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Abstract Local adaptation has been a central theme of eco-evolutionary research for decades. It is generally assumed that plant pathogens are locally adapted due to their standing interactions with biotic and abiotic factors in the ecosystem. Effectors, secreted small proteins encoded by pathogens, play critical roles in host–pathogen interactions, by activating host genotype-specific resistance, suppressing plant immunity, and playing other functions. In this study, we investigated the potential involvement of RXLR effector genes in ecological adaptation by examining the simple sequence repeat (SSR), virulence, and effector profiles in Phytophthora infestans isolates collected from two geographic regions differing in ecological environments. Genotypic analyses with SSR markers and virulence assays showed that the pathogen from the two regions shared genetic background but differed in virulence spectrums. High-throughput sequencing and expression analysis of 24 selected P. infestans isolates further showed variations in the RXLR effector repertoire, ranging from 536 to 548 for each isolate and the expression of effector genes was highly associated with the accumulation of homologous sRNA. Regional specific alleles were detected at 94 RXLR effector genes, and a specific accumulation of homologous 25–26 nt sRNAs was found at 67 RXLR effector genes. Two of the regional specific RXLR effector genes were confirmed to be virulence factors. Taken together, these results suggest that genomic and epigenetic variations in RXLR effector genes contribute significantly to the ecological adaptation of P. infestans populations and that regional specific effector genes will help to understand the adaptive landscape of pathogens and efficient use of host resistance genes.

Abstract Artificial oxide heterostructures have provided promising platforms for the exploration of emergent quantum phases with extraordinary properties. Here, we demonstrate an approach to stabilize a distinct oxygen octahedron rotation (OOR) characterized by $${a}^{-}{a}^{-}{c}^{+}$$ a − a − c + in the ultrathin LaNiO3 sublayers of the LaNiO3/CaTiO3 superlattices. Unlike the $${a}^{-}{a}^{-}{c}^{-}$$ a − a − c − OOR in the LaNiO3 bare film, the $${a}^{-}{a}^{-}{c}^{+}$$ a − a − c + OOR favors high conductivity, driving the LaNiO3 sublayer to a metallic state of ~100 K even when the layer thickness is as thin as 2 unit cells (u.c.). Simultaneously, strongly preferred occupation of $${d}_{{x}^{2}-{y}^{2}}$$ d x 2 − y 2 orbital is achieved in LaNiO3 sublayers. The largest change of occupancy is as high as 35%, observed in the 2 u.c.-thick LaNiO3 sublayers sandwiched between 4 u.c.-thick CaTiO3 sublayers. X-ray absorption spectra indicate that the $${a}^{-}{a}^{-}{c}^{+}$$ a − a − c + OOR pattern of LaNiO3 achieved in the LaNiO3/CaTiO3 heterostructures has significantly enhanced the Ni-3d/O-2p hybridization, stabilizing the metallic phase in ultrathin LaNiO3 sublayers. The present work demonstrates that modulating the mode of OOR through heteroepitaxial synthesis can modify the orbital-lattice correlations in correlated perovskite oxides, revealing hidden properties of the materials.

Abstract Acute kidney injury (AKI) has been noticed after both COVID-19 vaccination and infection, affecting risk-benefit evaluations and vaccine hesitancy. We conducted a large-scale N3C cohort study to compare AKI incidence following COVID-19 vaccination and infection. Participants from December 2020 to August 2023 were divided into two groups based on their initially observed COVID-19 antigen exposure: COVID-19 vaccination group (n = 2,953,219) and COVID-19 infection group (n = 3,616,802). AKI was defined by diagnostic codes and serum creatinine changes within a 30 day follow-up window after exposure. The absolute risk of AKI was 0.66% in the vaccination group versus 4.88% in the infection group. After adjusting for various confounders, COVID-19 infection was associated with a significantly higher risk of AKI than COVID-19 vaccination (aHR = 10.31, P

Abstract Background Hyperuricemia is considered as an independent risk factor for acute ischemic stroke (AIS), and some AIS patients are accompanied by an increase in serum uric acid. Recent studies have highlighted the important role of gut microbiota in both hyperuricemia and AIS, but there is little available data on the relationship between gut microbiota and the pathogenesis of AIS with hyperuricemia (HAS). Methods Here we profiled the gut microbiota composition in 63 HAS patients and 269 non-HAS patients through 16s rRNA sequencing. Male rat with hyperuricemia were subjected to middle cerebral artery occlusion (MCAO) to establish HAS model and were then treated with Parabacteroides distasonis. Subsequently, the neurological deficit, pathological damages and blood-brain barrier disruption were evaluated. Moreover, the levels of ROS, inflammatory cytokines, NF-𝜿B pathway related protein, and vascular density markers were determined. Results There were significant differences of gut microbiota composition between HAS patients and non-HAS patients, and a significant decrease in the abundance of Parabacteroides in HAS patients compared to non-HAS patients. Animal experiments showed that supplementation with P. distasonis increased beneficial commensal bacteria, significantly improved neurological deficits, pathological damages and BBB disruption, as well as reduced the level of serum uric acid in HAS rats. We further demonstrated that P. distasonis treatment decreased ROS level and increased SOD2 level, thereby reducing oxidative stress. Meanwhile, P. distasonis effectively inhibited NF-𝜿B signal pathway and reduced the production of inflammatory cytokines, including TNF-α and IL-1β, alleviating the inflammatory response. Notably, P. distasonis treatment increased the levels of vascular density markers including cluster of differentiation 31 (CD31) and alpha-smooth muscle actin (α-SMA), ameliorating vascular damage in HAS rats. Conclusions Together, these findings highlighted the important role of P. distasonis in the pathogenesis of HAS, and its mechanism was involved in the regulation of gut microbiota-gut-brain axis, which implied a novel strategy against HAS.

Abstract Asthenoteratozoospermia is a major cause of male infertility. Thus far, the identified related genes can explain only a small share of asthenoteratozoospermia cases, suggesting the involvement of other genes. The transmembrane protein TMEM232 is highly expressed in mouse testes. In the present study, to determine its function of TMEM232 in testes, we constructed a Tmem232-null mouse model using CRISPR–Cas9 technology. Tmem232 knockout (KO) male mice was completely infertile, and their sperm were immotile, with morphological defects of the flagellum. Electron microscopy revealed an aberrant midpiece-principal junction and the loss of the fourth outer microtubule doublet in the sperm of Tmem232 −/− mice. Sperm cells presented an 8 + 2 conformation and an irregular arrangement of the mitochondrial sheath. Proteomic analysis revealed altered expression of proteins related to flagellar motility, sperm capacitation, the integrity and stability of sperm structure, especially an upregulated expression of multiple ribosome components in TMEM232-deficient spermatids. Additionally, TMEM232 was observed to be involved in autophagy by interacting with autophagy-related proteins, such as ATG14, to regulate ribosome homeostasis during spermiogenesis. These results suggest that TMEM232, as a potential scaffold protein involving in the correct assembly, distribution, and stability maintenance of certain functional complexes by recruiting key intracellular proteins, is essential for the formation of a highly structured flagellum and plays an important role in the autophagic elimination of cytosolic ribosomes to provide energy for sperm motility.

In this paper, the directional modification behavior of rare earth Ce on sulfide inclusions in steel is studied by thermodynamic calculation and experiment methods, and the mechanism of directional modification of rare earth Ce on sulfide inclusions in U71Mn heavy rail steel is proved. The results show that U71Mn heavy rail steel contained more large-sized inclusions and their distribution is more concentrated without the addition of rare earth Ce element. After the addition of rare earth Ce element, the average size of sulfur-containing inclusions in the steel decrease from 5.22 μm to 1.85 μm, and the number density of sulfur-containing inclusions in the steel increase from 83.65 mm−2 to 217.68 mm−2, indicating that the number of sulfur-containing inclusions in the steel increases after the addition of Ce element, and more small-sized sulfur-containing inclusions will form in the steel. The addition of rare earth Ce element can effectively reduce the existence of large-sized inclusions in the steel and modify large-sized inclusions into small-sized inclusions.

