those induced by sitagliptin, and 100 mg cetagliptin showed a much longer sustained DPP-4 inhibition (≥80%) than sitagliptin. Compared with placebo group, plasma active GLP-1 AUEC0-24h increased by 2.20- and 3.36-fold in the 50 mg and 100 mg cetagliptin groups. A decrease of plasma glucose and increase of insulin and C-peptide were observed following OGTT in cetagliptin groups. Meanwhile, a tendency of reduced GA was observed, whereas no decreasing trend was observed in HbA1c. All adverse events related to cetagliptin and sitagliptin were assessed as mild. A population PK/PD model was successfully established. The two-compartment model and Sigmoid-Emax model could fit the observed data well. Total bilirubin (TBIL) was a covariate of volume of peripheral compartment distribution (V2), and V2 increased with the increase of TBIL.ConclusionsCetagliptin was well tolerated, inhibited plasma DPP-4 activity, increased plasma active GLP-1 levels, and exhibited a certain trend of glucose-lowering effect in patients with T2DM. The established population PK/PD model adequately described the PK and PD characteristics of cetagliptin.

In recent years, PM2.5 and O3 have been the two main pollutants affecting public health in China, but the interaction of the two pollutants on human health remains unclear. A two-stage analytical approach was used to investigate the relationships of PM2.5–O3 co-pollution with nonaccidental, cardiovascular, and respiratory mortality levels across 14 cities in China. We first utilized a generalized additive model (GAM) to determine the city-specific associations of PM2.5 and O3 with daily mortality. The associations were then combined at the national and regional levels using meta-analysis. To investigate the potential interactions between the two pollutants and cause-specific mortality, we performed stratified analyses by co-pollutant exposure levels and the synergy index (SI) (SI > 1 indicates a synergistic interaction). The effect of changes in the two pollutants’ concentrations (in 10 μg/m3 increases) on mortality was assessed. The stratification analysis results suggested that each 10 μg/m3 increase in PM2.5 at lag0-1 (lag01) in the low, moderate, and high strata of the O3 concentrations increased nonaccidental mortality by 0.07% (95% confidence interval: −0.03%, 0.17%), 0.33% (0.13%, 0.53%), and 0.68% (0.30%, 1.06%), respectively, with significant between-group differences (p < 0.001). Moreover, each 10 μg/m3 increase in O3 (lag01) in the low, moderate, and high strata of the PM2.5 concentrations increased nonaccidental mortality by 0.15% (−0.06%, 0.36%), 0.53% (0.19%, 0.87%), and 0.75% (0.14%, 1.36%), respectively, with significant between-group differences (p < 0.001). We also found substantial synergistic interactions between the two pollutants and nonaccidental, cardiovascular, and respiratory mortality levels, with SI values of 1.48, 1.51, and 1.33, respectively. Additionally, a subgroup analysis revealed that the interaction of these two pollutants on nonaccidental mortality were greater in South China compared to elsewhere, and during the warm season compared to during the cold season. Our findings suggested that the simultaneous control of PM2.5 and O3 within the context of combined air pollution could significantly decrease the disease risk, especially in southern China and during the warm season.

ABSTRACTGut microbiota plays a crucial role in providing colonization resistance against multi-drug resistant organisms including carbapenem-resistant Klebsiella pneumoniae (CRKP). However, the impact of different carbapenems on intestinal colonization resistance against CRKP remains poorly understood. In this study, we aimed to investigate the effects of three commonly used carbapenems (meropenem, imipenem, and ertapenem) administered at single-day doses, which are typically employed in emergency departments for managing infected patients, on CRKP gut colonization. We conducted experiments in mice by intravenously administering each carbapenem using human-simulated one-day regimens. The composition of the gut microbiota was analyzed using 16S rRNA amplicon sequencing before and after carbapenem administration. Our results revealed that all three carbapenems, when administered at a single-day dose significantly altered the abundance and diversity of the gut microbiota, leading to compromised colonization resistance against CRKP. Notably, the ertapenem and imipenem groups showed an increase in Allobaculum, Bifidobacterium, Enterobacteriaceae, while the meropenem and imipenem groups exhibited a decrease in Ruminococcaceae, S24-7, and Akkermania. Additionally, the Shannon index exhibited a negative correlation with both the number of days of CRKP colonization CFUs and the duration of bacteria shedding. Furthermore, the count of CRKP in mice after ertapenem administration on the first day and the duration of CRKP shedding were significantly lower compared to meropenem and imipenem. Predictive metabolic pathway analysis demonstrated that the three carbapenems similarly affected a range of metabolic pathways of gut microflora, including carbohydrate metabolism and vitamin B. Our findings emphasize that ertapenem, with its relatively narrow spectrum, minimizes perturbations of the gut microbiota and has a relatively less impact on gut colonization resistance against CRKP.IMPORTANCEThe intestinal colonization of carbapenem-resistant Klebsiella pneumoniae (CRKP) is an important source of clinical infection. Our research showed that even single-day dose use of carbapenems caused CRKP colonization and continuous bacterial shedding, which reminds clinical doctors to prescribe carbapenems cautiously. Whenever possible, ertapenem should be the preferred choice over other carbapenems especially when the identified or highly suspected pathogens can be effectively targeted by ertapenem.

