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Abstract Background Prostate cancer (PCa) has a high incidence in men worldwide, and almost all PCa patients progress to the androgen-independent stage which lacks effective treatment measures. PTENP1, a long non-coding RNA, has been shown to suppress tumor growth through the rescuing of PTEN expression via a competitive endogenous RNA (ceRNA) mechanism. However, PTENP1 was limited to be applied in the treatment of PCa for the reason of rapid enzymatic degradation, poor intracellular uptake, and excessively long base sequence to be synthesized. Considering the unique advantages of artificial nanomaterials in drug loading and transport, black phosphorus (BP) nanosheet was employed as a gene-drug carrier in this study. Results The sequence of PTENP1 was adopted as a template which was randomly divided into four segments with a length of about 1000 nucleotide bases to synthesize four different RNA fragments as gene drugs, and loaded onto polyethyleneimine (PEI)-modified BP nanosheets to construct BP-PEI@RNA delivery platforms. The RNAs could be effectively delivered into PC3 cells by BP-PEI nanosheets and elevating PTEN expression by competitive binding microRNAs (miRNAs) which target PTEN mRNA, ultimately exerting anti-tumor effects. Conclusions Therefore, this study demonstrated that BP-PEI@RNAs is a promising gene therapeutic platform for PCa treatment. Graphical Abstract

Objective To explore the risk factors for sleep disorders in maintenance hemodialysis （MHD） patients and construct a risk prediction model. Methods A retrospective study was conducted among 198 patients who underwent MHD between January 2018 and December 2022. Based upon whether or not there were complications of sleep disorders, they were assigned into two groups of sleep disorder （n = 134） and non-sleep disorder （n = 64）. Uni/multivariate Logistic regression analyses were performed for identifying the risk factors for sleep disorders in MHD patients. A nomogram model for sleep disorders in MHD patients was constructed with software R. The discrimination and calibration of this model were tested using the receiver operating characteristic （ROC） curve and calibration curve. Internal validation of this model was conducted byBootstrap. Results The total PSQI score was （10.32 ± 1.34）. There were 134 patients with PSQI score ≥7 and the incidence of sleep disorders was 67.68%（134/198）. Uni/multivariate Logistic regression analyses revealed that dialysis duration （OR = 1.573）, skin pruritus （OR = 3.044）, restless leg syndrome （RSL）（OR = 2.722） and serum parathyroid hormone （PTH）（OR = 1.030） were risk factors for sleep disorders in MHD patients （P

Abstract Background The purpose of this study was to investigate the photoprotection effect of peroxiredoxin 1 (PRDX1) protein in ultraviolet B (UVB) irradiation-induced damage of retinal pigment epithelium (RPE) and its possible molecular mechanism. Methods ARPE-19 cell viability and apoptosis were assessed by MTT assay and flow cytometry, respectively. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect the PRDX1 expression. The corresponding kits were employed to measure the levels or activities of lactate dehydrogenase (LDH), 8-hydroxy-2-deoxyguanosine (8-OHdG), reactive oxygen species (ROS), malondialdehyde (MDA), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD). Western blotting was applied to examine PRDX1 expression and mitogen-activated protein kinase (MAPK) signaling pathway-related proteins. Results After exposure to 20 mJ/cm2 intensity of UVB irradiation for 24 h, ARPE-19 cells viability was decreased, the leakage degree of LDH and 8-OHdG were increased, and cell apoptosis was elevated. The expression of PRDX1 was significantly down-regulated in UVB-induced ARPE-19 cells. The low expression of PRDX1 was involved in high irradiation intensity. Overexpression of PRDX1 increased cell activity, decreased cell apoptosis, and LDH as well as 8-OHdG leakage in UVB-induced ARPE-19 cells. In addition to alleviating UVB-induced cell damage, PRDX1 overexpression also inhibited UVB-induced oxidative stress (down-regulation of ROS and MDA levels, up-regulation of GSH-Px and SOD activities) and the activation of MAPK signaling pathway in ARPE-19 cells. Conclusion PRDX1 exerts a photoprotection effect on RPE by attenuating UVB-induced cell damage and inhibiting oxidative stress, which can be attributed to the inhibition of MAPK signaling pathway activation.

The two vegetation transfer parameters of [Formula: see text] (Vegetation Optical Depth,VOD) and [Formula: see text] (Omega) could vary significantly across microwave channels in terms of frequencies, polarizations, and incidence angles, and their channel-dependent characteristics have not yet been fully investigated. In this study, we investigate the channel dependence of vegetation effects on microwave emissions from soils using a higher-order vegetation radiative transfer model of Tor Vergata. Corn was selected as the subject of investigation, and a corn growth model was developed utilizing field data collected from the multifrequency and multi-angular ground-based microwave radiation experiment from the Soil Moisture Experiment in the Luan River (SMELR). Upon compilation of the simulation dataset of microwave emissions of the corn field, the effective scattering albedo across different channels were calculated using the Tor Vergata model. Results show that vertical polarization of the vegetation optical depth is more affected by incidence angle changes, while horizontal polarization exhibits lower variations in vegetation optical depth due to incidence angle adjustments. The channel dependence of vegetation optical depth can be described as the polarization dependence parameter ([Formula: see text]) and the frequency dependence parameter ([Formula: see text]). These two parameters enable the calculation of vegetation optical depth at any channel under three adjacent frequencies (L-band, C-band and X-band). The effective scattering albedo of vegetation does not vary significantly with vegetation height or angle. It primarily depends on frequency and polarization, showing an overall increasing trend with increasing frequency. The effective scattering albedo with vertical polarization is slightly higher than that with horizontal polarization at higher frequencies, while both are lower in the L-band. This investigation is helpful for understanding the vegetation effects on microwave emissions from soils, ultimately advancing the accuracy of large-scale soil moisture retrieval in vegetated areas.

Freezing is an important method for food preservation, and some frozen foods still require separate thawing processes before consumption. Traditional thawing methods suffer from issues such as uneven temperature rise, long processing time, and significant loss of juices. As a new thawing technology, physical field thawing has received extensive research and attention in recent years. This paper reviews the research progress of physical field thawing in frozen food processing, and elaborates on the mechanisms and application effects of technologies such as ultrasound, dielectric, and electric fields in the thawing process. Compared to traditional thawing methods, physical field thawing better preserves the nutritional components of the ingredients, maintains sensory quality, reduces juice loss, and improves thawing efficiency. Different types of food materials and thawing methods may yield different effects, requiring analysis of the response characteristics and physicochemical parameters, such as dielectric constant, conductivity, and fat content, of actual ingredients to determine the optimal thawing conditions. Future research will focus on exploring efficient, stable, and low-energy physical field-assisted technologies, continuing in-depth studies on the impact on ingredient quality and thawing effects, to better meet consumers' demand for efficient processing of frozen foods.