Abstract Immunity has shown potentials in informing drug development for cardiometabolic diseases, such as type 2 diabetes (T2D) and coronary artery disease (CAD). Here, we performed a transcriptome-wide Mendelian randomization (MR) study to estimate the putative causal effects of 11,021 gene expression profiles during CD4+ T cells activation on the development of T2D and CAD. Robust MR and colocalization evidence was observed for 162 genes altering T2D risk and 80 genes altering CAD risk, with 12% and 16% respectively demonstrating CD4+ T cell specificity. We observed temporal causal patterns during T cell activation in 69 gene-T2D pairs and 34 gene-CAD pairs. These genes were eight times more likely to show robust genetic evidence. We further identified 25 genes that were targets for drugs under clinical investigation, including LIPA and GCK. This study provides evidence to support immune-to-metabolic disease connections, and prioritises immune-mediated drug targets for cardiometabolic diseases.

Abstract Synthetic lethality (SL) is a gold mine of anticancer drug targets, exposing cancer-specific dependencies of cellular survival. To complement resource-intensive experimental screening, many machine learning methods for SL prediction have emerged recently. However, a comprehensive benchmarking is lacking. This study systematically benchmarks 12 recent machine learning methods for SL prediction, assessing their performance across diverse data splitting scenarios, negative sample ratios, and negative sampling techniques, on both classification and ranking tasks. We observe that all the methods can perform significantly better by improving data quality, e.g., excluding computationally derived SLs from training and sampling negative labels based on gene expression. Among the methods, SLMGAE performs the best. Furthermore, the methods have limitations in realistic scenarios such as cold-start independent tests and context-specific SLs. These results, together with source code and datasets made freely available, provide guidance for selecting suitable methods and developing more powerful techniques for SL virtual screening.

Abstract Immune memory has been expanded to group 2 innate lymphoid cells (ILC2s), but the cellular and molecular bases remain incompletely understood. Based on house dust mite (HDM)-induced mice asthma models and human samples, we applied flow cytometry, parabiosis, in vivo imaging and adoptive transplantation to confirm the persistence, migration and function of CD45+lineage–CD90.2+NK1.1–NKp46–ST2–KLRG1+IL-17RB+ memory-like ILC2s (ml-ILC2s). Regulated by CCR9/CCL25 and S1P signaling, ml-ILC2s reside in the lamina propria of small intestines (siLP) in asthma remission, and subsequently move to airway upon re-encountering antigens or alarmins. Furthermore, ml-ILC2s possess properties of longevity, potential of rapid proliferation and producing IL-13, and display transcriptional characteristics with up-regulation of Tox and Tcf-7. ml-ILC2s transplantation restore the asthmatic changes abrogated by Tox and Tcf7 knockdown. Our data identify siLP ml-ILC2s as a memory-like subset, which promotes asthma relapse. Targeting TCF-1 and TOX might be promising for preventing asthma recurrence.

Abstract Chemotherapy is one of the conventional treatments for cancer in clinical practice. However, poor delivery efficiency, systemic toxicity, and the lack of pharmacokinetic monitoring during treatment are the critical limitations of current chemotherapy. Herein, we reported a brand-new antitumor drug delivery strategy that harnesses an optical fiber endoscopically therapeutic probe. The fiber probe carries photosensitizers in the fiber core and antitumor agents on the fiber surface mediated by a temperature-responsive hydrogel film, giving rise to an activable photothermal-chemotherapy that orchestrates the localized hyperthermia and thermal-stimuli drug release to the tumor lesion. Furthermore, the dynamical drug release and in-situ temperature can be real-time supervised through the built-in fiber sensors, including the reflective Mach–Zehnder interferometer and fiber Bragg grating, to visualize the therapy process and thus improve the safety of treatment. Compared with conventional methods, the fiber-optic drug delivery can adequately take advantage of the chemotherapeutics through collaboratively recruiting the photoheating-mediated enhanced permeability and the hydrogel particle-assisted high drug retention, shedding new light on a “central-to-peripheral” drug pervasion and retention mechanism to destroy tumors completely. The fiber-optic chemotherapy strategy incorporates precise drug delivery, accurate controllability of drug release, high drug permeability and retention in tumor, low off-target rate, and real-time drug release and temperature feedback, performing a straightforward and precise photothermal-chemotherapy pathway. More than that, the proposed strategy holds tremendous promise to provide a revolutionized on-demand drug delivery platform for the highly efficient evaluation and screening of antitumor pharmaceuticals.

Abstract Prostate cancer (PCa) is one of the most common and prevalent cancers in men worldwide. The majority of PCa-related deaths result from metastasis rather than primary tumors. Several studies have focused on the relationship between male-specific genes encoded on the Y chromosome and PCa metastasis; however, the relationship between the male specific protein encoded on the Y chromosome and tumor suppression has not been fully clarified. Here, we report a male specific protein of this type, the histone H3 lysine 4 (H3K4) demethylase JARID1D, which has the ability to inhibit the gene expression program related to cell invasion, and can thus form a phenotype that inhibits the invasion of PCa cells. However, JARID1D exhibits low expression level in advanced PCa, and which is related to rapid invasion and metastasis in patients with PCa. Curcumin, as a multi-target drug, can enhance the expression and demethylation activity of JARID1D, affect the androgen receptor (AR) and epithelial-mesenchymal transition (EMT) signaling cascade, and inhibit the metastatic potential of castration resistant cancer (CRPC). These findings suggest that using curcumin to increase the expression and demethylation activity of JARID1D may be a feasible strategy to inhibit PCa metastasis by regulating EMT and AR.

Protein level of Histo-Blood Group ABO System Transferase (BGAT) has been reported to be associated with cardiometabolic diseases. But its effect on pregnancy related outcomes still remains unclear. Here we conducted a two-sample Mendelian randomization (MR) study to ascertain the putative causal roles of protein levels of BGAT in pregnancy related outcomes. Cis-acting protein quantitative trait loci (pQTLs) robustly associated with protein level of BGAT (P

Background: Sinistral portal hypertension (SPH) is the only type of portal hypertension that is entirely curable. However, it can easily cause varicose veins in the esophagus and/or stomach, as well as upper gastrointestinal hemorrhage. This study aimed to investigate the clinical characteristics and treatments of sinistral portal hypertension. Methods: All patients with pancreatic disease were included in this retrospective cohort study at the Affiliated Hospital of Southwest Medical University (Luzhou, China) from September 2019 to September 2021. The required information including the patient’s demographics, serum laboratory indicators, imaging and endoscopy examinations, and clinical features were gathered and evaluated. The results were expressed as numbers and percentages.Results: Out of the 830 patients with pancreatic diseases, 61 (7.3%) developed SPH. The most common cause of SPH was acute pancreatitis (80.3%), followed by chronic pancreatitis (11.5%). The splenic vein was the most frequently affected vein in patients (45/61, 73.8%). The findings of the contrast-enhanced computed tomography (CECT) indicated that 51 cases (83.6%) had gastric fundal-body varices, and three cases had combined gastric and esophageal varices. In the perigastric collateral channel formation, gastroepiploic varices (43/61, 70.5%) most frequently occurred in patients with SPH. Splenomegaly was a prevalent manifestation in SPH patients (45.9%). Five cases had gastrointestinal variceal hemorrhage.Conclusion: SPH was associated with the patency of the splenic vein and the formation of distinctive perigastric collateral veins. Surgery and/or endoscopic treatment were recommended, particularly for patients who have experienced a significant amount of gastrointestinal bleeding and have failed conservative treatment.