Non-technical losses are consistently a troubling issue for power suppliers. With the application and popularization of smart grid and advanced measurement systems, it has become possible to use data-driven methods to detect anomalous electricity consumption to reduce non-technical losses. A range of machine learning models have been utilized for detecting anomalous electricity consumption and have achieved promising results. However, with the evolution of techniques like electricity theft, coupled with the exponential increase in electricity consumption data, new challenges are constantly being posed for anomalous electricity consumption detection. We propose a Transformer-based method for detecting anomalous electricity consumption. The Transformer is composed of multi-head attention, layer normalization, point-wise feed-forward network, etc., which can effectively handle electricity consumption time-series data. Meanwhile, to alleviate the problem of imbalanced training data between anomalous and normal electricity consumption, we propose a method for synthesizing anomalies. The experimental results demonstrate that our proposed Transformer-based method outperforms the state-of-the-art methods in detecting anomalous electricity consumption, achieving a precision of 93.9%, a recall of 96.3%, an F1-score of 0.951, and an accuracy of 95.6% on a dataset released by the State Grid Corporation of China.

Abstract Reducing carbon emissions is a crucial way to achieve the goal of green and sustainable development. To accomplish this goal, electric vehicles (EVs) are considered system‐schedulable energy storage devices, suppressing the negative impact of the randomness and fluctuation of renewable energy on the system's operation. In this paper, a coordination control strategy aimed at minimising the carbon emissions of a distribution network between EVs, energy storage devices, and static var compensators (SVCs) is proposed. A model‐free deep reinforcement learning (DRL)‐based approach is developed to learn the optimal control strategy with the constraint of avoiding system overload caused by random EV access. The twin‐delayed deep deterministic policy gradient (TD3) framework is applied to design the learning method. After the model learning is completed, the neural network can quickly generate a real‐time low‐carbon scheduling strategy according to the system operating situation. Finally, simulation on the IEEE 33‐bus system verifies the effectiveness and robustness of this method. On the premise of meeting the charging demand of electric vehicles, this method can optimise the system operation by controlling the charge‐discharge process of EVs, effectively absorbing the renewable energy in the system and reducing the carbon emissions of the system operation.

Titanium (Ti) particles reinforced AZ91 matrix composite (Tip/AZ91) was prepared by powder metallurgy method. In the present work, we investigated the hot deformation behavior of Tip/AZ91 composite by isothermal compression tests at a range of temperature from 250 °C to 400 °C and strain rates from 0.001 s−1 to 1 s−1. Microstructure observations revealed that Ti particles were distributed uniformly in the composite, with the presence of a diffusion layer containing Mg, Ti, and Al elements between the Ti particles and the magnesium (Mg) matrix. The strain-compensated Arrhenius constitutive model was constructed, and the accuracy was evaluated by error analysis. The stress index exponent (n) was calculated as 4.98, indicating that the dislocation climb mechanism dominates the thermal deformation of Tip/AZ91 composite. Moreover, the calculated activation energy (Q) of 153.7 kJ/mol was observed to be lower than that of the pure AZ91 alloy, which can be attributed to the presence of a particle deformation zone (PDZ). Further microstructure analysis indicated that the continuous dynamic recrystallization mechanism (CDRX) occurred. As the recrystallized grains grow, the texture changes from a bimodal texture to a typical unimodal texture, resulting in a recrystallized //normal direction texture. In addition, the particle stimulated nucleation (PSN) phenomenon was observed around Ti particles at low Zener-Hollomon parameter (lnZ = 20.73) condition.

Thermodynamic theory was employed in this study to investigate the feasibility of separating antimony (Sb) from crude arsenic (As) using vacuum sublimation. Ab initio molecular dynamics simulations are used to calculate the structure, stability, and diffusion properties of AsmSbn (m + n ≤ 6) clusters. As4, As3Sb, As2Sb2, and AsSb3 are the possible clusters in this thermodynamic calculation, and the molecular dynamics results confirmed their structural stability and stabilization in the gas phase. As4 had the largest diffusion coefficients, which is the reason it separates from the Sb-containing clusters (As3Sb, As2Sb2, and AsSb3) during gas-phase diffusion and condensation processes. The experimental results show that As vapor was transformed from crystalline to amorphous with increasing subcooling, and the Sb-containing clusters that enter the gas phase were mainly condensed and deposited at the proximal end of the heating zone. Not considering the volatilization rate, the removal rate of Sb in products can reach 99.35% by increasing the condensation disk and expanding the condensation zone; thus, experiments confirmed that industrial crude arsenic can realize deep Sb removal after vacuum sublimation.