Abstract Hadal trenches are extreme environments situated over 6000 m below sea surface, where enormous hydrostatic pressure affects the biochemical cycling of elements. Recent studies have indicated that hadal trenches may represent a previously overlooked source of fixed nitrogen loss; however, the mechanisms and role of hydrostatic pressure in this process are still being debated. To this end, we investigate the effects of hydrostatic pressure (0.1 to 115 MPa) on the chemical profile, microbial community structure and functions of surface sediments from the Mariana Trench using a Deep Ocean Experimental Simulator supplied with nitrate and oxygen. We observe enhanced denitrification activity at high hydrostatic pressure under oxic conditions, while the anaerobic ammonium oxidation – a previously recognized dominant nitrogen loss pathway – is not detected. Additionally, we further confirm the simultaneous occurrence of nitrate reduction and aerobic respiration using a metatranscriptomic dataset from in situ RNA-fixed sediments in the Mariana Trench. Taken together, our findings demonstrate that hydrostatic pressure can influence microbial contributions to nitrogen cycling and that the hadal trenches are a potential nitrogen loss hotspot. Knowledge of the influence of hydrostatic pressure on anaerobic processes in oxygenated surface sediments can greatly broaden our understanding of element cycling in hadal trenches.

Abstract Background Chimeric antigen receptor natural killer (CAR-NK) cells represent a promising advancement in CAR cell therapy, addressing limitations observed in CAR-T cell therapy. However, our prior study revealed challenges in CAR-NK cells targeting CD19 antigens, as they failed to eliminate CD19+ Raji cells in NSG tumor-bearing mice, noting down-regulation or loss of CD19 antigen expression in some Raji cells. In response, this study aims to enhance CD19 CAR-NK cell efficacy and mitigate the risk of tumor recurrence due to target antigen escape by developing CD19 and CD20 (CD19/CD20) dual-targeted CAR-NK cells. Methods Initially, mRNA encoding anti-CD19 CARs (FMC63 scFv-CD8α-4-1BB-CD3ζ) and anti-CD20 CARs (LEU16 scFv-CD8α-4-1BB-CD3ζ) was constructed via in vitro transcription. Subsequently, CD19/CD20 dual-targeted CAR-NK cells were generated through simultaneous electrotransfection of CD19/CD20 CAR mRNA into umbilical cord blood-derived NK cells (UCB-NK). Results Following co-electroporation, the percentage of dual-CAR expression on NK cells was 86.4% ± 1.83%, as determined by flow cytometry. CAR expression was detectable at 8 h post-electric transfer, peaked at 24 h, and remained detectable at 96 h. CD19/CD20 dual-targeted CAR-NK cells exhibited increased specific cytotoxicity against acute lymphoblastic leukemia (ALL) cell lines (BALL-1: CD19+CD20+, REH: CD19+CD20−, Jurkat: CD19−CD20−) compared to UCB-NK, CD19 CAR-NK, and CD20 CAR-NK cells. Moreover, CD19/CD20 dual-targeted CAR-NK cells released elevated levels of perforin, IFN-γ, and IL-15. Multiple activation markers such as CD69 and cytotoxic substances were highly expressed. Conclusions The creation of CD19/CD20 dual-targeted CAR-NK cells addressed the risk of tumor escape due to antigen heterogeneity in ALL, offering efficient and safe 'off-the-shelf' cell products. These cells demonstrate efficacy in targeting CD20 and/or CD19 antigens in ALL, laying an experimental foundation for their application in ALL treatment.

Abstract Background Endovascular thrombectomy (EVT) is a standard treatment for acute ischemic stroke (AIS) with large vessel occlusion. Hypertension and increased blood pressure variability within the first 24 h after successful reperfusion are related to a higher risk of symptomatic intracerebral hemorrhage and higher mortality. AIS patients might suffer from ischemia-reperfusion injury following reperfusion, especially within 24 h. Dexmedetomidine (DEX), a sedative commonly used in EVT, can stabilize hemodynamics by inhibiting the sympathetic nervous system and alleviate ischemia-reperfusion injury through anti-inflammatory and antioxidative properties. Postoperative prolonged sedation for 24 h with DEX might be a potential pharmacological approach to improve long-term prognosis after EVT. Methods This single-center, open-label, prospective, randomized controlled trial will include 368 patients. The ethics committee has approved the protocol. After successful reperfusion (modified thrombolysis in cerebral infarction scores 2b–3, indicating reperfusion of at least 50% of the affected vascular territory), participants are randomly assigned to the intervention or control group. In the intervention group, participants will receive 0.1~1.0 μg/kg/h DEX for 24 h. In the control group, participants will receive an equal dose of saline for 24 h. The primary outcome is the functional outcome at 90 days, measured with the categorical scale of the modified Rankin Scale, ranging from 0 (no symptoms) to 6 (death). The secondary outcome includes (1) the changes in stroke severity between admission and 24 h and 7 days after EVT, measured by the National Institute of Health Stroke Scale (ranging from 0 to 42, with higher scores indicating greater severity); (2) the changes in ischemic penumbra volume/infarct volume between admission and 7 days after EVT, measured by neuroimaging scan; (3) the length of ICU/hospital stay; and (4) adverse events and the all-cause mortality rate at 90 days. Discussion This randomized clinical trial is expected to verify the hypothesis that postoperative prolonged sedation with DEX after successful reperfusion may promote the long-term prognosis of patients with AIS and may reduce the related socio-economic burden. Trial registration ClinicalTrials.gov NCT04916197. Prospectively registered on 7 June 2021.

Metal-air battery is an environmental friendly energy storage system with unique open structure. Magnesium (Mg) and its alloys have been extensively attempted as anodes for air batteries due to high theoretical energy density, low cost, and recyclability. However, the study on Mg-air battery (MAB) is still at the laboratory level currently, mainly owing to the low anodic efficiency caused by the poor corrosion resistance. In order to reduce corrosion losses and achieve optimal utilization efficiency of Mg anode, the design strategies are reviewed from microstructure perspectives. Firstly, the corrosion behaviors have been discussed, especially the negative difference effect derived by hydrogen evolution. Special attention is given to the effect of anode micro-structures on the MAB, which includes grain size, grain orientation, second phases, crystal structure, twins, and dislocations. For further improvement, the discharge performance, long period stacking ordered phase and its enhancing effect are considered. Meanwhile, given the current debates over Mg dendrites, the potential risk, the impact on discharge, and the elimination strategies are discussed. Microstructure control and single crystal would be promising ways for MAB anode.

Abstract Background The atherogenic index of plasma (AIP) has been demonstrated to be significantly associated with the incidence of prediabetes and diabetes. This study aimed to investigate the association between the AIP and undiagnosed diabetes in acute coronary syndrome (ACS) patients. Methods Among 113,650 ACS patients treated with coronary angiography at 240 hospitals in the Improving Care for Cardiovascular Disease in China-ACS Project from 2014 to 2019, 11,221 patients with available clinical and surgical information were included. We analyzed these patients’ clinical characteristics after stratification according to AIP tertiles, body mass index (BMI) and low-density lipoprotein cholesterol (LDL-C) levels. Results The AIP was independently associated with a greater incidence of undiagnosed diabetes. The undiagnosed diabetes was significantly greater in the T3 group than in the T1 group after adjustment for confounders [T3 OR 1.533 (1.199–1.959) p

In orthogonal frequency division multiplexing (OFDM) systems, the existing timing synchronization (TS) methods are challenged by high computational complexity, large processing delay, and performance degradation in wireless scenarios. To alleviate these issues, a lightweight cascaded one-dimensional convolutional neural network (1-D CNN)-based TS scheme is proposed in this paper, which is developed from the joint perspective of considering cascaded mode and network lightweight. Specifically, we meticulously design two lightweight subnetworks. The first one is implemented with only one 1-D CNN layer due to the coarse timing offset task, which aims to reduce the search range of TS for the following subnetwork. Based on the narrowed search range of TS, the second subnetwork is also light-weighted with a two-layer 1-D CNN, which refines the estimation of timing offset. By jointly considering the cascaded mode and the lightweight 1-D CNN, the proposed scheme improves the TS correctness with reduced computational complexity and processing delay compared with the existing works. Simulation results validate the effectiveness and robustness of the proposed TS scheme given variant parameters.

