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Abstract CRISPR/Cas9 technology has been widely adopted for genome editing in a wide range of organisms, including many fungi. Pyricularia oryzae is a filamentous fungal pathogen that causes the devastating rice blast disease. However, an efficient and cost-effective CRISPR/Cas9 system for the rice blast fungus has yet to be established. Here, we report an 84-bp arginyl (Arg)-tRNA promoter-driven CRISPR/Cas9 system, which enables efficient and cost-effective gene editing in P. oryzae. Preliminary screening of three tRNAs from the 179 predicted tRNAs in P. oryzae showed that two Arg-tRNA CRISPR/Cas9 cassettes reproducibly generated MoB56 disruption efficiently. Further, five genes located on distinct chromosomes, including two previously uncharacterized genes, were randomly picked up to test the efficiency of the Mo_tRNAArg24-gRNA-Cas9 cassette. Ppg1 is a gene essential to the pathogenicity and important for mycelial growth and conidiation of P. oryzae, which is located at chromosome 2 and exhibited a relatively low gene replacement rate (

Abstract Recurrent spontaneous abortion (RSA) has a complex pathogenesis with an increasing prevalence and is one of the most intractable clinical challenges in the field of reproductive medicine. Quercetin (QCT) is an effective active ingredient extracted from Semen Cuscutae and Herba Taxilli used in traditional Chinese medicine for tonifyng the kidneys and promoting fetal restoration. Although QCT helps improve adverse pregnancy outcomes, the specific mechanism remains unclear. The trophoblast cell line HTR‐8/SVneo cultured in vitro was treated with different concentrations of QCT, and the cell counting kit‐8 assay, wound healing assay, transwell assay, and western blotting were used to evaluate the effects and mechanisms of QCT on the proliferation, migration, and invasion of HTR‐8/SVneo cells, respectively. To assess the expression levels of miR‐149‐3p and AKT serine/threonine kinase 1 (AKT1), quantitative real‐time polymerase chain reaction (qRT‐PCR) and western blotting analysis were performed. A dual‐luciferase reporter assay was used to investigate the potential regulatory relationship between miR‐149‐3p and AKT1. Our results showed that QCT promoted the proliferation, migration, and invasion of trophoblast cells, promoted the expression of MMP2, MMP9, and vimentin, and downregulated the expression of E‐cadherin. Mechanistically, QCT downregulated the expression of miR‐149‐3p and upregulated the expression of AKT1, and miR‐149‐3p directly targets AKT1, negatively regulating its expression. Overexpression of miR‐149‐3p and silencing of AKT1 counteracted the promotional effects of QCT on trophoblast proliferation, migration, and invasion. Taken together, QCT regulates the migration and invasion abilities of HTR‐8/SVneo cells through the miR‐149‐3p/AKT1 axis, which may provide a promising therapeutic approach for RSA.

Abstract Background Bacteriophage has been renewed attention as a new antibacterial agent due to the limitations of antibiotic treatment. Bacteriophages are generally thought to be highly host specific and even strain specific, but a small number of polyvalent bacteriophages have been found to infect bacteria of different genera. Results In this study, a virulent lytic bacteriophage (named Salmonella phage PSH-1) of Salmonella Enteritidis was isolated from the sewage samples of a large-scale pig farm, PSH-1 demonstrated lytic activity against four multidrug-resistant Salmonella Enteritidis isolates and Escherichia coli, and then its biological characteristics, genome and bacteriostatic ability were investigated. The results showed that the initial titer of PSH-1 was 1.15 × 1010 PFU/mL and the optimal multiplicity of infection (MOI) was 0.01, PSH-1 has stable activity in the range of pH 3.0–11.0. One-step growth curve showed that its latent period was 20 min, burst time was 80 min, and the burst was 495 particles. The whole-genome sequencing results revealed phage PSH-1 had a linear dsDNA with 48,466 bp length. The G/C content was 45.33%. Non-coding RNA genes and virulence factors were not found. Eighty- five open reading frames (ORFs) were identified after online annotation. By tests, the use of phage could succeed in controlling the artificial Salmonella contamination in milk at a range of temperatures. Conclusions This study reports a novel Salmonella Enteritidis phage PSH-1, which has a robust lytic ability, no virulence factors, and good stability. The characterization and genomic analysis of PSH-1 will develop our understanding of phage biology and diversity and provide a potential arsenal for controlling of salmonellosis.