Soil salinization is one of the leading threats to global ecosystems, food security, and crop production. Plant growth-promoting rhizobacteria (PGPRs) are potential bioinoculants that offer an alternative eco-friendly agricultural approach to enhance crop productivity from salt-deteriorating lands. The current work presents bacterial strain CNUC13 from maize rhizosphere soil that exerted several PGPR traits and abiotic stress tolerance. The strain tolerated up to 1000 mM NaCl and 30% polyethylene glycol (PEG) 6000 and showed plant growth-promoting (PGP) traits, including the production of indole-3-acetic acid (IAA) and siderophore as well as phosphate solubilization. Phylogenetic analysis revealed that strain CNUC13 was Microbacterium azadirachtae. Maize plants exposed to high salinity exhibited osmotic and oxidative stresses, inhibition of seed germination, plant growth, and reduction in photosynthetic pigments. However, maize seedlings inoculated with strain CNUC13 resulted in significantly improved germination rates and seedling growth under the salt-stressed condition. Specifically, compared with the untreated control group, CNUC13-treated seedlings exhibited increased biomass, including fresh weight and root system proliferation. CNUC13 treatment also enhanced photosynthetic pigments (chlorophyll and carotenoids), reduced the accumulation of osmotic (proline) and oxidative (hydrogen peroxide and malondialdehyde) stress indicators, and positively influenced the activities of antioxidant enzymes (catalase, superoxide dismutase, and peroxidase). As a result, CNUC13 treatment alleviated oxidative stress and promoted salt tolerance in maize. Overall, this study demonstrates that M. azadirachtae CNUC13 significantly enhances the growth of salt-stressed maize seedlings by improving photosynthetic efficiency, osmotic regulators, oxidative stress resilience, and antioxidant enzyme activity. These findings emphasize the potential of utilizing M. azadirachtae CNUC13 as a bioinoculant to enhance salt stress tolerance in maize, providing an environmentally friendly approach to mitigate the negative effects of salinity and promote sustainable agriculture.

Senile osteoporosis (SOP) is a prevalent manifestation of age-related bone disorders, resulting from the dysregulation between osteoblast (OB)-mediated bone formation and osteoclast (OC)-mediated bone resorption, coupled with the escalating burden of cellular senescence. Traditional Chinese medicine (TCM) herbs, renowned for their remarkable attributes encompassing excellent tolerability, low toxicity, heightened efficacy, and minimal adverse reactions, have gained considerable traction in OP treatment. Emerging evidence substantiates the therapeutic benefits of various TCM formulations and their active constituents, including Zuogui wan, Fructus Ligustri Lucidi, and Resveratrol, in targeting cellular senescence to address SOP. However, a comprehensive review focusing on the therapeutic efficacy of TCM against SOP, with a particular emphasis on senescence, is currently lacking. In this review, we illuminate the pivotal involvement of cellular senescence in SOP and present a comprehensive exploration of TCM formulations and their active ingredients derived from TCM, delineating their potential in SOP treatment through their anti-senescence properties. Notably, we highlight their profound effects on distinct aging models that simulate SOP and various senescence characteristics. Finally, we provide a forward-looking discussion on utilizing TCM as a strategy for targeting cellular senescence and advancing SOP treatment. Our objective is to contribute to the unveiling of safer and more efficacious therapeutic agents for managing SOP.

Osteoporosis (OP), a prevalent public health concern primarily caused by osteoclast-induced bone resorption, requires potential therapeutic interventions. Natural compounds show potential as therapeutics for postmenopausal OP. Emerging evidence from in vitro osteoclastogenesis assay suggests that aconine (AC) serves as an osteoclast differentiation regulator without causing cytotoxicity. However, the in vivo functions of AC in various OP models need clarification. To address this, we administered intraperitoneal injections of AC to ovariectomy (OVX)-induced OP mice for 8 weeks and found that AC effectively reversed the OP phenotype of OVX mice, leading to a reduction in vertebral bone loss and restoration of high bone turnover markers. Specifically, AC significantly suppressed osteoclastogenesis in vivo and in vitro by decreasing the expression of osteoclast-specific genes such as NFATc1, c-Fos, Cathepsin K, and Mmp9. Importantly, AC can regulate osteoclast ferroptosis by suppressing Gpx4 and upregulating Acsl4, which is achieved through inhibition of the phosphorylation of I-κB and p65 in the NF-κB signaling pathway. These findings suggest that AC is a potential therapeutic option for managing OP by suppressing NF-κB signaling-mediated osteoclast ferroptosis and formation.