Abstract Background Vascular calcification is a common vascular lesion associated with high morbidity and mortality from cardiovascular events. Antibiotics can disrupt the gut microbiota (GM) and have been shown to exacerbate or attenuate several human diseases. However, whether antibiotic-induced GM disruption affects vascular calcification remains unclear. Methods Antibiotic cocktail (ABX) treatment was utilized to test the potential effects of antibiotics on vascular calcification. The effects of antibiotics on GM and serum short-chain fatty acids (SCFAs) in vascular calcification mice were analyzed using 16 S rRNA gene sequencing and targeted metabolomics, respectively. Further, the effects of acetate, propionate and butyrate on vascular calcification were evaluated. Finally, the potential mechanism by which acetate inhibits osteogenic transformation of VSMCs was explored by proteomics. Results ABX and vancomycin exacerbated vascular calcification. 16 S rRNA gene sequencing and targeted metabolomics analyses showed that ABX and vancomycin treatments resulted in decreased abundance of Bacteroidetes in the fecal microbiota of the mice and decreased serum levels of SCFAs. In addition, supplementation with acetate was found to reduce calcium salt deposition in the aorta of mice and inhibit osteogenic transformation in VSMCs. Finally, using proteomics, we found that the inhibition of osteogenic transformation of VSMCs by acetate may be related to glutathione metabolism and ubiquitin-mediated proteolysis. After adding the glutathione inhibitor Buthionine sulfoximine (BSO) and the ubiquitination inhibitor MG132, we found that the inhibitory effect of acetate on VSMC osteogenic differentiation was weakened by the intervention of BSO, but MG132 had no effect. Conclusion ABX exacerbates vascular calcification, possibly by depleting the abundance of Bacteroidetes and SCFAs in the intestine. Supplementation with acetate has the potential to alleviate vascular calcification, which may be an important target for future treatment of vascular calcification.

Abstract Background College and university students were an important population group of blood donors, especially in the current situation of tight blood supply. This study aimed to investigate the current status and determinants of blood donation among this population group in Wuhan using a structural equation model. Methods We conducted a cross-sectional study involving 12 colleges and universities in Wuhan, China, including 5168 students. Sociodemographic characteristics, health status, knowledge about blood donation, and attitude toward blood donation were treated as latent variables, with blood donation as the observed variable. Confirmatory factor analysis was conducted using the Mplus 8.0 statistical software application, followed by the establishment of a structural equation model to assess the relationships that exist between these variables. Results The overall blood donation rate among college and university students was 24.71%. The established model indicated that sociodemographic characteristics, health status, knowledge about blood donation, and attitude toward blood donation showed significant positive effects (0.135, 0.056, 0.321, and 0.389, respectively) on blood donation, among them, the direct effects were 0.076, -0.110, 0.143, and 0.389, respectively (P

Abstract Background Nurses often face challenges such as inadequate welfare protection, injustice, and workplace adversity including violence, bullying, and sexual harassment. In this context, providing sufficient support to nurses is crucial for the promotion of their professional well-being. This study examines the direct and indirect effects of perceived organizational support on nurses’ well-being, particularly highlighting the mediating roles of professional quality of life and the perception of decent work. Methods A cross-sectional survey design was employed in this study. Convenience sampling was used to survey 792 nurses from five tertiary A-grade hospitals in Shanxi Province in January 2024. Data collection tools included a custom demographic survey, the Perceived Organizational Support Scale, Professional Quality of Life Scale, Decent Work Perception Scale, and Nurse Occupational Well-being Questionnaire. Descriptive statistics, correlation analysis, and mediation effect analyses were performed. Results The findings demonstrate that perceived organizational support has a direct impact on nurses’ occupational well-being (β = 0.323, p

Abstract Background Escherichia. coli is the most frequent host for New Delhi metallo-β-lactamase (NDM) which hydrolyzes almost all β-lactams except aztreonam. The worldwide spread of blaNDM-carrying E. coli heavily threatens public health. Objective This study aimed to explore the global genomic epidemiology of blaNDM- carrying E. coli isolates, providing information for preventing the dissemination of such strains. Methods Global E. coli genomes were downloaded from NCBI database and blaNDM was detected using BLASTP. Per software was used to extract meta information on hosts, resources, collection data, and countries of origin from GenBank. The sequence types (STs) and distribution of antimicrobial resistance gene (ARG) were analyzed by CLC Workbench; Plasmid replicons, serotypes and virulence genes (VFs) were analyzed by submitting the genomes to the websites. Statistical analyses were performed to access the relationships among ARGs and plasmid replicons. Results Until March 2023, 1,774 out of 33,055 isolates collected during 2003–2022 were found to contain blaNDM in total. Among them, 15 blaNDM variants were found with blaNDM-5 (74.1%) being most frequent, followed by blaNDM-1 (16.6%) and blaNDM-9 (4.6%). Among the 213 ARGs identified, 27 blaCTX-M and 39 blaTEM variants were found with blaCTX-M-15 (n = 438, 24.7%) and blaTEM-1B (n = 1092, 61.6%) being the most frequent ones, respectively. In addition, 546 (30.8%) plasmids mediated ampC genes, 508 (28.6%) exogenously acquired 16 S rRNA methyltransferase encoding genes and 262 (14.8%) mcr were also detected. Among the 232 distinct STs, ST167 (17.2%) were the most prevalent. As for plasmids, more than half of isolates contained IncFII, IncFIB and IncX3. The VF terC, gad, traT and iss as well as the serotypes O101:H9 (n = 231, 13.0%), O8:H9 (n = 115, 6.5%) and O9:H30 (n = 99, 5.6%) were frequently observed. Conclusions The study delves into the intricate relationship between plasmid types, virulence factors, and ARGs, which provides valuable insights for clinical treatment and public health interventions, and serves as a critical resource for guiding future research, surveillance, and implementation of effective strategies to address the challenges posed by blaNDM-carrying E. coli. The findings underscore the urgent need for sustained global collaboration, surveillance efforts, and antimicrobial stewardship to mitigate the impact of these highly resistant strains on public health.

Abstract Background Sex-related differences in colorectal (CRC) incidence and mortality are well-documented. However, the impact of sex on metabolic pathways that drive cancer growth is not well understood. High expression of asparagine synthetase (ASNS) is associated with inferior survival for female CRC patients only. Here, we used a CRISPR/Cas9 technology to generate HCT116 ASNS −/− and HCT 116 ASNS +/+ cancer cell lines. We examine the effects of ASNS deletion on tumor growth and the subsequent rewiring of metabolic pathways in male and female Rag2/IL2RG mice. Results ASNS loss reduces cancer burden in male and female tumor-bearing mice (40% reduction, q < 0.05), triggers metabolic reprogramming including gluconeogenesis, but confers a survival improvement (30 days median survival, q < 0.05) in female tumor-bearing mice alone. Transcriptomic analyses revealed upregulation of G-protein coupled estrogen receptor (GPER1) in tumors from male and female mice with HCT116 ASNS −/− xenograft. Estradiol activates GPER1 in vitro in the presence of ASNS and suppresses tumor growth. Conclusions Our study indicates that inferior survival for female CRC patients with high ASNS may be due to metabolic reprogramming that sustains tumor growth. These findings have translational relevance as ASNS/GPER1 signaling could be a future therapeutic target to improve the survival of female CRC patients.