Abstract Continuous renal replacement therapy (CRRT) is a life-saving procedure for sepsis but the benefit of CRRT varies and prediction of clinical outcomes is valuable in efficient treatment planning. This study aimed to use machine learning (ML) models trained using MIMIC III data for identifying sepsis patients who would benefit from CRRT. We first selected patients with sepsis and CRRT in the ICU setting and their gender, and an array of routine lab results were included as features to train machine learning models using 30-day mortality as the primary outcome. A total of 4161 patients were included for analysis, among whom there were 1342 deaths within 30 days. Without data augmentation, extreme gradient boosting (XGBoost) showed an accuracy of 64.2% with AUC-ROC of 0.61. Data augmentation using a conditional generative adversarial neural network (c-GAN) resulted in a significantly improved accuracy (82%) and ROC-AUC (0.78%). To enable prediction on pediatric patients, we adopted transfer learning approaches, where the weights of all but the last hidden layer were fixed, followed by fine-tuning of the weights of the last hidden layer using pediatric data of 200 patients as the inputs. A significant improvement was observed using the transfer learning approach (AUCROC = 0.76) compared to direct training on the pediatric cohort (AUCROC = 0.62). Through this transfer-learning-facilitated patient outcome prediction, our study showed that ML can aid in clinical decision-making by predicting patient responses to CRRT for managing pediatric sepsis.

Abstract Most of the van der Waals homo- and hetero-junctions of group VIB two-dimensional (2D) transition-metal dichalcogenides (TMDs; MoS2, WS2, MoSe2, and WSe2) show indirect energy band gaps which hinders some of their applications especially in optoelectronics. In the current work, we demonstrate that most of the bilayers and even few-layers consisting of group VIB TMDs can have direct gaps by efficient weakening of their interlayer interactions via real and/or energy spaces tuning, which is based on insights from quantitative analyses of interlayer electronic hybridizations. Real space tuning here means introducing large-angle rotational misalignment between layers, which has been realized in a very recent experiment; and, energy space tuning means introducing energy mismatch between layers which can be introduced efficiently by different means thanks to the small vertical dielectric constant of 2D semiconducting TMDs. The efficient tuning in both real and energy spaces proposed here paves an avenue for indirect-direct gap regulation of homo- and hetero-junctions of TMDs and other 2D semiconductors. Notably, both tuning can be permanently preserved and hence our work is of great significance for the diverse applications of 2D semiconductors.

Abstract Background Plerocercoid larvae of the tapeworm Spirometra mansoni can infect both humans and animals, leading to severe parasitic zoonosis worldwide. Despite ongoing research efforts, our understanding of the developmental process of S. mansoni remains inadequate. To better characterize posttranslational regulation associated with parasite growth, development, and reproduction, a comparative phosphoproteomic study was conducted on the plerocercoid and adult stages of S. mansoni. Methods In this study, site-specific phosphoproteomic analysis was conducted via 4D label-free quantitative analysis technology to obtain primary information about the overall phosphorylation status of plerocercoids and adults. Results A total of 778 differentially abundant proteins (DAPs) were detected between adults and plerocercoids, of which 704 DAPs were upregulated and only 74 were downregulated. DAPs involved in metabolic activity were upregulated in plerocercoid larvae compared with adults, whereas DAPs associated with binding were upregulated in adults. Gene Ontology (GO) and Kyoto Encyclopedia of Genes (KEGG) analyses indicated that most DAPs involved in signal transduction and environmental information processing pathways were highly active in adults. DAPs upregulated in the plerocercoid group were enriched mainly in metabolic activities. The kinases PKACA, GSK3B, and smMLCK closely interact, suggesting potential active roles in the growth and development of S. mansoni. Conclusions The dataset presented in this study offers a valuable resource for forthcoming research on signaling pathways as well as new insights into functional studies on the molecular mechanisms of S. mansoni. Graphical abstract