Abstract Background The tourniquet technique is often used in total knee arthroplasty (TKA). However, its effect on postoperative delirium (POD) in elderly patients undergoing TKA is unknown. Methods This prospective randomized controlled trial assessed the eligibility of 245 elderly patients. A total of 197 patients who met the inclusion criteria were randomly divided into a tourniquet group (n = 98) and a non-tourniquet group (n = 99). The primary outcome was the incidence of POD within 72 h after surgery. The secondary outcome was the quality of rehabilitation, including inflammatory reaction, postoperative pain, hypoproteinemia and anemia. Results Of 245 patients, 184 patients completed this clinical trial, with 92 cases in each group. There were 14 patients (15.22%) with POD in the tourniquet group and 5 patients (5.43%) in the non-tourniquet group (95% CI 1.076 to 9.067, P = 0.029). The changes in white blood cell count (WBC), the proportion of neutrophils (NEUT%), c-reactive protein (CRP), interleukin-6 (IL-6) and middle patellar circumference in the tourniquet group were higher than those in the non-tourniquet group (P

Abstract Background Changes in modern industrial production practices can easily lead to shoulder work-related musculoskeletal disorders (WMSD). The current reports on shoulder WMSD are limited to some industries are less well studied, and the sample size is usually small. This study aimed to describe the prevalence and severity of shoulder WMSD in a large sample of Chinese workers from 15 industries, analyze the possible correlations with sociodemographic and work-related variables, and compare the differences between industries. Methods A cross-sectional study was conducted among a sample of 55,749 participants from 252 enterprises in 15 industries throughout China. A Chinese version of the musculoskeletal disease questionnaire was used to collect the demographic factors, shoulder symptoms in past 12 months, and work-related factors including posture-related factors, repetition, vibration, work organization, job control, and environmental factors as independent variables. Descriptive statistics were used, and the binary logistic regression analysis was performed to explore the association between shoulder WMSD and potential demographic and work-related factors. Results Nearly 35.5% of participants reported shoulder pain and discomfort in the previous 12 months. Biopharmaceutical manufacturing (56.2%), medical services (54.4%), and aviation services (50.1%) were the three industries with the highest prevalence of shoulder WMSD. The pain score of aviation services workers was the highest. The related factors for shoulder WMSD varied among the different industries. Conclusion Our study found a relatively high prevalence of shoulder WMSD in China. There were large differences in the prevalence of shoulder WMSD among industries, and the related factors were particular to each industry. Such information is useful to help occupational health practitioners and policymakers conduct preventive programs to reduce shoulder disorders in these working populations.

Osteoporosis (OP) is a systemic skeletal disease prevalent in older adults, characterized by substantial bone loss and deterioration of microstructure, resulting in heightened bone fragility and risk of fracture. Traditional Chinese Medicine (TCM) herbs have been widely employed in OP treatment owing to their advantages, such as good tolerance, low toxicity, high efficiency, and minimal adverse reactions. Increasing evidence also reveals that many plant-based compounds (or secondary metabolites) from these TCM formulas, such as resveratrol, naringin, and ginsenoside, have demonstrated beneficial effects in reducing the risk of OP. Nonetheless, the comprehensive roles of these natural products in OP have not been thoroughly clarified, impeding the development of synergistic formulas for optimal OP treatment. In this review, we sum up the pathological mechanisms of OP based on evidence from basic and clinical research; emphasis is placed on the in vitro and preclinical in vivo evidence-based anti-OP mechanisms of TCM formulas and their chemically active plant constituents, especially their effects on imbalanced bone homeostasis regulated by osteoblasts (responsible for bone formation), osteoclasts (responsible for bone resorption), bone marrow mesenchymal stem cells as well as bone microstructure, angiogenesis, and immune system. Furthermore, we prospectively discuss the combinatory ingredients from natural products from these TCM formulas. Our goal is to improve comprehension of the pharmacological mechanisms of TCM formulas and their chemically active constituents, which could inform the development of new strategies for managing OP.

Water inrush is one of the most serious phenomena threatening the safety of tunnel construction. The West Qinling 1# tunnel, as the major section of the Bailong River diversion project, traverses a complicated karst area and would be faced with a water inrush disaster. Based on geological and hydrogeological conditions, the Finite element subsurface flow system software is used to simulate and predict the development of the natural seepage field and dredging construction conditions of the seepage field on the West Qinling 1# tunnel area. The prediction results show that the groundwater level will drop up to 113.9 m under dredging construction conditions, with an impact radius of up to 11.5 km. Seepage field evolution and water influx were simulated under two conditions of construction plugging construction, respectively. The prediction results show that the groundwater level in the middle part of tunnel 1# is 112.68 m depth without blocking condition with an influence range of 10.5 km. The maximum water volume per unit length of the karst cave increases to 4.32 m3/d·m. In the plugging condition, the influencing scope does not significantly reduce, but the extent of the impact is greatly weakened. The groundwater level generally dropped at 10–25 m depth and the karst cave section unit length of the maximum water volume of 0.83 m3/d·m in the rainy season. The achievements of this study would provide a vital reference for the prevention of water inrush in karst tunnel construction.