BackgroundThe objective of this study was to conduct a systematic review and meta-analysis of the clinical application effects of transnasal high flow nasal cannula compared to other conventional modalities for oxygen therapy devices in patients undergoing bronchoscopy.MethodsA comprehensive literature search was conducted in multiple English databases, including PubMed, Web of Science, and Cochrane Library, to collect relevant studies on the application of high flow nasal cannula in patients undergoing bronchoscopy, and conducted a meta-analysis utilizing RevMan 5.4 software, following the predetermined inclusion and exclusion criteria.ResultsA total of 12 studies meeting the inclusion criteria were included, involving 1,631 patients (HFNC group: n = 811, other oxygen therapy group: n = 820). The meta-analysis results demonstrated that HFNC significantly reduced the incidence of hypoxemia and improved the minimum oxygen saturation compared to conventional oxygen therapy (RR = 0.27, 95% CI: 0.18–0.41, p

Introduction Postoperative ileus (POI) is a postoperative complication that can cause lingering recovery after colorectal resection and a heavy healthcare system burden. Acupuncture aims to prevent postoperative complications, reduce the duration of POI, help recovery and shorten hospital stays. We hypothesise that preoperative electroacupuncture (EA) can promote POI recovery under the enhanced recovery after surgery protocol after laparoscopic surgery in patients with POI.Methods and analysis This is a multicentre, randomised, sham-controlled trial. A total of 80 patients will be enrolled and randomly assigned to the EA or sham electroacupuncture (SA) group. The eligible patients will receive EA or SA for one session per day with treatment frequency starting on preoperative day 1 for four consecutive days. The primary outcome is the time to first defecation. The secondary outcomes include the time to first flatus, length of postoperative hospital stay, time to tolerability of semiliquid and solid food, postoperative nausea, vomiting, pain and extent of abdominal distention, time to first ambulation, preoperative anxiety, 30-day readmission rate, the usage of anaesthetics and analgesics during operation, length of postanaesthesia care unit stay. A mechanistic study by single-cell RNA sequencing in which postintervention normal intestinal tissue samples will be collected. The results of this study will provide evidence of the effects of acupuncture on POI and promote good clinical decision to millions of patients globally every year.Ethics and dissemination This study has been approved by the ethical application of Beijing University of Chinese Medicine (2022BZYLL0401), Beijing Friendship Hospital Affiliated to Capital Medical University(2022-P2-368-02), Cancer Hospital Chinese Academy of Medical Science (23/175-3917), Huanxing Cancer Hospital (2023-002-02). The results will be published in a medical journal. In addition, we plan to present them at scientific conferences.Trial registration number ChiCTR2300077633.

Background: Postoperative hypothermia (POH) is a common issue in colorectal surgery patients, leading to complications. This study aimed to develop and validate a predictive model for identifying POH in colorectal surgery patients. Methods: A retrospective analysis of 1,316 patients who underwent colorectal surgery between June 2020 and September 2022 was conducted using institutional medical records. Intraoperative core temperatures and potential influencing factors were collected, and regression analysis was used to identify risk factors for POH and create a model. The model's performance was evaluated using the receiver operating characteristic curve analysis. Results: Intraoperative hypothermia occurred in 51.5 % of patients. Significant predictors of POH included gender, alcohol consumption, surgery duration, platelet count, and age. The constructed model included factors like fluid intake, platelets, cigarette use, alcohol consumption, surgery type, muscle relaxants, age, ABSI, and gender. The model showed good predictive performance with an area under the ROC curve of 0.981 and a Hosmer-Lemeshow test p-value of 0.676. The Youden index, sensitivity, specificity, and practical application rate were 0.602, 0.790, 0.812, and 98.81 %, respectively. Conclusion: This study developed a predictive model for POH in colorectal surgery patients, considering individual factors and exploring underlying causes. Understanding risk factors and consequences of POH is crucial for nurses and perioperative professionals in clinical practice.

Summary: Salt fractionation is a classical approach for separating chromatin based on its differential salt solubility and physical properties. Here, we present a protocol to apply salt fractionation for genome-scale profiling of chromatin isolated from livers at different stages of aging in mice. We elaborate on the steps to isolate nuclei, digest with micrococcal nuclease, sequentially salt fractionate, purify DNA, and construct libraries for genome profiling. We also include information on a computational pipeline for data analysis.For complete details on the use and execution of this protocol, please refer to Yang et al.1 This protocol is an adaptation of the salt fractionation method of Teves and Henikoff.2 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

The inactivation of microorganisms is critical for ensuring the safety of food products. Currently, emerging electrotechnologies have attracted considerable attention. These non-conventional technologies for food processing rely on thermal effects, non-thermal effects, or a combination of them to achieve this goal. Conventional pasteurization requires a heat transfer medium. It is often performed at high temperatures, leadinging to food quality degradation and flavour distortion. Electrotechnologies contain ohmic heating (OH), pulsed electric field (PEF), and induced electric field (IEF) treatment, which utilize both electric potential difference and current. Compared to conventional heating, they can reduce inactivation temperature thresholds and duration while retaining nutritional value, having a minimal negative impact on food quality, flavor, and color. Since the main purpose of food processing is based on microorganism inactivation to ensure food safety and storability, it is worthwhile to pay attention to the current application of electric field technologies. This paper reviews the research progress on the inactivation of microorganisms by OH, PEF, and IEF treatment. Additionally, it presents the generation characteristics of electrotechnologies and an outlook on future development.

Background Lipoprotein(a) (Lp(a)) is considered to be a causal risk factor of atherosclerotic cardiovascular disease (ASCVD), but whether there is an independent or joint association of Lp(a) and atherosclerotic plaque with ASCVD risk remains uncertain. This study aims to assess ASCVD risk independently or jointly conferred by Lp(a) and carotid atherosclerotic plaque. Methods and Results A total of 5471 participants with no history of cardiovascular disease at baseline were recruited and followed up for ASCVD events (all fatal and nonfatal acute coronary and ischemic stroke events) over a median of 11.5 years. Independent association of Lp(a), or the joint association of Lp(a) and carotid plaque with ASCVD risk, was explored using Cox proportional hazards models. Overall, 7.6% of the participants (60.0±7.9 years of age; 2649 [48.4%] men) had Lp(a) ≥50 mg/dL, and 539 (8.4/1000 person‐years) incident ASCVD events occurred. Lp(a) concentrations were independently associated with long‐term risk of total ASCVD events, as well as coronary events and ischemic stroke events. Participants with Lp(a) ≥50 mg/dL had a 62% higher risk of ASCVD incidence (95% CI, 1.19–2.21) than those with Lp(a)