Abstract Purpose Bone metastases occur in 50-70% of patients with breast cancer (BC) and result in high mortality. Platelet distribution width (PDW), a commonly used parameter of activated platelets, has been associated with a poor prognosis in BC. We aim to investigate the prognostic role of PDW for bone metastasis in BC patients. Methods 515 patients who received BC surgery in the Harbin Medical University Cancer Hospital from July 1, 2016, to December 31, 2017, were reviewed. Patients’ characteristics and platelet indices upon enrollment in this study were collected. The Kaplan-Meier method was used to estimate the 5-year bone metastasis incidence. The univariate and multivariate Cox regression analyses were utilized to identify risk factors associated with bone metastasis. Results The patients with bone metastases exhibited lower PDW levels than the patients without bone metastases. Moreover, decreased PDW was significantly correlated with histologic type, multifocal disease, and lymph node status. In addition, the patients with reduced PDW levels were more likely to develop bone metastasis. Multivariate analysis showed that PDW was an independent predictor for bone metastasis. Conclusion PDW is an independent predictor of bone metastasis in BC. Further research is warranted.

Abstract Objective Pregnancy care can improve maternal pregnancy outcomes. Cluster nursing, an evidence-based, patient-centered model, enhances pregnancy care, can provide patients with high-quality nursing services, has been widely used in clinical practice in recent years. However, most previous studies evaluated cluster nursing program only for a single clinical scenario. In this study, we developed and implemented a antenatal cluster care program for various prenatal issues faced by puerpera to analyze its application effect. Methods This is a historical before and after control study. 89 expectant mothers who had their prenatal information files registered in the outpatient department of a grade III, level A hospital from June 2020 to September 2021 were finally enrolled in observation group, and received prenatal cluster management. Another set of 89 expectant mothers from January 2019 to December 2019 were included in the control group and received traditional routine prenatal management. The effect of cluster nursing management on maternal delivery and postpartum rehabilitation was evaluated and compared between the two groups. Results Compared with the control group, the observation group had a significantly higher natural delivery rate, better neonatal prognosis, higher rates of exclusive breastfeeding, lower incidence of postpartum complications, shorter postpartum hospital stay, better postpartum health status, and higher satisfaction with nursing services. Compared with before intervention, the SAS and SDS scores of the observation group showed significant improvement after intervention. Conclusion Antenatal cluster care is beneficial to improve maternal and neonatal outcomes, and can have positive effects on natural pregnancy and breastfeeding, while improving the multimedia health education ability of medical care and emphasizing the importance of social support.

Abstract The female reproductive system comprises the internal and external genitalia, which communicate through intricate endocrine pathways. Besides secreting hormones that maintain the female secondary sexual characteristics, it also produces follicles and offspring. However, the in vitro systems have been very limited in recapitulating the specific anatomy and pathophysiology of women. Organ-on-a-chip technology, based on microfluidics, can better simulate the cellular microenvironment in vivo, opening a new field for the basic and clinical research of female reproductive system diseases. This technology can not only reconstruct the organ structure but also emulate the organ function as much as possible. The precisely controlled fluidic microenvironment provided by microfluidics vividly mimics the complex endocrine hormone crosstalk among various organs of the female reproductive system, making it a powerful preclinical tool and the future of pathophysiological models of the female reproductive system. Here, we review the research on the application of organ-on-a-chip platforms in the female reproductive systems, focusing on the latest progress in developing models that reproduce the physiological functions or disease features of female reproductive organs and tissues, and highlighting the challenges and future directions in this field.