BackgroundSepsis is a complex condition involving multiorgan failure, resulting from the hosts’ deleterious systemic immune response to infection. It is characterized by high mortality, with limited effective detection and treatment options. Dysregulated endoplasmic reticulum (ER) stress is directly involved in the pathophysiology of immune-mediated diseases.MethodsClinical samples were obtained from Gene Expression Omnibus datasets (i.e., GSE65682, GSE54514, and GSE95233) to perform the differential analysis in this study. A weighted gene co-expression network analysis algorithm combining multiple machine learning algorithms was used to identify the diagnostic biomarkers for sepsis. Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and the single-sample gene set enrichment analysis algorithm were used to analyze immune infiltration characteristics in sepsis. PCR analysis and western blotting were used to demonstrate the potential role of TXN in sepsis.ResultsFour ERRGs, namely SET, LPIN1, TXN, and CD74, have been identified as characteristic diagnostic biomarkers for sepsis. Immune infiltration has been repeatedly proved to play a vital role both in sepsis and ER. Subsequently, the immune infiltration characteristics result indicated that the development of sepsis is mediated by immune-related function, as four diagnostic biomarkers were strongly associated with the immune infiltration landscape of sepsis. The biological experiments in vitro and vivo demonstrate TXN is emerging as crucial player in maintaining ER homeostasis in sepsis.ConclusionOur research identified novel potential biomarkers for sepsis diagnosis, which point toward a potential strategy for the diagnosis and treatment of sepsis.

Interferon and chemokine-mediated immune responses are two general antiviral programs of the innate immune system in response to viral infections and have recently emerged as important players in systemic metabolism. This study found that the chemokine CCL4 is negatively regulated by glucose metabolism and avian leukosis virus subgroup J (ALV-J) infection in chicken macrophages. Low expression levels of CCL4 define this immune response to high glucose treatment or ALV-J infection. Moreover, the ALV-J envelope protein is responsible for CCL4 inhibition. We confirmed that CCL4 could inhibit glucose metabolism and ALV-J replication in chicken macrophages. The present study provides novel insights into the antiviral defense mechanism and metabolic regulation of the chemokine CCL4 in chicken macrophages.

Neurogenesis is a fundamental process in the development and plasticity of the nervous system, and its regulation is tightly linked to mitochondrial dynamics. Imbalanced mitochondrial dynamics can result in oxidative stress, which has been implicated in various neurological disorders. Paraquat (PQ), a commonly used agricultural chemical known to be neurotoxic, induces oxidative stress that can lead to mitochondrial fragmentation. In this study, we investigated the effects of PQ on neurogenesis in primary murine neural progenitor cells (mNPCs) isolated from neonatal C57BL/6 mice. We treated the mNPCs with 0–40 μM PQ for 24 h and observed that PQ inhibited their proliferation, migration, and differentiation into neurons in a concentration-dependent manner. Moreover, PQ induced excessive mitochondrial fragmentation and upregulated the expression of Drp-1, p-Drp1, and Fis-1, while downregulating the expression of Mfn2 and Opa1. To confirm our findings, we used Mdivi-1, an inhibitor of mitochondrial fission, which reversed the adverse effects of PQ on neurogenesis, particularly differentiation into neurons and migration of mNPCs. Additionally, we found that Mito-TEMPO, a mitochondria-targeted antioxidant, ameliorated excessive mitochondrial fragmentation caused by PQ. Our study suggests that PQ exposure impairs neurogenesis by inducing excessive mitochondrial fission and abnormal mitochondrial fragmentation via oxidative stress. These findings identify mitochondrial fission as a potential therapeutic target for PQ-induced neurotoxicity. Further research is needed to elucidate the underlying mechanisms of mitochondrial dynamics and neurogenesis in the context of oxidative stress-induced neurological disorders.

Phosphorus (P) stands as a pivotal macroelement in relation to the growth of plants. It plays a significant role in physiological processes, as components of biofilms and nucleotides, and in metabolic activities within plants. The deprivation of phosphorus detrimentally impacts the growth and developmental of plants. However, the rhizosphere’s beneficial fungi and bacteria augment the efficacy of phosphorus uptake, participate in the molecular regulation of phosphorus, stimulate physiological alterations in plants, and facilitate signal transmission. In order to give readers a better understanding of the effects and positive roles of soil beneficial fungi and bacteria in regulating plant phosphorus acquisition and transport, this present review introduces the role and influence of rhizosphere microorganisms (fungi and bacteria) in assisting plant phosphorus absorption, and summarizes the key phosphorus transporters found in their interaction with plants. Using mixed microbial populations as composite microbial fertilizers has a positive effect on plants under phosphorus-deficiency conditions. It will be conducive to a better understanding of the mutualistic relationship between fungi, bacteria, and plants to provide a way to reduce the application of phosphorus fertilizers efficiently, and to provide a research background for the development of microbiological fertilizers.