Abstract Background The exploration of cancer vaccines has yielded a multitude of studies, resulting in a diverse collection of information. The heterogeneity of cancer vaccine data significantly impedes effective integration and analysis. While CanVaxKB serves as a pioneering database for over 670 manually annotated cancer vaccines, it is important to distinguish that a database, on its own, does not offer the structured relationships and standardized definitions found in an ontology. Recognizing this, we expanded the Vaccine Ontology (VO) to include those cancer vaccines present in CanVaxKB that were not initially covered, enhancing VO’s capacity to systematically define and interrelate cancer vaccines. Results An ontology design pattern (ODP) was first developed and applied to semantically represent various cancer vaccines, capturing their associated entities and relations. By applying the ODP, we generated a cancer vaccine template in a tabular format and converted it into the RDF/OWL format for generation of cancer vaccine terms in the VO. ‘12MP vaccine’ was used as an example of cancer vaccines to demonstrate the application of the ODP. VO also reuses reference ontology terms to represent entities such as cancer diseases and vaccine hosts. Description Logic (DL) and SPARQL query scripts were developed and used to query for cancer vaccines based on different vaccine’s features and to demonstrate the versatility of the VO representation. Additionally, ontological modeling was applied to illustrate cancer vaccine related concepts and studies for in-depth cancer vaccine analysis. A cancer vaccine-specific VO view, referred to as “CVO,” was generated, and it contains 928 classes including 704 cancer vaccines. The CVO OWL file is publicly available on: http://purl.obolibrary.org/obo/vo/cvo.owl , for sharing and applications. Conclusion To facilitate the standardization, integration, and analysis of cancer vaccine data, we expanded the Vaccine Ontology (VO) to systematically model and represent cancer vaccines. We also developed a pipeline to automate the inclusion of cancer vaccines and associated terms in the VO. This not only enriches the data’s standardization and integration, but also leverages ontological modeling to deepen the analysis of cancer vaccine information, maximizing benefits for researchers and clinicians. Availability The VO-cancer GitHub website is: https://github.com/vaccineontology/VO/tree/master/CVO .

Abstract Respiratory syncytial virus (RSV) is the major cause of bronchiolitis and pneumonia in young children and the elderly. There are currently no approved RSV-specific therapeutic small molecules available. Using high-throughput antiviral screening, we identified an oral drug, the prenylation inhibitor lonafarnib, which showed potent inhibition of the RSV fusion process. Lonafarnib exhibited antiviral activity against both the RSV A and B genotypes and showed low cytotoxicity in HEp-2 and human primary bronchial epithelial cells (HBEC). Time-of-addition and pseudovirus assays demonstrated that lonafarnib inhibits RSV entry, but has farnesyltransferase-independent antiviral efficacy. Cryo-electron microscopy revealed that lonafarnib binds to a triple-symmetric pocket within the central cavity of the RSV F metastable pre-fusion conformation. Mutants at the RSV F sites interacting with lonafarnib showed resistance to lonafarnib but remained fully sensitive to the neutralizing monoclonal antibody palivizumab. Furthermore, lonafarnib dose-dependently reduced the replication of RSV in BALB/c mice. Collectively, lonafarnib could be a potential fusion inhibitor for RSV infection.

Abstract Background Saiga antelope horn (SAH) is a traditional Chinese medicine for treating febrile seizure (FS) with precise efficacy, but its mechanism of action and functional substances are still unclear. Given the need for further research on SAH, our group conducted studies to elucidate its mechanisms and active substances. Methods An FS rat pup model was constructed through intraperitoneal injection of LPS and hyperthermia induction. Behavioural indicators of seizures, hippocampal histopathological alterations, serum levels of inflammatory cytokines and hippocampal levels of neurotransmitters were observed and measured to investigate the effects of SAH on FS model rats. Hippocampal metabolomics and network pharmacology analyses were conducted to reveal the differential metabolites, key peptides and pathways involved in the suppression of FS by SAH. Results SAH suppressed FS, decreased the inflammatory response and regulated the Glu-GABA balance. Metabolomic analysis revealed 13 biomarkers of FS, of which SAH improved the levels of 8 differential metabolites. Combined with network pharmacology, a “biomarker-core target-key peptide” network was constructed. The peptides of SAH, such as YGQL and LTGGF, could exert therapeutic effects via the arachidonic acid pathway. Molecular docking and ELISA results indicated that functional peptides of SAH could bind to PTGS2 target, inhibiting the generation of AA and its metabolites in hippocampal samples. Conclusion In summary, the functional peptides contained in SAH are the main material basis for the treatment of FS, potentially acting through neurotransmitter regulation and the arachidonic acid pathway. Graphical abstract

Abstract Pain is estimated to affect more than 20% of the global population, imposing incalculable health and economic burdens. Effective pain management is crucial for individuals suffering from pain. However, the current methods for pain assessment and treatment fall short of clinical needs. Benefiting from advances in neuroscience and biotechnology, the neuronal circuits and molecular mechanisms critically involved in pain modulation have been elucidated. These research achievements have incited progress in identifying new diagnostic and therapeutic targets. In this review, we first introduce fundamental knowledge about pain, setting the stage for the subsequent contents. The review next delves into the molecular mechanisms underlying pain disorders, including gene mutation, epigenetic modification, posttranslational modification, inflammasome, signaling pathways and microbiota. To better present a comprehensive view of pain research, two prominent issues, sexual dimorphism and pain comorbidities, are discussed in detail based on current findings. The status quo of pain evaluation and manipulation is summarized. A series of improved and innovative pain management strategies, such as gene therapy, monoclonal antibody, brain-computer interface and microbial intervention, are making strides towards clinical application. We highlight existing limitations and future directions for enhancing the quality of preclinical and clinical research. Efforts to decipher the complexities of pain pathology will be instrumental in translating scientific discoveries into clinical practice, thereby improving pain management from bench to bedside.

This study aims to address the potential and challenges of multimodal medical information in the diagnosis of interstitial lung disease (ILD) by developing an ILD identification model (ILDIM) based on the multimodal fusion attention mechanism (MFAM) to improve the accuracy and reliability of ILD. Large-scale multimodal medical information data, including chest CT image slices, physiological indicator time series data, and patient history text information were collected. These data are professionally cleaned and normalized to ensure data quality and consistency. Convolutional Neural Network (CNN) is used to extract CT image features, Bidirectional Long Short-Term Memory Network (Bi-LSTM) model is used to learn temporal physiological metrics data under long-term dependency, and Self-Attention Mechanism is used to encode textual semantic information in patient’s self-reporting and medical prescriptions. In addition, the multimodal perception mechanism uses a Transformer-based model to improve the diagnostic performance of ILD by learning the importance weights of each modality’s data to optimally fuse the different modalities. Finally, the ablation test and comparison results show that the model performs well in terms of comprehensive performance. By combining multimodal data sources, the model not only improved the Precision, Recall and F1 score, but also significantly increased the AUC value. This suggests that the combined use of different modal information can provide a more comprehensive assessment of a patient’s health status, thereby improving the diagnostic comprehensiveness and accuracy of ILD. This study also considered the computational complexity of the model, and the results show that ILDIM-MFAM has a relatively low number of model parameters and computational complexity, which is very favorable for practical deployment and operational efficiency.

BackgroundSoil salinization is one of the significant factors limiting high crop yields and expansion of arable land, seriously affecting global agricultural production. Rice is an essential food crop throughout the world, and its seedlings are particularly susceptible to salt stress, which can directly affect the growth and development of rice and its final yield. We used the natural population as the material for genome-wide association study (GWAS) and the recombinant inbred line (RIL) population from CD (salt sensitive)/WD20342 (salt tolerant) hybridization as the material for linkage analysis.ResultsThe degree of salt tolerance was evaluated by using the relative root length (RRL), relative root number (RRN), relative root fresh weight (RRFW), and relative root dry weight (RRDW) as indicators. Fifteen and six major quantitative trait loci (QTLs) were identified by GWAS and linkage analysis, respectively. Meanwhile, the GWAS identified the lead SNP (Chr2_22340368), which was located within qRRL2 and qRRDW2 identified by linkage analysis. GWAS, combined with linkage analysis, selected a 196-kb overlapping region on chromosome 2, including 22 candidate genes. LOC_Os02g36880 was discovered as the candidate gene involved in salt tolerance by haplotype analysis, qRT-PCR, and sequence analysis. The score of salinity toxicity (SST) and seedling survival rate (SSR) were determined for CRISPR/Cas9 mutants (CR-1 and CR-15) and wild-type (ZH11), respectively.ConclusionThe phenotypic validation indicated that LOC_Os02g36880 negatively regulated the salt tolerance at the seedling stage. This study provides resources for breeding Japonica rice to improve its response to salt stress.