Abstract We study quantum steering and Bell nonlocality harvested by the local interaction of two Unruh-DeWitt detectors with the vacuum massless scalar field, both in the presence of gravitational waves and in Minkowski spacetime. It is shown that quantum steerability under the influence of gravitational waves can be greater than or less than quantum steerability in Minkowski spacetime, which means that the gravitational waves can amplify or degrade the harvested steering. In particular, a resonance effect occurs when the energy gap of the detector is tuned to the frequency of the gravitational wave. We also find that the harvesting-achievable separation range of vacuum steering can be expanded or reduced by the presence of gravitational waves, which depends on the energy gap, the gravitational wave frequency, and the duration of the gravitational wave action. It is interesting to note that two detector systems that satisfy the Bell inequality in most parameter spaces, regardless of the existence of gravitational waves, indicating that steering harvesting cannot be considered to be nonlocal.

Abstract Coherent interconversion between microwave and optical frequencies can serve as both classical and quantum interfaces for computing, communication, and sensing. Here, we present a compact microwave-optical transducer based on monolithic integration of piezoelectric actuators on silicon nitride photonic circuits. Such an actuator couples microwave signals to a high-overtone bulk acoustic resonator defined by the silica cladding of the optical waveguide core, suspended to enhance electromechanical and optomechanical couplings. At room temperature, this triply resonant piezo-optomechanical transducer achieves an off-chip photon number conversion efficiency of 1.6 × 10−5 over a bandwidth of 25 MHz at an input pump power of 21 dBm. The approach is scalable in manufacturing and does not rely on superconducting resonators. As the transduction process is bidirectional, we further demonstrate the synthesis of microwave pulses from a purely optical input. Capable of leveraging multiple acoustic modes for transduction, this platform offers prospects for frequency-multiplexed qubit interconnects and microwave photonics at large.

Abstract Background Horizontal gene transfer (HGT) events have rarely been reported in gymnosperms. Gnetum is a gymnosperm genus comprising 25‒35 species sympatric with angiosperms in West African, South American, and Southeast Asian rainforests. Only a single acquisition of an angiosperm mitochondrial intron has been documented to date in Asian Gnetum mitogenomes. We wanted to develop a more comprehensive understanding of frequency and fragment length distribution of such events as well as their evolutionary history in this genus. Results We sequenced and assembled mitogenomes from five Asian Gnetum species. These genomes vary remarkably in size and foreign DNA content. We identified 15 mitochondrion-derived and five plastid-derived (MTPT) foreign genes. Our phylogenetic analyses strongly indicate that these foreign genes were transferred from diverse eudicots—mostly from the Rubiaceae genus Coptosapelta and ten genera of Malpighiales. This indicates that Asian Gnetum has experienced multiple independent HGT events. Patterns of sequence evolution strongly suggest DNA-mediated transfer between mitochondria as the primary mechanism giving rise to these HGT events. Most Asian Gnetum species are lianas and often entwined with sympatric angiosperms. We therefore propose that close apposition of Gnetum and angiosperm stems presents opportunities for interspecific cell-to-cell contact through friction and wounding, leading to HGT. Conclusions Our study reveals that multiple HGT events have resulted in massive amounts of angiosperm mitochondrial DNA integrated into Asian Gnetum mitogenomes. Gnetum and its neighboring angiosperms are often entwined with each other, possibly accounting for frequent HGT between these two phylogenetically remote lineages.