Risk prediction models are an important part of assessing operative mortality and postoperative complication rates in current cardiac surgery practice. Furthermore, they guide clinical decision-making and perioperative patient management. In recent years, a variety of clinical prediction models have been developed in China and other countries to assess the risk of mortality and complications after cardiac surgery. Currently, the most widely used and mature models are the new version of the European Cardiac Surgery Evaluation System (EuroSCORE II), the American Society of Thoracic Surgeons Cardiac Surgery Risk Model (STS score), and the Chinese Coronary Artery Bypass Graft Surgery Risk Evaluation System (SinoSCORE). This article reviews the application of these three risk prediction models, to identify the optimal model for guiding clinical practice.

Oil crops are the second most cultivated economic crop in the world after food crops, and they are an important source of both edible and industrial oil. The growth of oil crops is limited by biotic and abiotic stresses, which hinder their yield and quality. Among all the agronomic measures, plant growth promoting bacteria (PGPB) play a crucial role in improving the yield, quality, and adaptability of oil crops. In this review, we considered the recent research on the sources of beneficial bacteria and their interactions with and influences on host plants, with a focus on summarizing the important roles and molecular mechanisms of PGPB in promoting growth and resisting biotic and abiotic stresses in oil crops. Finally, we outlined the current opportunities and challenges of microbial strategies for the improvement of the yield, quality, and adaptability of oil crops, providing a theoretical basis for the future use of microbial inoculants in these crops.

The compromise between strength and plasticity has greatly limited the potential application of particles reinforced magnesium matrix composites (MMCs). In this work, the Ti particles reinforced AZ31 magnesium (Mg) matrix composites achieved simultaneous improvement in strength, elongation and wear resistance. The Ti particles reinforced AZ31 composites were fabricated by ultrasonic-assisted stir casting with hot extrusion. The results showed that a strong interfacial bonding was obtained at Ti/Mg interface because of the formation of semi-coherent orientation relationship of TiAl/Mg, TiAl/Al2Ti and Al2Ti/Mg interfaces. The as-extruded 6 wt.%Ti/AZ31 composite presented the best compressive mechanical properties and wear resistance with ultimate tensile strength, elongation and wear rate of 327 MPa, 20.4% and 9.026 × 10−3 mm3/m, obviously higher than those of AZ31 alloys. The enhanced mechanical properties were attributed to the grain refinement and strong interfacial bonding. The improved wear resistance was closely related to the increased hardness of composites and the formation of protective oxidation films.

The regularities of the world render an intricate interplay between past and present. Even across independent trials, current-trial perception can be automatically shifted by preceding trials, namely the "serial bias." Meanwhile, the neural implementation of the spontaneous shift of present by past that operates on multiple features remains unknown. In two auditory categorization experiments with human electrophysiological recordings, we demonstrate that serial bias arises from the co-occurrence of past-trial neural reactivation and the neural encoding of current-trial features. The meeting of past and present shifts the neural representation of current-trial features and modulates serial bias behavior. Critically, past-trial features (i.e., pitch, category choice, motor response) keep their respective identities in memory and are only reactivated by the corresponding features in the current trial, giving rise to dissociated feature-specific serial biases. The feature-specific automatic reactivation might constitute a fundamental mechanism for adaptive past-to-present generalizations over multiple features.

Abstract Osteosarcoma (OS) is the most common type of primary malignant bone tumor. The high-throughput sequencing technology has shown potential abilities to illuminate the pathogenic genes in OS. This study was designed to find a powerful gene signature that can predict clinical outcomes. We selected OS cases with gene expression and survival data in the TARGET-OS dataset and GSE21257 datasets as training cohort and validation cohort, respectively. The univariate Cox regression and Kaplan–Meier analysis were conducted to determine potential prognostic genes from the training cohort. These potential prognostic genes underwent a LASSO regression, which then generated a gene signature. The harvested signature’s predictive ability was further examined by the Kaplan–Meier analysis, Cox analysis, and receiver operating characteristic (ROC curve). More importantly, we listed similar studies in the most recent year and compared theirs with ours. Finally, we performed functional annotation, immune relevant signature correlation identification, and immune infiltrating analysis to better study he functional mechanism of the signature and the immune cells’ roles in the gene signature’s prognosis ability. A seventeen-gene signature (UBE2L3, PLD3, SLC45A4, CLTC, CTNNBIP1, FBXL5, MKL2, SELPLG, C3orf14, WDR53, ZFP90, UHRF2, ARX, CORT, DDX26B, MYC, and SLC16A3) was generated from the LASSO regression. The signature was then confirmed having strong and stable prognostic capacity in all studied cohorts by several statistical methods. We revealed the superiority of our signature after comparing it to our predecessors, and the GO and KEGG annotations uncovered the specifically mechanism of action related to the gene signature. Six immune signatures, including PRF1, CD8A, HAVCR2, LAG3, CD274, and GZMA were identified associating with our signature. The immune-infiltrating analysis recognized the vital roles of T cells CD8 and Mast cells activated, which potentially support the seventeen-gene signature’s prognosis ability. We identified a robust seventeen-gene signature that can accurately predict OS prognosis. We identified potential immunotherapy targets to the gene signature. The T cells CD8 and Mast cells activated were identified linked with the seventeen-gene signature predictive power.