Abstract Background An updated definition was developed to better evaluate cardiovascular health (CVH). We aimed to investigate whether optimal or improvement of six CVH metrics defined by new Life's Essential 8 (LE8) may counteract the risk of subclinical atherosclerosis among patients with hyperglycemia. Methods We conducted a prospective analysis of 5225 participants without prior cardiovascular diseases, of whom 4768 had complete data on CVH change. Subjects with CVH scores of 0–49, 50–79, and 80–100 points were categorized as having low, moderate, or high CVH, respectively. Subclinical atherosclerosis was evaluated by brachial‐ankle pulse wave velocity, pulse pressure and albuminuria, both separately and in combination. Results Of the 5225 participants, 1937 (37.1%) had normal glucose regulation, while 3288 (62.9%) had hyperglycemia. The multivariable‐adjusted odds ratio (OR) for composite subclinical atherosclerosis was 2.34 (95% confidence interval [CI], 1.88–2.91), 1.43 (95% CI, 1.21–1.70), and 0.74 (95% CI, 0.46–1.18), for participants with hyperglycemia who had low, moderate, or high overall CVH scores, respectively, compared with participants with normal glucose regulation. In addition, compared with those with stable CVH and normal glucose regulation, participants who exhibited greater improvements in overall CVH from 2010 to 2014 had a reduced risk of composite subclinical atherosclerosis with an OR of 0.72 (95% CI, 0.53–0.98) for those with normal glucose regulation, and 1.13 (95% CI, 0.87–1.48) for those with hyperglycemia. Conclusions The novel defined CVH using six metrics was inversely associated with subsequent risk of subclinical atherosclerosis. Both the status of CVH and its changes modified the relationship between hyperglycemia and subclinical atherosclerosis.

Background and aimsCurrent guidelines are controversial regarding the continuation of nucleos(t)ide analogues (NAs) therapy after delivery in Hepatitis B virus (HBV)-infected pregnant women. The postpartum period may be an opportune moment for achieving hepatitis B e antigen (HBeAg) seroconversion earlier with constant NAs therapy due to the restoration of immune function after delivery. We investigated prenatal and pregnant factors associated with HBeAg seroconversion after pregnancy and developed a nomogram to predict HBeAg seroconversion rates, aiding decision-making for optimal management in women.MethodsWe retrospectively included 489 HBeAg-positive mothers as the training cohort from January 2014 to December 2018 and prospectively enrolled 94 patients as the external validation cohort from January 2019 to December 2021 at the First Affiliated Hospital of Xi’an Jiaotong University. In the training cohort, independent predictors were identified using the least absolute shrinkage and selection operator (LASSO) regression algorithm. Subsequently, multivariate logistic regression was employed to establish the nomogram. Model performance was assessed using the area under the receiver operating characteristic curve (AUC), calibration plots, and decision curve analysis (DCA). Both discrimination and calibration were evaluated through bootstrapping with 1,000 resamples. The external validation cohort was subsequently used to validate the nomogram.ResultsFactors such as pregnancy hepatitis flare (OR: 5.122, 95% CI: 2.725–9.928, p

Quantum non-demolition measurement with an off-resonance polarized probe is a widely utilized technique for atomic sensors. We observe previously unexplored spin-alignment polarization induced by the far-detuned off-resonance linear probe in an ultrasensitive optical polarimetry. The evolution of probe-generated multipole moments exacerbates probe noise due to strong magnetic couplings. We demonstrate a method to decouple spin-alignment from magnetic fields by manipulating the multipole moments in zero-fields. The probe noise is suppressed by 10 dB with the proposed method, achieving a noise floor at the standard quantum limit. The realized shot-noise-limited optical polarimetry holds significant promise for atomic sensors aimed at ultra-sensitivity.

BackgroundAntiphospholipid syndrome (APS) is a systemic autoimmune disorder that can manifest as thrombosis in the pediatric population, characterized by persistently positive antiphospholipid antibodies. APS is infrequently observed in children and could represent non-criteria manifestations.Case presentationA six-year-old Chinese female presented with jaundice and dark urine, leading to a diagnosis of hemolytic anemia. Prednisone therapy initially improved her complexion, but she later developed neurological symptoms. Further laboratory tests showed intravascular hemolysis, coagulation abnormalities, and a positive lupus anticoagulant (LA) test result. Magnetic resonance imaging (MRI) scan revealed abnormal signals in the pons and cerebellar hemispheres, and an occluded part of the basilar artery. She was subsequently diagnosed with autoimmune encephalitis and received IG(immunoglobulin) and high-dose glucocorticoid (GC) treatment, leading to improvement in her clinical symptoms. However, the symptoms of hemolytic anemia worsened after two years. Subsequent laboratory assessments demonstrated the presence of intravascular hemolysis, coagulation abnormalities, and positive tests of anticardiolipin, LA, and anti-beta2 glycoprotein I antibodies. Elevated troponin I and N-terminal pro-brain natriuretic peptide levels, along with electrocardiogram and echocardiogram findings, indicated a myocardial infarction and a thrombus-like mass in the left auricle. Brain MRI showed multifocal infarction and cerebrovascular obstruction. She was diagnosed with APS accompanied by hemolytic anemia, cerebrovascular obstruction, and myocardial infarction. After several weeks of treatment with GC, IG, rituximab, hydroxychloroquine alone with low-molecular-weight heparin sodium, and warfarin, there was a marked improvement in the patient's condition.ConclusionPediatricians should be familiar with various presentations of pediatric APS to promptly detect possible aPL-related complications and initiate appropriate management strategies early on.

ObjectiveThe research focused on a comparative analysis of triage strategies for women with Atypical Squamous Cells of Undetermined Significance (ASC-US) before and after receiving the HPV vaccine, aiming to optimize cervical cancer prevention strategies, especially in resource-limited healthcare settings.Materials and methodsBetween September 2018 and December 2023, 7,511 women aged 21 years or older who underwent liquid-based cytology for cervical cancer screening were recruited. Women diagnosed with ASC-US were included in the study. All participants underwent HPV testing and liquid-based cytology examination, and those with abnormal results were referred for colposcopy. Women with abnormal colposcopy findings underwent further histopathological examination. The gold standard for diagnosis was pathological, with cervical intraepithelial neoplasia grade 2 or higher (CIN2+) on histology as the endpoints. In the final analysis, 933 women with ASC-US were enrolled as the unvaccinated group, with 179 of them testing positive for HPV 16/18. Assuming that all women would receive the bivalent vaccine targeting HPV 16/18 in the post-vaccine era, and given that the vaccine protection rate is 100% against HPV 16/18, then 754 women excluding those of HPV 16/18 positive would comprise the vaccinated group.ResultsIn the unvaccinated group, the overall HPV positivity rate was 59.27% among ASC-US women, with a 100% HPV prevalence rate among those with CIN2+ lesions. The combination genotyping model of HPV16/18 showed the highest specificity (81.77%) and the lowest referral rate (32.37%). In the vaccinated group, the HPV positivity rate was 49.61% among ASC-US women, with a 100% HPV prevalence rate among those with CIN2+ lesions. The specificity of HPV33/58 was the highest (86.99%), and the colposcopy referral rate was lowest (27.54%), with statistical significance. Sensitivity, positive predictive value, and negative predictive value were not statistically significant.ConclusionHPV16/18 demonstrated a more efficacious triaging effect in the unvaccinated group. HPV33/58 will potentially replace HPV16/18 as the priority screening genotyping among vaccinated populations.