Abstract Background Metabolic reprograming and immune escape are two hallmarks of cancer. However, how metabolic disorders drive immune escape in head and neck squamous cell carcinoma (HNSCC) remains unclear. Therefore, the aim of the present study was to investigate the metabolic landscape of HNSCC and its mechanism of driving immune escape. Methods Analysis of paired tumor tissues and adjacent normal tissues from 69 HNSCC patients was performed using liquid/gas chromatography‐mass spectrometry and RNA‐sequencing. The tumor‐promoting function of kynurenine (Kyn) was explored in vitro and in vivo. The downstream target of Kyn was investigated in CD8+ T cells. The regulation of CD8+ T cells was investigated after Siglec‐15 overexpression in vivo. An engineering nanoparticle was established to deliver Siglec‐15 small interfering RNA (siS15), and its association with immunotherapy response were investigated. The association between Siglec‐15 and CD8+ programmed cell death 1 (PD‐1)+ T cells was analyzed in a HNSCC patient cohort. Results A total of 178 metabolites showed significant dysregulation in HNSCC, including carbohydrates, lipids and lipid‐like molecules, and amino acids. Among these, amino acid metabolism was the most significantly altered, especially Kyn, which promoted tumor proliferation and metastasis. In addition, most immune checkpoint molecules were upregulated in Kyn‐high patients based on RNA‐sequencing. Furthermore, tumor‐derived Kyn was transferred into CD8+ T cells and induced T cell functional exhaustion, and blocking Kyn transporters restored its killing activity. Accroding to the results, mechanistically, Kyn transcriptionally regulated the expression of Siglec‐15 via aryl hydrocarbon receptor (AhR), and overexpression of Siglec‐15 promoted immune escape by suppressing T cell infiltration and activation. Targeting AhR in vivo reduced Kyn‐mediated Siglec‐15 expression and promoted intratumoral CD8+ T cell infiltration and killing capacity. Finally, a NH2‐modified mesoporous silica nanoparticle was designed to deliver siS15, which restored CD8+ T cell function status and enhanced anti‐PD‐1 efficacy in tumor‐bearing immunocompetent mice. Clinically, Siglec‐15 was positively correlated with AhR expression and CD8+PD‐1+ T cell infiltration in HNSCC tissues. Conclusions The findings describe the metabolic landscape of HNSCC comprehensively and reveal that the Kyn/Siglec‐15 axis may be a novel potential immunometabolism mechanism, providing a promising therapeutic strategy for cancers.

Abstract A generation method of new metric in the case of static spherically symmetric space-time is derived. Using this approach, we construct a metric which describes Euler–Heisenberg black hole surrounded by perfect fluid dark matter and investigate its optical and thermodynamic properties. We found that radius of shadow will increase with the increase of dark matter effect, and more strong dark matter will diminish the light intensity of accretion disk generally. Moreover, in thermodynamics, when quantum electrodynamic parameter is positive, there will be a critical value of dark matter parameter, which determine the number of black hole’s critical points.

Abstract Biochar can potentially reduce heavy metals (HMs) mobility and bioavailability during composting. However, siderophores secreted by functional microbes might lead to the re-mobilization of metals like Cu and Zn. Therefore, this study intended to explore the impacts of Mikania micrantha Kunth (MM) and MM-derived biochar (MMB) in the reduction of Cu and Zn bioavailability, and siderophore-related gene abundances during composting. Compared with MM and corn straw (CS) composts, a significant decline was noticed in the extractable and reducible Cu [(2.3 mg kg−1 + 12.1 mg kg−1), and (3.3 mg kg−1 + 14.6 mg kg−1)], and Zn [(103.1 mg kg−1 + 110.1 mg kg−1), and (109.6 mg kg−1 + 117.2 mg kg−1)] in MMB and corn straw biochar (CSB) composts, respectively. Besides, the lowest relative abundance of HMs-resistant bacteria particularly Corynebacterium (0.40%), Pseudomonas (0.46%), and Enterobacter (0.47%), was noted in MMB compost. Also, a significant increase in sesquiterpenoid and triterpenoid biosynthesis abundance (5.77%) accompanied by a reduction in the abundance of clusters related to siderophore transport, and siderophore transmembrane transporter activity was detected in MMB compost. Multivariate analysis labeled temperature, moisture content, total organic carbon, Corynebacterium, and Bacillus as the primary factors significantly correlated with the Cu and Zn bioavailability (− 0.90 ≤ r ≤ 0.90, P