Abstract Background GRAS is a family of plant-specific transcription factors (TFs) that play a vital role in plant growth and development and response to adversity stress. However, systematic studies of the GRAS TF family in kiwifruit have not been reported. Results In this study, we used a bioinformatics approach to identify eighty-six AcGRAS TFs located on twenty-six chromosomes and phylogenetic analysis classified them into ten subfamilies. It was found that the gene structure is relatively conserved for these genes and that fragmental duplication is the prime force for the evolution of AcGRAS genes. However, the promoter region of the AcGRAS genes mainly contains cis-acting elements related to hormones and environmental stresses, similar to the results of GO and KEGG enrichment analysis, suggesting that hormone signaling pathways of the AcGRAS family play a vital role in regulating plant growth and development and adversity stress. Protein interaction network analysis showed that the AcGRAS51 protein is a relational protein linking DELLA, SCR, and SHR subfamily proteins. The results demonstrated that 81 genes were expressed in kiwifruit AcGRAS under salt stress, including 17 differentially expressed genes, 13 upregulated, and four downregulated. This indicates that the upregulated AcGRAS55 , AcGRAS69, AcGRAS86 and other GRAS genes can reduce the salt damage caused by kiwifruit plants by positively regulating salt stress, thus improving the salt tolerance of the plants. Conclusions These results provide a theoretical basis for future exploration of the characteristics and functions of more AcGRAS genes. This study provides a basis for further research on kiwifruit breeding for resistance to salt stress. RT-qPCR analysis showed that the expression of 3 AcGRAS genes was elevated under salt stress, indicating that AcGRAS exhibited a specific expression pattern under salt stress conditions.

In 2021, the Chinese Ministry of Education introduced the "Double Reduction" policy to ease students' academic pressure while promoting increased engagement in sports activities. This policy has opened up fresh prospects for the non-disciplinary training sector, particularly in sports training. This study examines the extent of implementation of off-campus youth sports training in Chengdu following the enactment of the "Double Reduction" policy. It delves into the challenges and obstacles faced in executing such training programs. The study utilized quantitative and qualitative methods, involving 72 coaches and 36 club owners from 36 clubs across 12 districts in Chengdu. It analyzed factors like sex and education to assess the correlation between sports training implementation and the "Double Reduction" policy. It also conducted interviews to investigate challenges in off-campus youth sports training in Chengdu. Consensus exists among coaches and club owners regarding implementing off-campus youth sports training in Chengdu, with no significant differences observed in various aspects. However, significant differences were noted in perceptions of Chengdu's "Double Reduction" policy implementation, particularly concerning regulatory processes, service provision, and industry development. The study underscores governmental ambiguity and industry disarray in management, emphasizing the need to address homogenized training, limited service variety, and inadequate systems. Solutions involve implementing robust frameworks, enhancing owner competencies, addressing staff shortages, improving service quality, and diversifying marketing approaches to bolster resilience against risks.

Abstract Heat shock proteins play crucial roles in various biochemical processes, encompassing protein folding and translocation. HSP90B1, a conserved member of the heat shock protein family, growing evidences have demonstrated that it might be closely associated with cancer development. In the present study, we employed multi-omics analyses and cohort validations to explore the dynamic expression of HSP90B1 in pan-cancer and comprehensively evaluate HSP90B1 as a novel biomarker that hold promise for precision cancer diagnostics and therapeutics. The results suggest HSP90B1 was highly expressed in various kinds of tumors, often correlating with a poor prognosis. Notably, methylation of HSP90B1 emerged as a protective factor in several cancer types. In immune infiltration analysis, the expression of HSP90B1 in most tumors showed a negative association with CD8 + T cells. HSP90B1 expression was positively correlated with microsatellite instability and tumor mutational burden. HSP90B1 expression was also discovered to be positively correlated with tumor metabolism, cell cycle-related pathways and the expression of immune checkpoint genes. The expression of HSP90B1 was mainly negatively correlated with immunostimulatory genes and positively correlated with immunosuppressive genes, as well as strongly correlated with chemokines and their receptor genes. In addition, the HSP90B1 inhibitor PU-WS13 demonstrated significant efficacy in suppressing cancer cell proliferation in both leukemic and solid tumor cells, and remarkably reduced the expression of the cancer cell surface immune checkpoint PD-L1. The single-cell RNA sequencing analysis further highlighted that HSP90B1 was significantly higher in tumor cells compared to surrounding cells, revealing a potential target therapeutic window. Taken together, HSP90B1 emerges as a promising avenue for breakthroughs in cancer diagnosis, prognosis and therapy. This study provides a rationale for HSP90B1 targeted cancer diagnosis and therapy in future.

Abstract Immunotherapy has rapidly evolved in the past decades in the battle against cancer. Chimeric antigen receptor (CAR)-engineered T cells have demonstrated significant success in certain hematologic malignancies, although they still face certain limitations, including high costs and toxic effects. Natural killer cells (NK cells), as a vital component of the immune system, serve as the “first responders” in the context of cancer development. In this literature review, we provide an updated understanding of NK cell development, functions, and their applications in disease therapy. Furthermore, we explore the rationale for utilizing engineered NK cell therapies, such as CAR-NK cells, and discuss the differences between CAR-T and CAR-NK cells. We also provide insights into the key elements and strategies involved in CAR design for engineered NK cells. In addition, we highlight the challenges currently encountered and discuss the future directions in NK cell research and utilization, including pre-clinical investigations and ongoing clinical trials. Based on the outstanding antitumor potential of NK cells, it is highly likely that they will lead to groundbreaking advancements in cancer treatment in the future.

Abstract. Background:. Oral anti-coagulants (OAC) are the intervention for the prevention of stroke, which consistently improve clinical outcomes and survival among patients with atrial fibrillation (AF). The main purpose of this study is to identify problems in OAC utilization among hospitalized patients with AF in China. Methods:. Using data from the Improving Care for Cardiovascular Disease in China-Atrial Fibrillation (CCC-AF) registry, guideline-recommended OAC use in eligible patients was assessed. Results:. A total of 52,530 patients with non-valvular AF were enrolled from February 2015 to December 2019, of whom 38,203 were at a high risk of stroke, 9717 were at a moderate risk, and 4610 were at a low risk. On admission, only 20.0% (6075/30,420) of patients with a diagnosed AF and a high risk of stroke were taking OAC. The use of pre-hospital OAC on admission was associated with a lower risk of new-onset ischemic stroke/transient ischemic attack among the diagnosed AF population (adjusted odds ratio: 0.54, 95% confidence interval: 0.43–0.68; P 70% of AF patients were at a high risk of stroke. Although poor performance on guideline-recommended OAC use was found in this study, over time the CCC-AF project has made progress in stroke prevention in the Chinese AF population.Registration:ClinicalTrials.gov, NCT02309398.

Abstract This study aimed to evaluate the association between polymyxin B (PMB) exposure and acute kidney injury (AKI) and analyze the risk factors for PMB‐induced AKI in critically ill patients. Plasma concentrations of PMB were determined using an ultraperformance liquid chromatography–tandem mass spectrometer in intensive care unit patients who were administered PMB. Univariate and multivariate analyses were conducted to identify risk factors. A receiver operating characteristic curve was constructed to assess the discriminant power of the factors and to identify the cutoff value for AKI. The white blood cell count and estimated area under the concentration–time curve (AUC) of patients administered PMB were independent risk factors for PMB‐induced AKI, where AUC were calculated using a first‐order pharmacokinetic equation based on the mid‐dosing interval concentration (C1/2t) and peak concentration. The area under the receiver operating characteristic curve of the final model was 0.805 (95% confidence interval, 0.690–0.921). The cutoff value for the combined predictor was 0.57. Alternatively, when using C1/2t, which was strongly correlated with AUC, as the only independent risk factor, the analysis showed that the 3.47 μg/ml threshold provides favorable differentiation between the AKI and non‐AKI groups. These results provide insightful information for therapeutic drug monitoring–guiding PMB dosing in clinical practice.