Human umbilical cord mesenchymal stem cells (UCMSCs) are a novel stem-cell source to treat osteoarthritis (OA). Here we investigated the therapeutic effects of UCMSCs injection strategies on knee OA in a rabbit model. Thirty OA rabbits randomly received normal saline, a single dose of 1 × 106 UCMSCs, or three injections of 1 × 106 UCMSCs at 2, 4, 6 weeks. Articular cartilages were collected after 8 weeks. Macroscopic and histological assessments indicated that intra-articular injection of UCMSCs, both single and multiple injection, significantly reduced the formation of periarticular osteophytes and articular cartilage degeneration when compared with the control. Furthermore, both UCMSCs injections increased the expression of chondrogenic markers in the articular cartilage, and reduced the levels of TNF-α and IL-6 in synovium. Micro-CT showed significant reduction of sub-chondral bone degeneration and osteophytes in the multiple-injection group compared to the control and single-injection group. Taken together, intra-articular injection of UCMSCs for OA treatment is safe and effective. Single and multiple injection of UCMSCs had comparable reparative effect on cartilage lesions, while multiple injection of UCMSCs further exerted effect on enhancing subchondral bone volume.

Forest ecosystems, especially within biodiversity hotspots, heavily rely on the often-overlooked understory herbaceous communities (USHC) for their structural integrity and ecological functions. Because of their modest stature, these communities have garnered insufficient attention from researchers. Therefore, in this study attention is focused on USHC, which attempts to fill this research gap. To achieve this, we established 105 sample plots in 2022 within forest ecosystems situated in the biodiversity hotspot of southwest China. Our investigation unveiled a rich biodiversity tapestry, identifying 424 plant species from 108 families and 284 genera. Notable were the 217 herbaceous species identified in the understory layer, representing 67 families and 163 genera. These understory herbaceous species accounted for 51.2 % of the overall species count. Through a detailed analysis, the sample plots were categorized into eight distinct communities using a two-way indicator species analysis. These communities exhibited diverse variations in species composition, diversity, biomass, and nutrient characteristics. Notably, community I (Eucalyptus robusta Smith + Rubus corchorifolius L. f. + Alternanthera philoxeroides (Mart.) Griseb.), V (Camptotheca acuminata Decne + Rubus parkeri Hance + Iris tectorum Maxim), VIII (Platycladus orientalis (L.) Franco + Viburnum dilatatum Thunb. + Cyclosorus interruptus (Willd.) H. Ito) stood out for their exceptional species diversity and productivity. Moreover, correlation analyses highlighted the substantial impact of topographic and soil factors on USHC. Altitude, soil water content, and total carbon content emerged as the primary determinants of species diversity. Biomass demonstrated close associations with total soil carbon and nitrogen. Furthermore, the nutrient characteristics displayed significant correlations with soil nutrient contents. These findings underscore the critical importance of prioritizing USHC attention in forest conservation and management strategies within biodiversity hotspots. The implications strongly advocate for the inclusion of these communities in planning and decision-making processes, emphasizing their pivotal role in maintaining structural and functional diversity in ecosystems.

Hypoxic-ischemic encephalopathy (HIE) poses a significant challenge in neonatal medicine, often resulting in profound and lasting neurological deficits. Current therapeutic strategies for hypoxia-ischemia brain damage (HIBD) remain limited. Ferroptosis has been reported to play a crucial role in HIE and serves as a potential therapeutic target. However, the mechanisms underlying ferroptosis in HIBD remain largely unclear. In this study, we found that elevated lysyl oxidase (LOX) expression correlates closely with the severity of HIE, suggesting LOX as a potential biomarker for HIE. LOX expression levels and enzymatic activity were significantly increased in HI-induced neuronal models both in vitro and in vivo. Notably, we discovered that HI-induced brain tissue injury results in increased stiffness and observed a selective upregulation of the mechanosensitive ion channel Piezo1 in both brain tissue of HIBD and primary cortex neurons. Mechanistically, LOX increases its catalytic substrates, the Collagen I/III components, promoting extracellular matrix (ECM) remodeling and possibly mediating ECM cross-linking, which leads to increased stiffness at the site of injury and subsequent activation of the Piezo1 channel. Piezo1 senses these stiffness stimuli and then induces neuronal ferroptosis in a GPX4-dependent manner. Pharmacological inhibition of LOX or Piezo1 ameliorated brain neuronal ferroptosis and improved learning and memory impairments. Furthermore, we identified traumatic acid (TA) as a novel LOX inhibitor that effectively suppresses LOX enzymatic activity, mitigating neuronal ferroptosis and promoting synaptic plasticity. In conclusion, our findings elucidate a critical role for LOX-mediated ECM mechanical stress-induced Piezo1 activation in regulating ferroptotic cell death in HIBD. This mechanistic insight provides a basis for developing targeted therapies aimed at ameliorating neurological outcomes in neonates affected by HIBD.

Abstract Understanding the endogenous mechanism of adaptive response to drug‐induced liver injury (arDILI) may discover innovative strategies to manage DILI. To gain mechanistic insight into arDILI, we investigated exosomal miRNAs in the adaptive response to toosendanin‐induced liver injury (TILI) of mice. Exosomal miR‐106b‐5p was identified as a specific regulator of arDILI by comprehensive miRNA profiling. Outstandingly, miR‐106b‐5p agomir treatment alleviated TILI and other DILI by inhibiting apoptosis and promoting hepatocyte proliferation. Conversely, antagomir treatments had opposite effects, indicating that miR‐106b‐5p protects mice from liver injury. Injured hepatocytes released miR‐106b‐5p‐enriched exosomes taken up by surrounding hepatocytes. Vim (encodes vimentin) was identified as an important target of miR‐106b‐5p by dual luciferase reporter and siRNA assays. Furthermore, single‐cell RNA‐sequencing analysis of toosendanin‐injured mouse liver revealed a cluster of Vim+ hepatocytes; nonetheless declined following miR‐106b‐5p cotreatment. More importantly, Vim knockout protected mice from acetaminophen poisoning and TILI. In the clinic, serum miR‐106b‐5p expression levels correlated with the severity of DILI. Indeed, liver biopsies of clinical cases exposed to different DILI causing drugs revealed marked vimentin expression among harmed hepatocytes, confirming clinical relevance. Together, we report mechanisms of arDILI whereby miR‐106b‐5p safeguards restorative tissue repair by targeting vimentin.

Summary: The interplay between intestinal barrier degradation and trace element insufficiency worsens inflammatory bowel disease (IBD). Selenium (se) is essential for glutathione peroxidase 4 (GPX4) synthesis, which protects against intestinal epithelial cell injury in IBD. However, malnutrition and malabsorption limit the availability of dietary selenium. This study investigated the protective effects of naturally occurring seleno-amino acids on the intestinal barrier in an IBD animal model by promoting GPX4 synthesis. L-se-methylselenocystine (seMc) supplementation reversed decreased GPX4 expression levels, alleviated glutathione depletion and scavenged reactive oxygen species in vitro. In vivo, enteral nutrition combined with seMc protected the intestinal barrier and alleviated IBD-related symptoms by inhibiting ferroptosis and reversing lipid peroxidation in epithelial cells while reducing immune cell infiltration. Our findings suggest that seleno-amino acid-based nutritional formulations may provide a basis for nutritional support to alleviate complex cycles between intestinal barrier damage and malnutrition in IBD patients.

Essential mineral elements such as zinc and iron play a crucial role in maintaining crop growth and development, as well as ensuring human health. Foxtail millet is an ancient food crop rich in mineral elements and constitutes an important dietary supplement for nutrient-deficient populations. The ZIP (ZRT, IRT-like protein) transporters are primarily responsible for the absorption, transportation and accumulation of Zn, Fe and other metal ions in plants. Here, we identified 14 ZIP transporters in foxtail millet (SiZIP) and systematically characterized their phylogenetic relationships, expression characteristics, sequence variations, and responses to various abiotic stresses. As a result, SiZIPs display rich spatiotemporal expression characteristics in foxtail millet. Multiple SiZIPs demonstrated significant responses to Fe, Cd, Na, and K metal ions, as well as drought and cold stresses. Based on homologous comparisons, expression characteristics and previous studies, the functions of SiZIPs were predicted as being classified into several categories: absorption/efflux, transport/distribution and accumulation of metal ions. Simultaneously, a schematic diagram of SiZIP was drawn. In general, SiZIPs have diverse functions and extensively involve in the transport of metal ions and osmotic regulation under abiotic stresses. This work provides a fundamental framework for the transport and accumulation of mineral elements and will facilitate the quality improvement of foxtail millet.