Pericentric inversion of chromosome 9 (inv[9]) is a common chromosomal structural variant, but its impact on clinical outcomes remains debated. The screening criteria of sperm banks are rarely mentioned to individuals with inv(9). In this study, we evaluated the fertility of sperm donors with inv(9) who met eligibility criteria for sperm banks (inv[9]-eligible donors). From March 2004 to May 2022, chromosomal analysis of 16 124 sperm donors at CITIC-Xiangya Human Sperm Bank in Hunan Province (Changsha, China) found that 251 (1.6%) had chromosome variations, with inv(9) being the most prevalent at 1.1%. All 169 inv(9)-eligible donors were contacted to collect fertility outcome data, along with 206 eligible donors without inv(9) as controls. In addition, semen samples from inv(9)-eligible donors and eligible donors underwent assessments of sperm fluorescence in situ hybridization (FISH), mitochondrial membrane potential, DNA fragmentation index, acrosome integrity, reactive oxygen species (ROS), and sperm morphology. Results showed that inv(9) did not significantly increase reproductive risks overall. Despite detecting ROS level differences, the clinical impact may be insignificant. This study provides new data on the inv(9) population that can serve as a valuable reference for decision-making by sperm banks as well as for genetic counseling and clinical guidance for individuals carrying inv(9) variant.

Abstract Background Seasonal freeze‒thaw (FT) processes alter soil formation and cause changes in soil microbial communities, which regulate the decomposition of organic matter in alpine ecosystems. Soil aggregates are basic structural units and play a critical role in microbial habitation. However, the impact of seasonal FT processes on the distribution of microbial communities associated with soil pores in different aggregate fractions under climate change has been overlooked. In this study, we sampled soil aggregates from two typical alpine ecosystems (alpine meadow and alpine shrubland) during the seasonal FT processes (UFP: unstable freezing period, SFP: stable frozen period, UTP: unstable thawing period and STP: stable thawed period). The phospholipid fatty acid (PLFA) method was used to determine the biomass of living microbes in different aggregate fractions. Results The microbial biomass of 0.25–2 mm and 0.053–0.25 mm aggregates did not change significantly during the seasonal FT process while the microbial biomass of > 2 mm aggregates presented a significant difference between the STP and UTP. Bacterial communities dominated the microbes in aggregates, accounting for over 80% of the total PLFAs. The microbial communities of soil aggregates in the surface layer were more sensitive to the seasonal FT process than those in other soil layers. In the thawing period, Gram positive bacteria (GP) was more dominant. In the freezing period, the ratio of Gram-positive to Gram-negative bacterial PLFAs (GP/GN) was low because the enrichment of plant litter facilitated the formation of organic matter. In the freezing process, pores of 30–80 μm (mesopores) favored the habitation of fungal and actinobacterial communities while total PLFAs and bacterial PLFAs were negatively correlated with mesopores in the thawing process. Conclusions The freezing process caused a greater variability in microbial biomass of different aggregate fractions. The thawing process increased the differences in microbial biomass among soil horizons. Mesopores of aggregates supported the habitation of actinobacterial and fungal communities while they were not conducive to bacterial growth. These findings provide a further comprehension of biodiversity and accurate estimation of global carbon cycle.