Abstract Ligand-induced receptor dimerization or oligomerization is a widespread mechanism for ensuring communication specificity, safeguarding receptor activation, and facilitating amplification of signal transduction across the cellular membrane. However, cell-surface antigen-induced multimerization (dubbed AIM herein) has not yet been consciously leveraged in chimeric antigen receptor (CAR) engineering for enriching T cell-based therapies. We co-developed ciltacabtagene autoleucel (cilta-cel), whose CAR incorporates two B-cell maturation antigen (BCMA)-targeted nanobodies in tandem, for treating multiple myeloma. Here we elucidated a structural and functional model in which BCMA-induced cilta-cel CAR multimerization amplifies myeloma-targeted T cell-mediated cytotoxicity. Crystallographic analysis of BCMA–nanobody complexes revealed atomic details of antigen–antibody hetero-multimerization whilst analytical ultracentrifugation and small-angle X-ray scattering characterized interdependent BCMA apposition and CAR juxtaposition in solution. BCMA-induced nanobody CAR multimerization enhanced cytotoxicity, alongside elevated immune synapse formation and cytotoxicity-mediating cytokine release, towards myeloma-derived cells. Our results provide a framework for contemplating the AIM approach in designing next-generation CARs.

Abstract Background Depression and anxiety are frequently coexisted mental illness. The lack of solid objective diagnostic criteria has led to a high rate of suicide. The brain-gut axis bridges the gastrointestinal system with neuropsychiatric disorders. However, it is still not possible to reflect mental disease with gastrointestinal information. The study aimed to explore the auxiliary diagnostic value of gastrointestinal myoelectrical activity in anxiety-depression disorders (ADD) without gastrointestinal disturbance. Methods A natural population cohort from 3 districts in Western China were established. The Patient Health Questionnaire-9 and the Generalized Anxiety Disorder-7 were used to assess ADD. Gastrointestinal myoelectrical activity of ADD were measured by multi-channel cutaneous electrogastroenterogram (EGEG). Then the parameters of EGEG between ADD and healthy controls were analyzed. Results The average amplitude and response area of intestinal channel in ADD were significantly lower than those of controls (153.49 ± 78.69 vs. 179.83 ± 103.90, 57.27 ± 29.05 vs. 67.70 ± 38.32), which were shown to be protective factors for ADD (OR = 0.944 and 0.844, respectively). Further, the scale item scores related to the core symptoms of anxiety and depression were also associated with these two channels (p

Purposes Shanxi Province has the largest number of ancient timber structures in China. With the larch wood replaced by maintenance from an ancient building in Shanxi as the test object, the material property tests of density, moisture content, compressive strength along the grain, bending strength, and bending elastic modulus, and the non-destructive tests of micro-drilling resistance value and stress wave velocity were carried out. Methods According to the test data, the correlation between the mechanical properties and the non-destructive parameters was analyzed, and the optimal calculation model of material property was selected by comparative analysis. Then, the influence of different testing conditions (drill needle speed, drill needle direction) on the results of non-destructive testing was studied. Findings The test results show that the optimal calculate model is to use microdrill resistance to calculate the wood density, while to use wave resistance modulus to calcula te wood compressive strength along the grain, bending strength and bending elastic modulus. The resistance values of microdrill decrease with the increase of drill needle speed, and the resistance values of chord detection are greater than those of cross detection. The research results of this paper can provide support for the safety assessment of ancient wooden structures in Shanxi.

Abstract Pathogenic Escherichia coli is one of the most common causes of diarrhea diseases and its characteristic component of the outer membrane-lipopolysaccharide (LPS) is a major inducer of sepsis. Few drugs have been proven to kill bacteria and simultaneously neutralize LPS toxicity. Here, the chimeric peptides-R7, A7 and G7 were generated by connecting LBP14 (LPS-targeting domain) with L7 (killing domain) via different linkers to improve antibacterial and anti-inflammatory activities. Compared to parent LBP14-RKRR and L7, the antibacterial activity of R7 with a cleavable “RKRR” linker and the “LBP14-RKRR + L7” cocktail against Escherichia coli, Salmonella typhimurium and Staphylococcus aureus was increased by 2 ~ 4-fold. Both A7 and G7 with non-cleavable linkers almost lost antibacterial activity. The ability of R7 to neutralize LPS was markedly higher than that of LBP14-RKRR and L7. In vivo, R7 could be cleaved by furin in a time-dependent manner, and release L7 and LBP14-RKRR in serum. In vivo, R7 can enhance mouse survival more effectively than L7 and alleviate lung injuries by selective inhibition of the NF-κB signaling pathways and promoting higher IAP activity. It suggests that R7 may be promising dual-function candidates as antibacterial and anti-endotoxin agents.

ABSTRACT: Lactoferrin is an iron-binding glycoprotein of the transferrin family that is found in most bodily fluids of mammals and has a variety of biological and beneficial functions, with great importance in health enhancement as a supplement for humans and other animals. More than 300 t of lactoferrin were produced in 2021, and this number is expected to grow yearly by 10% to 12%, to over 580 t in 2030. With new and important functions of lactoferrin being revealed and studied, focus on its industrial production and application is increasing accordingly. However, lactoferrin is mainly sourced from cheese whey or skim milk by cation-exchange column chromatography, which is a costly and low-quality method. A potential solution for lactoferrin global supply chain construction is proposed in this article as a complement to traditional routes of purification from whey or skim milk. The large-scale production of lactoferrin, mainly by recombinant yeast, mammal, and grain systems, as well as the market niche and product design, are discussed.

Cancer-associated fibroblasts (CAFs), a class of stromal cells in the tumor microenvironment (TME), play a key role in controlling cancer cell invasion and metastasis, immune evasion, angiogenesis, and resistance to chemotherapy. CAFs mediate their activities by secreting soluble chemicals, releasing exosomes, and altering the extracellular matrix (ECM). Exosomes contain various biomolecules, such as nucleic acids, lipids, and proteins. microRNA (miRNA), a 22–26 nucleotide non-coding RNA, can regulate the cellular transcription processes. Studies have shown that miRNA-loaded exosomes secreted by CAFs engage in various regulatory communication networks with other TME constituents. This study focused on the roles of CAF-derived exosomal miRNAs in generating cancer malignant characteristics, including immune modulation, tumor growth, migration and invasion, epithelial-mesenchymal transition (EMT), and treatment resistance. This study thoroughly examines miRNA’s dual regulatory roles in promoting and suppressing cancer. Thus, changes in the CAF-derived exosomal miRNAs can be used as biomarkers for the diagnosis and prognosis of patients, and their specificity can be used to develop newer therapies. This review also discusses the pressing problems that require immediate attention, aiming to inspire researchers to explore more novel avenues in this field.