In this article, industrial-specification Mg-Gd-Y-Zn-Zr alloy cylinder parts were successfully prepared by rotary backward extrusion process. The microstructure distribution and mechanical properties evolution of the whole wall of different cylinder parts were investigated, and the effects of different rotation speeds on the microstructure and properties were also revealed. The results showed that the strain of the cylinder wall increased significantly with rotation speed increased, thereby generating a higher driving force for the microstructure refinement. The transformation of the inner wall progressed from the deformed zone (bulk-shaped long period stacking ordered (LPSO) phases, coarse deformed grains, and fine recrystallized grains) to the strongly affected zone (particle-shaped LPSO phases and fine recrystallized grains), with the latter expanding as rotation speed increased. Furthermore, there was a gradient distribution of strain in the cylinder walls, with the strain gradient intensifying alongside rotation speed. The transformation of the strongly affected zone into the deformed region from the inner to the outer wall suggested a diminishing effect of rotation speed on LPSO phases fragmentation and grain refinement. Notably, increasing rotation speed rendered improvements in the strength and ductility of the cylinder wall. And mechanical properties also displayed a gradient decrease from the inner wall to the outer wall. This variation in mechanical properties of different regions was closely associated with the contributions of grain boundary strengthening, texture strengthening and second phase strengthening.

In this paper, Mg-9.5Gd-4Y–2Zn-0.5Zr cylindrical parts were prepared by the conventional backward extrusion (CBE) process and rotating backward extrusion (RBE) process. The effects of the two processes on the microstructure and mechanical properties of different orientation regions of rare earth magnesium alloy were analyzed and compared. The RBE process introduces a torsional shear quantity based on the CBE process. By changing the direction of plastic flow, has a positive effect on the elongation (EL) of the alloy. It was found that dynamic recrystallization (DRX) occurred in both CBE and RBE processes. With the transition of deformation, the strain continues to accumulate, and the DRX mechanism changes from discontinuous dynamic recrystallization (DDRX) to continuous dynamic recrystallization (CDRX). Compared with the CBE process, the grain refinement of the RBE process is more significant. After deformation, a more significant heterostructure is obtained in the RBE-45° region, and the average grain size reaches 24.7 μm. The ultimate tensile strength (UTS), yield strength (YS), and EL of the alloy in this region are 292.5 ± 7.7 MPa, 226.6 ± 7.4 MPa, and 21.5 ± 1.3 %, respectively. Although the strength is slightly lower than that of CBE alloy, better plasticity is obtained. The excellent strength-toughness synergy is attributed to the synergistic effect between heterogeneous regions of non-uniform microstructure. This study provides some theoretical guidance for the industrial production of large-size magnesium alloy cylindrical parts and subsequent applications.

In this paper, the microstructure and mechanical properties of SLM-GH3230 superalloy treated by different post treatments (single hot isostatic pressing and heat treatments after hot isostatic pressing) were studied. The micro-morphologies show that the grains along building direction after HIP + HT are mainly columnar grains, which is consistent to that after single HIP. The granular precipitates distribute intergranularly and intragranularly after HIP, but gradually re-dissolve into matrix with the increase of the temperature of the post HT processes. XRD and EDS analyses results indicate that the matrix mainly consists of austenitic γ phase and the granular precipitates are mainly M6C carbides enriched in W element. The average grain size decreases after HT compared to that after HIP, and the crystallographic orientation of grains tends to be more uniform. The Vickers hardness decreases after HIP and HIP + HT processes within a certain degree. According to tensile test results, the sample shows a better combination of strength and plastic performance under HIP+1250 °C/30 min processing, which can also be verified by the characteristic of the fracture morphology with more tearing dimples.

This study develops a rapid algorithm coupled with the finite element method to predict the fatigue crack propagation process and select the enhancement factor for the equivalent random load spectrum of accelerated fatigue tests. The proposed algorithm is validated by several fatigue tests of an aluminum alloy under the accelerated random load spectra. In the validation process, two kinds of panels with different geometries and sizes are used to calculate the stress intensity factor, critical crack length, and crack propagation life. The simulated and experimental findings indicate that when the aluminum alloy is in a low plasticity state, the crack propagation life exhibits a linear relationship with the acceleration factor. When the aluminum alloy is in a high plasticity state, this study proposes an empirical formula to calculate the equivalent stress intensity factor and crack propagation life. The normalized empirical formula is independent of the geometry and size of different samples, although the fracture processes are different in the two kinds of panels used in our study. Overall, the numerical method proposed in this paper can be applied to predict the fatigue crack propagation life for the random spectrum of large samples based on the results of the simulated accelerated crack propagation process and the accelerated fatigue tests of small samples to reduce the cost and time of the testing.

Pepper originated in South America and was introduced to China in the 16th century. With high nutritional value, pepper has an important role in health care, beauty, food, medicine, violence and other industries. It becomes one of the most important vegetable crops in China. With the gradual increase of cultivation area pepper ranks the top among vegetable crops in China in this aspect. In the process of pepper production, it inevitably suffers from various diseases, causing great losses to production. It is the most economical and effective measure to control diseases through selecting disease-resistant varieties, although the chemical control methods and agricultural control measures can reduce the harm to a certain extent. With the development of molecular biology, the combination of molecular breeding and conventional breeding methods for disease resistance is a direction of future breakthroughs. In recent years, great progress has been made in the molecular breeding of pepper disease resistance, especially, the molecular mechanism of disease resistance. Molecular breeding mainly includes two parts: one is marker-assisted breeding, and the other is creating disease-resistant breeding materials by means of genetic engineering. In marker-assisted breeding, molecular markers must be found first. Molecular markers are divided into gene markers, markers obtained by linkage analysis in segregation populations, and markers gotten by association analysis through sequencing of a large number of materials. The premise of genetic engineering is to isolate and obtain disease resistance genes, and then introduce them into pepper breeding materials with good economic traits, or mutate negatively regulated genes through gene editing technology or gene silencing technology to improve disease resistance of plants. In this paper, molecular markers and marker-assisted selection, molecular mechanism of disease resistance and disease-resistant germplasm (resistance to virus, bacterial wilt and Phytophthora capsici) obtained by genetic engineering technology are comprehensively introduced, and the development trend and research focus in the future are prospected.

Abstract Background Pathogenic parasites are responsible for multiple diseases, such as malaria and Chagas disease, in humans and livestock. Traditionally, pathogenic parasites have been largely an evasive topic for vaccine design, with most successful vaccines only emerging recently. To aid vaccine design, the VIOLIN vaccine knowledgebase has collected vaccines from all sources to serve as a comprehensive vaccine knowledgebase. VIOLIN utilizes the Vaccine Ontology (VO) to standardize the modeling of vaccine data. VO did not model complex life cycles as seen in parasites. With the inclusion of successful parasite vaccines, an update in parasite vaccine modeling was needed. Results VIOLIN was expanded to include 258 parasite vaccines against 23 protozoan species, and 607 new parasite vaccine-related terms were added to VO since 2022. The updated VO design for parasite vaccines accounts for parasite life stages and for transmission-blocking vaccines. A total of 356 terms from the Ontology of Parasite Lifecycle (OPL) were imported to VO to help represent the effect of different parasite life stages. A new VO class term, ‘transmission-blocking vaccine,’ was added to represent vaccines able to block infectious transmission, and one new VO object property, ‘blocks transmission of pathogen via vaccine,’ was added to link vaccine and pathogen in which the vaccine blocks the transmission of the pathogen. Additionally, our Gene Set Enrichment Analysis (GSEA) of 140 parasite antigens used in the parasitic vaccines identified enriched features. For example, significant patterns, such as signal, plasma membrane, and entry into host, were found in the antigens of the vaccines against two parasite species: Plasmodium falciparum and Toxoplasma gondii. The analysis found 18 out of the 140 parasite antigens involved with the malaria disease process. Moreover, a majority (15 out of 54) of P. falciparum parasite antigens are localized in the cell membrane. T. gondii antigens, in contrast, have a majority (19/24) of their proteins related to signaling pathways. The antigen-enriched patterns align with the life cycle stage patterns identified in our ontological parasite vaccine modeling. Conclusions The updated VO modeling and GSEA analysis capture the influence of the complex parasite life cycles and their associated antigens on vaccine development.