IntroductionWith the continued prevalence of COVID-19, repeated infection caused by SARS-CoV-2 has become common. However, studies on immune persistence post Omicron XBB reinfection are limited.MethodsWe prospectively studied the durability and cross-reactivity of neutralizing antibodies (NAbs) and T cell responses among 20 subjects who suffered Omicron BA.5 infection with or without Omicron XBB reinfection over 6-month through the pseudovirus neutralization test and the fluorospot assay.ResultsNAbs against EG.5.1, BA.2.86, and JN.1 subvariants were decreased and undetectable at 6-month post Omicron BA.5 infection, while those elicited by Omicron XBB reinfection were significant increased and remained detectable against all detected variants within 6-month. Furthermore, in subjects with Omicron XBB reinfection, memory T cell responses could cross-recognized wild-type and Omicron spike peptides and reached peak at 3-month. Interestingly, comparable robust T cell responses were observed among non-seroconverted subjects post Omicron XBB exposure.ConclusionThough the NAbs against various emerging Omicron subvariants elicited by Omicron XBB reinfection can persist for at least 6-month, the HCWs should strengthen personal protection and timely be immunized with updated vaccines upon current circulating variants or conserved T epitope.

Natriuretic peptide receptor-C (NPR-C) is highly expressed in adipose tissues and regulates obesity-related diseases; however, the detailed mechanism remains unknown. In this research, we aimed to explore the potential role of NPR-C in cold exposure and high-fat/high-sugar (HF/HS) diet-induced metabolic changes, especially in regulating white adipose tissue (WAT) mitochondrial function. Our findings showed that NPR-C expression, especially in epididymal WAT (eWAT), was reduced after cold exposure. Global Npr3 (gene encoding NPR-C protein) deficiency led to reduced body weight, increased WAT browning, thermogenesis, and enhanced expression of genes related to mitochondrial biogenesis. RNA-sequencing of eWAT showed that Npr3 deficiency enhanced the expression of mitochondrial respiratory chain complex genes and promoted mitochondrial oxidative phosphorylation in response to cold exposure. In addition, Npr3 KO mice were able to resist obesity induced by HF/HS diet. Npr3 knockdown in stromal vascular fraction (SVF)-induced white adipocytes promoted the expression of proliferator-activated receptor gamma coactivator 1α (PGC1α), uncoupling protein one (UCP1), and mitochondrial respiratory chain complexes. Mechanistically, NPR-C inhibited cGMP and calcium signaling in an NPR-B-dependent manner but suppressed cAMP signaling in an NPR-B-independent manner. Moreover, Npr3 knockdown induced browning via AKT and p38 pathway activation, which were attenuated by Npr2 knockdown. Importantly, treatment with the NPR-C-specific antagonist, AP-811, decreased WAT mass and increased PGC-1α, UCP1, and mitochondrial complex expression. Our findings reveal that NPR-C deficiency enhances mitochondrial function and energy expenditure in white adipose tissue, contributing to improved metabolic health and resistance to obesity.

Summary: Sepsis-induced arrhythmia, linked to sudden cardiac death, is associated with gut microbiota, though the exact relationship is unclear. This study aimed to elucidate the relationship between Cronobacter sakazakii (C. sakazakii) and arrhythmia. The relative abundance of C. sakazakii was increased in cecal ligation and puncture (CLP)-induced septic mice. Live C. sakazakii, supernatant, and outer membrane vesicles (OMVs) resulted in premature ventricular beat (PVB), sinus arrhythmia (SA), and increased arrhythmia and mortality in sepsis model through dysregulated ion channel proteins. Moreover, short-chain fatty acids (SCFAs) showed antibacterial effects in vitro. We confirmed sodium acetate (C2) and sodium butyrate (C4) protect from C. sakazakii-induced arrhythmia, and C2 and C4 protected from septic arrhythmia by activating free fatty acid receptor 2 and 3 (FFAR2 and FFAR3) in mice. These findings point to how C. sakazakii’s OMVs trigger arrhythmia, and SCFAs may be a treatment for septic arrhythmia.