ObjectiveThe objective of this study was to provide a multi-modal deep learning framework for forecasting the survival of rectal cancer patients by utilizing both digital pathological images data and non-imaging clinical data.Materials and methodsThe research included patients diagnosed with rectal cancer by pathological confirmation from January 2015 to December 2016. Patients were allocated to training and testing sets in a randomized manner, with a ratio of 4:1. The tissue microarrays (TMAs) and clinical indicators were obtained. Subsequently, we selected distinct deep learning models to individually forecast patient survival. We conducted a scanning procedure on the TMAs in order to transform them into digital pathology pictures. Additionally, we performed pre-processing on the clinical data of the patients. Subsequently, we selected distinct deep learning algorithms to conduct survival prediction analysis using patients’ pathological images and clinical data, respectively.ResultsA total of 292 patients with rectal cancer were randomly allocated into two groups: a training set consisting of 234 cases, and a testing set consisting of 58 instances. Initially, we make direct predictions about the survival status by using pre-processed Hematoxylin and Eosin (H&E) pathological images of rectal cancer. We utilized the ResNest model to extract data from histopathological images of patients, resulting in a survival status prediction with an AUC (Area Under the Curve) of 0.797. Furthermore, we employ a multi-head attention fusion (MHAF) model to combine image features and clinical features in order to accurately forecast the survival rate of rectal cancer patients. The findings of our experiment show that the multi-modal structure works better than directly predicting from histopathological images. It achieves an AUC of 0.837 in predicting overall survival (OS).ConclusionsOur study highlights the potential of multi-modal deep learning models in predicting survival status from histopathological images and clinical information, thus offering valuable insights for clinical applications.

Nocardia seriolae is the primary pathogen causing nocardiosis in various fish species, leads to significant economic losses in the aquaculture industry. In this study, 10 bacterial strains isolated from Micropterus salmoides and Channa argus infected with nocardiosis, were identified as N. seriolae by physiological and biochemical identification, as well as 16S rDNA sequencing. Moreover, the key virulence-related genes such as ESX-1, T7SS-2, T7SS-3, EspG1, sodC, sod2 and ESAT6 were all positive, and showing high homology among different strains. Pathogenicity testing revealed mortality rates ranging from 70 to 100%, accompanied by the presence of white nodules in the viscera of deceased fish. The drug sensitivity test demonstrated that LY21811, the most lethal strain, exhibited high sensitivity to nine types of antibiotics, including azithromycin, doxycycline, florfenicol and compound sulfamethoxazole, yet showed complete resistance to β-lactam antibiotics. Additionally, the tannic acid also demonstrated potent inhibitory effects against LY21811, with a minimum inhibitory concentration of 0.0625 mg/mL. These results showed that N. seriolae originated from M. salmoides and C. argus in Zhejiang Province were highly conserved, demonstrating a high homogeneity in genetic characteristics, pathogenicity and antimicrobial susceptibilities. These results provide a foundation for further research on the pathogenic characteristics and disease prevention of N. seriolae infections.

Kidney disease is a serious public health problem and various kidney diseases could progress to end-stage renal disease. The many complications of end-stage renal disease. have a significant impact on the physical and mental health of patients. Ultrasound can be the test of choice for evaluating the kidney and perirenal tissue as it is real-time, available and non-radioactive. To overcome substantial interobserver variability in renal ultrasound interpretation, artificial intelligence (AI) has the potential to be a new method to help radiologists make clinical decisions. This review introduces the applications of AI in renal ultrasound, including automatic segmentation of the kidney, measurement of the renal volume, prediction of the kidney function, diagnosis of the kidney diseases. The advantages and disadvantages of the applications will also be presented clinicians to conduct research. Additionally, the challenges and future perspectives of AI are discussed.

Summary: Craniofacial microsomia (CFM) is a congenital defect that usually results from aberrant development of embryonic pharyngeal arches. However, the molecular basis of CFM pathogenesis is largely unknown. Here, we employ the zebrafish model to investigate mechanisms of CFM pathogenesis. In early embryos, tet2 and tet3 are essential for pharyngeal cartilage development. Single-cell RNA sequencing reveals that loss of Tet2/3 impairs chondrocyte differentiation due to insufficient BMP signaling. Moreover, biochemical and genetic evidence reveals that the sequence-specific 5mC/5hmC-binding protein, Sall4, binds the promoter of bmp4 to activate bmp4 expression and control pharyngeal cartilage development. Mechanistically, Sall4 directs co-phase separation of Tet2/3 with Sall4 to form condensates that mediate 5mC oxidation on the bmp4 promoter, thereby promoting bmp4 expression and enabling sufficient BMP signaling. These findings suggest the TET-BMP-Sall4 regulatory axis is critical for pharyngeal cartilage development. Collectively, our study provides insights into understanding craniofacial development and CFM pathogenesis.

ABSTRACT: To study the effects of mineral fulvic acid (FuA) on broiler performance, slaughter performance, blood biochemistry index, antioxidant function, immune performance, and intestinal microflora, 360 Arbor Acres (AA) broiler chickens with similar body weights were randomly divided into 5 groups with 6 replicates in each group and 12 chickens in each replicate in the current study. Chickens in the control group (C) were fed with the basal diet, and chickens in the test groups (I, II, III, and IV) were fed with the diet supplemented with 0.05%, 0.1%, 0.2%, and 0.3% mineral FuA, respectively. The indicators were measured on the hatching day, d 21 and d 35. From the whole experimental period, FuA supplement significantly increased average body weight (ABW) (P < 0.05), average daily gain (ADG) of broilers (P < 0.05), and thymus weight (P < 0.05) in II and IV groups, but bascially reduced the pH value of thigh meat. FuA supplement significantly improved aspartate aminotransferase (AST) activity in the group III on d 35 (P < 0.05) and the serum levels of IgA and IgG on d 21 and d 35 (P < 0.05), but reduced glutathione peroxidase (GSH-Px) level on d 21 (P < 0.05) and malondialdehyde (MDA) level in serum on d 35 (P < 0.05). FuA supplement significantly affected the abundance of Barnesiella, Lachnospiraceae, Alistipes, Lactobacillus, and Christensenellaceae on genus level. Differences between group III and other groups were significant in the genera microflora composition on d 21 and d 35. Functional analysis showed that the cecum microbiota were mainly enriched in carbohydrate metabolism, amino acid metabolism, and energy metabolism. In conclusion, FuA may potentially have significant positive effects on the growth performance and immune function of AA chickens through the modulation of the gut microbiota, and the 0.1% FuA was the best in broiler diet based on the present study.

The fermentation process of traditional Baijiu Daqu involves extremely complex changes in microbial communities, and the microbial communities work collaboratively to determine the quality of Daqu. Analyzing the composition and functions of microbial community during Daqu fermentation is the key to revealing its fermentation mechanism, putting forward a rational control strategy and stabilizing the quality of Daqu. Therefore, microbial communities and functions have always been the focus of Daqu research. In this paper, the characteristics of microbial community structure in different types of Baijiu Daqu are summarized. The microbial sources involved in Daqu fermentation, the succession of microbial community and its driving factors, and the changes of microbial community during the storage period of Daqu are reviewed. The functions of microorganisms involved in Daqu fermentation are summarized. Finally, future research prospects are discussed. This review is expected to provide a reference for further research on the fermentation mechanism of Daqu.