ABSTRACT The growing prevalence of antimicrobial resistance poses a grave threat to human health. Among the most difficult bacterial infections to treat are those caused by multidrug-resistant (MDR) Gram-negative pathogens because few effective regimens are available. One approach to this problem is to find ways to increase the activity of old antimicrobials that had seen limited application. Bicyclomycin, an inhibitor of transcription termination, is an example in which the additional inhibition of protein or RNA synthesis increases bicyclomycin-mediated lethality against Gram-negative bacteria. To examine the potential of bicyclomycin for the treatment of MDR bacterial pathogens, we first measured the MICs of bicyclomycin and other widely used antimicrobials against more than 100 multidrug-resistant Gram-negative clinical isolates. Bicyclomycin showed good coverage of carbapenem-resistant Enterobacteriaceae (CRE) and Escherichia coli (MIC50/MIC90 of 25/50 μg/mL for both bacteria) and moderate activity against Klebsiella pneumoniae (MIC50/MIC90 of 50/200 μg/mL). Bicyclomycin also exhibited synergy (e.g., fractional inhibitory concentration [FIC] index of

Background. Thoracoscopic lung cancer surgery is accompanied by severe pain. Both continuous paravertebral block (CPVB) and continuous wound infiltration (CWI) are widely used for perioperative analgesia in thoracoscopic surgery. However, the effects of these different methods on chronic postsurgical pain (CPSP) are still unknown. Patients and Methods. This prospective randomized controlled trial assessed the eligibility of 113 patients. Ninety-seven patients who met the inclusion criteria were randomly divided into a CPVB group and a CWI group, and 80 patients were analyzed in the final study. The primary outcome measures were the incidence and intensity of chronic postsurgical pain (CPSP) at 3, 6, and 9 months after surgery. The secondary outcome measures were the numerical rating scale (NRS) score of rest and activity at 12, 18, and 24 hours and on the 2nd, 3rd, and 7th days postoperatively; the Barthel Activities of Daily Living (ADL) score of activity levels on the 1st, 2nd, 3rd, and 7th days postoperatively; and the long-term quality of the life score at 3, 6, and 9 months postoperatively. Results. The incidence of chronic postsurgical pain in the CWI group was significantly higher than that in the CPVB group at 3, 6, and 9 months after surgery (all P

The relationship between conscious experience and brain activity has intrigued scientists and philosophers for centuries. In the last decades, several theories have suggested different accounts for these relationships. These theories have developed in parallel, with little to no cross-talk among them. To advance research on consciousness, we established an adversarial collaboration between proponents of two of the major theories in the field, Global Neuronal Workspace and Integrated Information Theory. Together, we devised and preregistered two experiments that test contrasting predictions of these theories concerning the location and timing of correlates of visual consciousness, which have been endorsed by the theories' proponents. Predicted outcomes should either support, refute, or challenge these theories. Six theory-impartial laboratories will follow the study protocol specified here, using three complementary methods: Functional Magnetic Resonance Imaging (fMRI), Magneto-Electroencephalography (M-EEG), and intracranial electroencephalography (iEEG). The study protocol will include built-in replications, both between labs and within datasets. Through this ambitious undertaking, we hope to provide decisive evidence in favor or against the two theories and clarify the footprints of conscious visual perception in the human brain, while also providing an innovative model of large-scale, collaborative, and open science practice.