Abstract Trace elements are important for human health but may exert toxic or adverse effects. Mechanisms of uptake, distribution, metabolism, and excretion are partly under genetic control but have not yet been extensively mapped. Here we report a comprehensive multi-element genome-wide association study of 57 essential and non-essential trace elements. We perform genome-wide association meta-analyses of 14 trace elements in up to 6564 Scandinavian whole blood samples, and genome-wide association studies of 43 trace elements in up to 2819 samples measured only in the Trøndelag Health Study (HUNT). We identify 11 novel genetic loci associated with blood concentrations of arsenic, cadmium, manganese, selenium, and zinc in genome-wide association meta-analyses. In HUNT, several genome-wide significant loci are also indicated for other trace elements. Using two-sample Mendelian randomization, we find several indications of weak to moderate effects on health outcomes, the most precise being a weak harmful effect of increased zinc on prostate cancer. However, independent validation is needed. Our current understanding of trace element-associated genetic variants may help establish consequences of trace elements on human health.

Abstract Background 'Benign ethnic neutropenia' (BEN) is a heritable condition characterized by lower neutrophil counts, predominantly observed in individuals of African ancestry, and the genetic basis of BEN remains a subject of extensive research. In this study, we aimed to dissect the genetic architecture underlying neutrophil count variation through a linear-mixed model genome-wide association study (GWAS) in a population of African ancestry (N = 5976). Malaria caused by P. falciparum imposes a tremendous public health burden on people living in sub-Saharan Africa. Individuals living in malaria endemic regions often have a reduced circulating neutrophil count due to BEN, raising the possibility that reduced neutrophil counts modulate severity of malaria in susceptible populations. As a follow-up, we tested this hypothesis by conducting a Mendelian randomization (MR) analysis of neutrophil counts on severe malaria (MalariaGEN, N = 17,056). Results We carried out a GWAS of neutrophil count in individuals associated to an African continental ancestry group within UK Biobank, identifying 73 loci (r 2 = 0.1) and 10 index SNPs (GCTA-COJO loci) associated with neutrophil count, including previously unknown rare loci regulating neutrophil count in a non-European population. BOLT-LMM was reliable when conducted in a non-European population, and additional covariates added to the model did not largely alter the results of the top loci or index SNPs. The two-sample bi-directional MR analysis between neutrophil count and severe malaria showed the greatest evidence for an effect between neutrophil count and severe anaemia, although the confidence intervals crossed the null. Conclusion Our GWAS of neutrophil count revealed unique loci present in individuals of African ancestry. We note that a small sample-size reduced our power to identify variants with low allele frequencies and/or low effect sizes in our GWAS. Our work highlights the need for conducting large-scale biobank studies in Africa and for further exploring the link between neutrophils and severe malaria.

In recent years, there has been significant research interest in the field of immunotherapy for non-small cell lung cancer (NSCLC) within the academic community. Given the observed variations in individual responses, despite similarities in histopathologic type, immunohistochemical index, TNM stage, or mutation status, the identification of a reliable biomarker for early prediction of therapeutic responses is of utmost importance. Conventional medical imaging techniques primarily focus on macroscopic tumor monitoring, which may no longer adequately fulfill the requirements of clinical diagnosis and treatment. CT (computerized tomography) or PEF/CT-based radiomics has the potential to investigate the molecular-level biological attributes of tumors, such as PD-1/PD-L1 expression and tumor mutation burden, which offers a novel approach to assess the effectiveness of immunotherapy and forecast patient prognosis. The utilization of cutting-edge radiological imaging techniques, including radiomics, PET/CT, machine learning, and artificial intelligence, demonstrates significant potential in predicting diagnosis, treatment response, immunosuppressive characteristics, and immune-related adverse events. The current review highlights that CT scan-based radiomics is a reliable and feasible way to predict the benefits of immunotherapy in patients with advanced NSCLC.

Background and aimsLimited data have been reported on achieving functional cure using pegylated interferon (Peg-IFN) alpha-2b treatment for postpartum hepatitis B e antigen (HBeAg)-negative women with chronic hepatitis B virus (HBV) infection. This study was to assess the effectiveness and safety of Peg-IFN alpha-2b in HBV postpartum women without HBeAg and identify factors linked to the functional cure.MethodsA total of 150 HBeAg-negative postpartum women were retrospectively recruited.47 patients received Peg-IFN alpha-2b [Peg-IFN(+) group] and 103 patients did not [Peg-IFN(-) group]. Propensity score matching (PSM) was used to adjust the baseline imbalance between the two groups. The patients were followed for at least 48 weeks. The primary endpoints were hepatitis B surface antigen(HBsAg) loss and HBsAg seroconversion at 48 weeks. Logistic regression analysis was used to assess factors associated with HBsAg loss at 48 weeks.ResultsAt week 48,the HBsAg loss and seroconversion rate in Peg-IFN(+) group were 51.06%(24/47) and 40.43%(19/47), respectively. Even after PSM, Peg-IFN(+) group still showed higher HBsAg loss rate (50.00% vs 7.14%,p12IU/mL were good predictors of HBsAg loss. No serious adverse events were reported.ConclusionPeg-IFN alpha-2b treatment could achieve a high rate of HBsAg loss and seroconversion in HBeAg-negative postpartum women with reliable safety, particularly for patients experience postpartum flare and have low baseline HBsAg levels.

IntroductionThe cardiothoracic ratio (CTR) based on postero-anterior chest X-rays (P-A CXR) images is one of the most commonly used cardiac measurement methods and an indicator for initially evaluating cardiac diseases. However, the hearts are not readily observable on P-A CXR images compared to the lung fields. Therefore, radiologists often manually determine the CTR’s right and left heart border points of the adjacent left and right lung fields to the heart based on P-A CXR images. Meanwhile, manual CTR measurement based on the P-A CXR image requires experienced radiologists and is time-consuming and laborious.MethodsBased on the above, this article proposes a novel, fully automatic CTR calculation method based on lung fields abstracted from the P-A CXR images using convolutional neural networks (CNNs), overcoming the limitations to heart segmentation and avoiding errors in heart segmentation. First, the lung field mask images are abstracted from the P-A CXR images based on the pre-trained CNNs. Second, a novel localization method of the heart’s right and left border points is proposed based on the two-dimensional projection morphology of the lung field mask images using graphics.ResultsThe results show that the mean distance errors at the x-axis direction of the CTR’s four key points in the test sets T1 (21 × 512 × 512 static P-A CXR images) and T2 (13 × 512 × 512 dynamic P-A CXR images) based on various pre-trained CNNs are 4.1161 and 3.2116 pixels, respectively. In addition, the mean CTR errors on the test sets T1 and T2 based on four proposed models are 0.0208 and 0.0180, respectively.DiscussionOur proposed model achieves the equivalent performance of CTR calculation as the previous CardioNet model, overcomes heart segmentation, and takes less time. Therefore, our proposed method is practical and feasible and may become an effective tool for initially evaluating cardiac diseases.