Abstract Preeclampsia is a pregnancy disorder that seriously affects the outcome of mothers and infants and lacks effective prediction and diagnosis methods. ELABELA is the second endogenous ligand of the apelin receptor (APJ) and is associated with the pathogenesis of preeclampsia. In a previous study, the authors found that the downregulation of ELABELA expression is closely related to late‐onset preeclampsia, which may be a marker for the clinical diagnosis of late‐onset preeclampsia. In this study, the authors again collected 120 maternal blood samples, including 60 pregnant women with a medical diagnosis of late‐onset preeclampsia. ELISA results showed that the serum ELABELA concentration in late‐onset preeclampsia pregnant women (12.57 ± 7.77 ng/mL) was significantly lower than that in normal pregnant women (36.99 ± 23.58 ng/mL), which was consistent with previously reported results. Therefore, the authors used an ELABELA monoclonal antibody to label four colloidal gold nanoparticles with different diameters (15, 30, 55, and 150 nm) and developed a transverse‐flow immunochromatographic band for the rapid and accurate detection of serum ELABELA levels. The strip test shows that colloidal gold with a diameter of 30 nm can be used as a good ELABELA detection marker and had more than 90% positive detection effect. Therefore, the authors hope that the colloidal gold strip with ELABELA as the diagnostic index developed by us will be popularized and applied in clinical diagnosis.

Abstract With the invasion of green tides and the increase of urban green areas worldwide, multimillion tons of Enteromorpha need to be reutilized. In this study, Enteromorpha prolifera powder is considered a promising biomass resource for the production of commercial chemical products production. Ilamycins, novel cyclic heptapeptides with significant anti-TB activities, are isolated from Streptomyces atratus SCSIO ZH16, a deep-sea-derived strain. Using EP powder as a nitrogen source, the production of ilamycins reached 709.97 mg/L through optimization of the nitrogen source using the engineered strain S. atratus SCSIO ZH16 ΔR. After mutant strain constructions and tests, strain S. atratus SCSIO ZH16 ΔR::bldD EP powder achieved a higher production titer of ilamycins. Furthermore, the production titer of ilamycins and ilamycin E reached 1561.77 mg/L and 745.44 mg/L, respectively, in a 5 L bioreactor. This study suggests that E. prolifera is a promising and eco-friendly nitrogen source for the production of ilamycins.

The Hongyang kiwifruit (Actinidia chinensis var. chinensis ‘Hongyang’) has high economic and nutritional values and good prospects for market development. However, in recent years Hongyang kiwifruit production areas such as Yunnan and Sichuan have been subjected to extreme weather such as inversions on several occasions, and its poor cold resistance has limited its scope for development. In this study, ethyl methanesulfonate (EMS) was used to induce mutants of Hongyang kiwifruit in a tissue culture process, which led to the screening of cold-tolerant mutants and the investigation of their stress response mechanisms through transcriptome analysis. In this study, mutants were induced using EMS induction technology using Hongyang kiwifruit leaves as experimental material in tissue culture (4.4 g·L-1 MS + 4.5 g·L-1 agar + 1.5 mg·L-1 6-BA + 0.1 mg·L-1 NAA + 15 g·L-1 sucrose + 0.01-0.10 g·L-1 EMS) and screened for cold-tolerant mutants under low temperature. Selected cold-tolerant mutants and normal Hongyang kiwifruit tissue culture seedlings were subjected to 4℃ 12 h cold stress treatment, while later, transcriptome sequencing analysis was performed. The results were as follows: (1) According to the preliminary phenotypic identification, some of the mutants induced by the 0.06 g·L-1 EMS were phenotypically resistant to cold; (2) In the GO functional enrichment analysis of transcriptome sequencing data, the most enriched entries were in the biological processes; (3) When using KEGG database analysis, a total of 21 differentially expressed genes (DEGs) were annotated in 15 pathways, and which were all up-regulated. The protein processing pathway (ath04141) in the endoplasmic reticulum had the most DEGs, and sHSF, Hsp70, and NEF in this pathway may be related to the regulation of cold-tolerant mechanisms. The above findings provide a material basis and theoretical rationale for the research and utilization of cold-tolerant germplasm resources of Hongyang kiwifruit.

Abstract Background Anti‐folate drug pemetrexed is a vital chemotherapy medication for non‐small cell lung cancer (NSCLC). Its response varies widely and often develops resistance to the treatment. Therefore, it is urgent to identify biomarkers and establish models for drug efficacy evaluation and prediction for rational drug use. Methods A total of 360 subjects were screened and 323 subjects were recruited. Using metabolomics in combination with machine learning methods, we are trying to select potential biomarkers to diagnose NSCLC and evaluate the efficacy of pemetrexed in treating NSCLC. Furtherly, we measured the concentration of eight metabolites in the tryptophan metabolism pathway in the validation set containing 201 subjects using a targeted metabolomics method with UPLC‐MS/MS. Results In the discovery set containing 122 subjects, the metabolic profile of healthy controls (H), newly diagnosed NSCLC patients (ND), patients who responded well to pemetrexed treatment (S) and pemetrexed‐resistant patients (R) differed significantly on the PLS‐DA scores plot. Pathway analysis showed that glycine, serine and threonine metabolism occurred in every two group comparisons. TCA cycle, pyruvate metabolism and glycerolipid metabolism are the most significantly changed pathways between ND and H group, pyruvate metabolism was the most altered pathway between S and ND group, and tryptophan metabolism was the most changed pathway between S and R group. We found Random forest method had the maximum area under the curve (AUC) and can be easily interpreted. The AUC is 0.981 for diagnosing patients with NSCLC and 0.954 for evaluating pemetrexed efficiency. Conclusion We compared eight mathematical models to evaluate pemetrexed efficiency for treating NSCLC. The Random forest model established with metabolic markers tryptophan, kynurenine and xanthurenic acidcan accurately diagnose NSCLC and evaluate the response of pemetrexed.

Abstract Background Lipodystrophy-associated metabolic disorders caused by Seipin deficiency lead to not only severe lipodystrophy but also neurological disorders. However, the underlying mechanism of Seipin deficiency-induced neuropathy is not well elucidated, and the possible restorative strategy needs to be explored. Methods In the present study, we used Seipin knockout (KO) mice, combined with transcriptome analysis, mass spectrometry imaging, neurobehavior test, and cellular and molecular assay to investigate the systemic lipid metabolic abnormalities in lipodystrophic mice model and their effects on adult neurogenesis in the subventricular zone (SVZ) and olfactory function. After subcutaneous adipose tissue (AT) transplantation, metabolic and neurological function was measured in Seipin KO mice to clarify whether restoring lipid metabolic homeostasis would improve neurobehavior. Results It was found that Seipin KO mice presented the ectopic accumulation of lipids in the lateral ventricle, accompanied by decreased neurogenesis in adult SVZ, diminished new neuron formation in the olfactory bulb, and impaired olfactory-related memory. Transcriptome analysis showed that the differentially expressed genes (DEGs) in SVZ of adult Seipin KO mice were significantly enriched in lipid metabolism. Mass spectrometry imaging showed that the levels of glycerophospholipid and diglyceride (DG) were significantly increased. Furthermore, we found that AT transplantation rescued the abnormality of peripheral metabolism in Seipin KO mice and ameliorated the ectopic lipid accumulation, concomitant with restoration of the SVZ neurogenesis and olfactory function. Mechanistically, PKCα expression was up-regulated in SVZ tissues of Seipin KO mice, which may be a potential mediator between lipid dysregulation and neurological disorder. DG analogue (Dic8) can up-regulate PKCα and inhibit the proliferation and differentiation of neural stem cells (NSCs) in vitro, while PKCα inhibitor can block this effect. Conclusion This study demonstrates that Seipin deficiency can lead to systemic lipid disorder with concomitant SVZ neurogenesis and impaired olfactory memory. However, AT restores lipid homeostasis and neurogenesis. PKCα is a key mediator mediating Seipin KO-induced abnormal lipid metabolism and impaired neurogenesis in the SVZ, and inhibition of PKCα can restore the impaired neurogenesis. This work reveals the underlying mechanism of Seipin deficiency-induced neurological dysfunction and provides new ideas for the treatment of neurological dysfunction caused by metabolic disorders.