Cadmium (Cd) is a ubiquitous toxic metal and environmental pollutant. Increasing studies have shown that Cd exposure increases the incidence of various endocrine system diseases, including thyrotoxicity reflected by thyroid structural damage and endocrine toxicity. However, the observed outcomes are complex and conflicting, leading to the mechanism of Cd-induced thyrotoxicity remaining obscure. In this study, 4-week-old male C57BL/6 mice were given 2 or 7 mg/kg Cadmium Chloride (CdCl2) intragastrically for 4 and 8 weeks, and the Cd-mediated thyrotoxicity was evaluated by determining alterations in thyroid structure and endocrine function, and alterations of oxidant stress, apoptosis, and pyroptosis. Our data showed that Cd exposure could reduce body weight and induce thyrotoxicity by impairing thyroid follicular morphology and endocrine function, accompanied by elevated oxidative stress and apoptosis, macrophage infiltration, and inflammatory cytokine secretion. Importantly, Cd significantly promoted thyroid follicular cell pyroptosis by increasing Nlrp3, Asc, Caspase-1, Gsdmd, IL-1β, and IL-18 expression. Mechanistical analysis suggested that Cd treatment could inhibit antioxidant pathway by downregulating antioxidant response protein, Nrf2, and upregulating its negative feedback regulator, Keap1. Collectively, our in vivo findings suggest that Cd exposure could facilitate thyroid follicular cell pyroptosis by inhibiting Nrf2/Keap1 signaling, thereby disrupting thyroid tissue structure and endocrine function, which offers novel insights into the Cd-mediated detrimental consequences on thyroid homeostasis.

Multidrug-resistant (MDR) bacteria pose a significant clinical threat to human health, but the development of antibiotics cannot meet the urgent need for effective agents, especially those that can kill persisters and biofilms. Here, we reported that nigericin showed potent bactericidal activity against various clinical MDR Gram-positive bacteria, persisters and biofilms, with low frequencies of resistance development. Moreover, nigericin exhibited favorable in vivo efficacy in deep-seated mouse biofilm, murine skin and bloodstream infection models. With Staphylococcus aureus, nigericin disrupted ATP production and electron transport chain; cell death was associated with altered membrane structure and permeability. Obtaining nigericin-resistant/tolerant mutants required multiple rounds of challenge, and, cross-resistance to members of several antimicrobial classes was absent, probably due to distinct nigericin action with the GraSR two-component regulatory system. Thus, our work reveals that nigericin is a promising antibiotic candidate for the treatment of chronic or recurrent infections caused by Gram-positive bacteria.

During a disease survey on weeds and minor cultivated crops in Korea, a brown leaf spot disease was observed on Sonchus asper. Leaf lesions were round or irregular in shape, and grayish brown to brown with a purple margin. In severe infection, lesions enlarged and coalesced, resulting in blighting of the leaves. The isolates from these leaf lesions were identified as Alternaira sonchi based on morphological characteristics and phylogenetic analyses of Internal transcribed spacer region, Alternaria allergen a1, glyceraldehyde 3-phosphate dehydrogenase, RNA polymerase II, and translation elongation factor genes. This study provides a comprehensive description of the morphological characteristics and phylogenetical traits of A. sonchi causing brown leaf spot on S. asper in Korea.

Background and purposeA growing body of research suggests that inflammation and maternal infections may lead to an increased risk of neurodevelopmental problems such as attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), cerebral palsy (CP), and epilepsy in offspring. The aim of this study was to observe the connection between prenatal antibiotic exposure and the risk of these neurodevelopmental disorders in offspring.Patients and methodsA comprehensive search was conducted in the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Google Scholar, and Scopus databases for observational studies that looked into the link between prenatal exposure to antibiotics and the risk of neurodevelopmental problems in offspring, published from 1 January 1950 to 31 January 2022. The Newcastle–Ottawa Scale (NOS) was used to assess the quality of the included studies. Data were analyzed using the STATA version 12 software, and an odds ratio (OR) with a 95% confidence interval (CI) was reported.ResultsA total of 15 studies were included in the meta-analysis. Prenatal antibiotic exposure was associated with the increased risk of ADHD (OR = 1.14; 95% CI = 1.13 to 1.15; I2 = 0%) and epilepsy (OR = 1.34; 95% CI = 1.02 to 1.66; I2 = 96.8%). The link between prenatal antibiotic exposure and the risk of ASD [OR = 1.09; 95 % CI = 0.88 to 1.31; I2 = 78.9%] and CP [OR = 0.99; 95% CI = 0.56 to 1.43; I2 = 91%] was found to be non-significant. In all of the included prospective cohort studies, subgroup analysis suggested a significant association between prenatal antibiotic exposure and the incidence of ASD [OR = 1.17; 95% CI = 1.03 to 1.31; I2 = 48.1%] and CP [OR = 1.18; 95% CI = 1.02 to 1.34; I2 = 0%].ConclusionPrenatal antibiotic exposure during pregnancy is linked to a higher incidence of ADHD and epilepsy in the offspring. Further prospective studies that compare prenatal antibiotic use and are adjusted for various confounders are needed to further assess the association of prenatal antibiotic exposure and neurological disorders in offspring.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier: CRD42022306248.