Abstract Toxoplasma gondii is thought to infect all nucleated cells in warm-blooded animals, including poultry, mammals, and humans. However, it is unclear whether T. gondii can infect chicken erythrocytes due to the nucleated nature of these cells. Due to the special role of chicken erythrocytes in innate immunity, we investigated the cell‒cell interaction between T. gondii and erythrocytes to elucidate the role of chicken erythrocytes in T. gondii infection. Cellular apoptosis was analyzed by transwell assay and flow cytometry. An immunofluorescence method was used to examine the reorganization of vimentin during T. gondii infection in both Vero cells and chicken erythrocytes. The reorganization of actin was evaluated to further examine the invasion capacity of tachyzoites on chicken erythrocytes during infection. We discovered that T. gondii can adhere to but not invade chicken erythrocytes and eventually cause apoptosis in chicken erythrocytes. When tachyzoites were cocultured with chicken erythrocytes in vitro, the transcriptional levels of T. gondii MIC3, ROP16, and ROP18 were significantly decreased. In addition, the rearrangement of host cell vimentin, a type III cytoskeleton protein regulated by T. gondii infection, was not observed. Similarly, the parasite-induced ring-shaped actin structure was not formed in the host-parasite junction. T. gondii (RH strain) tachyzoites preferentially invaded Vero cells and replicated in chicken blood monocytes, but they were not found in chicken erythrocytes. These findings showed that although T. gondii could attach to the surface of chicken erythrocytes, but couldn’t invade successfully. Interestingly, we found that the T. gondii secretome, lysates, and intact tachyzoites could cause apoptosis of chicken erythrocytes, which suggested a complex mechanism involved in the apoptosis of chicken erythrocytes induced by T. gondii. This study elucidated that T. gondii could not infect nucleated chicken erythrocytes and enriched our understanding of the transmission mechanism of T. gondii among avian species.

Abstract Due to the implementation bottleneck of training data collection in realistic wireless communications systems, supervised learning‐based timing synchronization (TS) is challenged by the incompleteness of training data. To tackle this bottleneck, the computer‐aided approach is extended, with which the local device can generate the training data instead of generating learning labels from the received samples collected in realistic systems, and then construct an extreme learning machine (ELM)‐based TS network in orthogonal frequency division multiplexing (OFDM) systems. Specifically, by leveraging the rough information of channel impulse responses (CIRs), i.e. root‐mean‐square (r.m.s) delay, the loose constraint‐based and flexible constraint‐based training strategies are proposed for the learning‐label design against the maximum multi‐path delay. The underlying mechanism is to improve the completeness of multi‐path delays that may appear in the realistic wireless channels and thus increase the statistical efficiency of the designed TS learner. By this means, the proposed ELM‐based TS network can alleviate the degradation of generalization performance. Numerical results reveal the robustness and generalization of the proposed scheme against varying parameters.

Abstract Segmental femoral bone defects are a severe challenge for orthopedic trauma surgeons. The objective of this study was to compare the efficacy of the shortening/re-lengthening and nailing (SRN) technique with the traditional bone transport (BT) technique in treating patients with such defects. A retrospective study was conducted involving 46 patients with segmental femoral bone defects, with 21 cases treated using the SRN technique (SRN group) and 25 cases managed with the traditional BT technique (BT group). The mean length of the bone defect was 5.8 ± 1.1 cm in the SRN group and 6.1 ± 1.6 cm in the BT group. Various parameters including time in frame, external fixation index, self-rating anxiety scale (SAS) scores, bone healing scores, limb function scores, and complications were recorded. The mean time in frame for the SRN group was 3.7 ± 1.4 months, significantly shorter than the 9.4 ± 3.7 months observed in the BT group (p

Abstract Background Triple-negative breast cancer (TNBC) is one of the most aggressive human cancers and has poor prognosis. Approximately 80% of TNBC cases belong to the molecular basal-like subtype, which can be exploited therapeutically by inducing differentiation. However, the strategies for inducing the differentiation of TNBC remain underexplored. Methods A three-dimensional (3D) morphological screening model based on a natural compound library was used to identify possible candidate compounds that can induce TNBC cell differentiation. The efficacy of rutaecarpine was verified using assays: RT-qPCR, RNA-seq, flow cytometry, immunofluorescence, SCENITH and label-free LC–MS/MS. The direct targets of rutaecarpine were identified through drug affinity responsive target stability (DARTS) assay. A xenograft mice model was also constructed to confirm the effect of rutaecarpine in vivo. Results We identified that rutaecarpine, an indolopyridoquinazolinone, induces luminal differentiation of basal TNBC cells in both 3D spheroids and in vivo mice models. Mechanistically, rutaecarpine treatment leads to global metabolic stress and elevated ROS in 3D cultured TNBC cells. Moreover, NAC, a scavenger of ROS, impedes rutaecarpine-induced differentiation of TNBC cells in 3D culture. Finally, we identified fumarate hydratase (FH) as the direct interacting target of rutaecarpine. The inhibition of FH and the knockdown of FH consistently induced the differentiation of TNBC cells in 3D culture. Conclusions Our results provide a platform for differentiation therapy drug discovery using 3D culture models and identify rutaecarpine as a potential compound for TNBC treatment.

Abstract Background This study analyzed the clinical features and biomarkers of alcohol-associated liver disease (ALD) to investigate the diagnostic value of age, bilirubin, international normalized ratio (INR), and creatinine (ABIC) score to triglyceride (TG) ratio (ABIC/TG) in ALD-associated primary liver carcinoma (PLC). Materials and methods Data were collected from 410 participants with ALD, and the epidemiological and clinical records of 266 participants were analyzed. Participants were divided into ALD-without-PLC and ALD-associated-PLC groups. Relationships between clinical characteristics, biomarkers and ALD-associated PLC were estimated. Serum lipid levels and liver function were compared between ALD patients without PLC and patients with ALD-associated PLC. Scoring systems were calculated to investigate ALD severity. The robustness of the relationship was analyzed by the receiver operating characteristic (ROC) curve. Results Age and dyslipidemia were more strongly associated with ALD-associated PLC than with ALD-without PLC, with AORs of 2.39 and 0.25, respectively, with P less than 0.05. Drinking time and average daily intake, ABIC score, and ABIC/TG ratio were significantly higher in the ALD-associated-PLC group than in the ALD-without-PLC group. The AUC for the ABIC/TG ratio predicting the incidence of PLC was 0.80 (P