Zearalenone (ZEN) has been shown to cause reproductive damage by inducing oxidative stress. Astaxanthin and L-carnitine are widely used to alleviate oxidative stress and promote sperm maturation. However, it remains uncertain whether they are effective in mitigating spermatogenesis disorders induced by ZEN. This study aimed to investigate the therapeutic efficacy and potential mechanisms of Vigor King (Vig), a compound preparation primarily consisting of astaxanthin and L-carnitine, in alleviating ZEN-induced spermatogenesis disorders. In the experiment, mice received continuous oral gavage of ZEN (80 μg/kg) for 35 days, accompanied by a rescue strategy with Vig (200 mg/kg). The results showed that Vig effectively reduced the negative impact on semen quality and improved the structural and functional abnormalities of the seminiferous epithelium caused by ZEN. Additionally, the accumulation of reactive oxygen species (ROS), DNA double-strand breaks, apoptosis, and autophagy abnormalities were all significantly ameliorated. Intriguingly, the GSK3β-dependent BTRC-NRF2 signaling pathway was found to play an important role in this process. Furthermore, testing of offspring indicated that Vig could extend its protective effects to the next generation, effectively combating the transgenerational toxic effects of ZEN. In summary, our research suggests that Vig supplementation holds considerable promise in alleviating spermatogenesis disorders induced by zearalenone.

Aim of the study: To analyze the progress in Mongolian medicine and medicinal materials and to highlight its development process, emerging trends, and hotspots. Materials and methods: Papers on Mongolian medicine and medicinal materials from January 2000 to May 2022 were retrieved from the China National Knowledge Infrastructure (CNKI) database. Using the collaboration network analysis of CiteSpace V and VOSviewer software, the cooperation among individuals and institutions in the field of scientific research was analyzed. The functions of frequency analysis, cluster analysis, and burst analysis were employed to conduct bibliometric analysis on research hotspots and trends in the field of Mongolian medicine research. Furthermore, the data visualization function was utilized to clearly display data trends and changes. Results: A total of 8362 papers on Mongolian medicine medicinal materials from CNKI were identified and analyzed.The research on Mongolian medicine has gone through three stages: the initial stage, the exploratory stage, and the developmental stage. The top two institutions in the number of papers are Inner Mongolia Medical University and Inner Mongolia University for Nationalities. Bagenna from Inner Mongolia Medical University is the author with the most papers. “clinical efficacy”, “clinical research”, and “quality standards” were the most frequently used keywords. Research in the field of Mongolian medicine has focused on several diseases, including skeletal system disorders, cardiovascular diseases, and digestive system disorders. Conclusion: Since 2000, there have been growing attention and efforts made in the field of Mongolian medicine and medicinal materials. The research in the field of Mongolian medicine had undergone three stages, namely the initial stage, the exploratory stage, and the developmental stage. The focus shifted from basic research such as the analysis of medicinal ingredients in Mongolian herbs to the application-oriented directions of traditional treatment techniques and advantageous diseases in Mongolian medicine. To make breakthroughs in this field, further research is needed to improve the persuasiveness and authority of Mongolian medicine and medicinal materials in terms of mechanism, standardization, and safety, to promote the development of Mongolian medicine and medicinal materials.

Background: Previous observational studies have investigated the correlation between calcium homeostasis modulator levels and endometriosis risk. Yet, the genetic association between body calcium homeostasis and endometriosis risk remains to be elucidated. Methods: Four tiers of Mendelian randomization (MR) analysis were conducted, as follows: (1) single univariate MR and (2) multivariate MR to evaluate the correlation between calcium homeostasis regulators and endometriosis; (3) inverse MR to probe the influence of endometriosis on body calcium homeostasis; (4) two-sample MR to scrutinize the connection between calcium levels and endometriosis categories. Results: The two-sample MR analysis unveiled a robust positive correlation between genetically inferred calcium levels and endometriosis risk (IVW: OR = 1.15, 95 % CI: 1.02–1.29, p = 0.018). The MVMR analysis corroborated that the positive correlation of calcium levels with endometriosis persisted after adjusting for 25(OH)D and PTH. The inverse MR analysis disclosed a significant association between endometriosis and 25(OH)D (β = 0.01, 95 % CI: 0.00–0.02, p = 0.007) and calcium (β = 0.02, 95 % CI: 0.00–0.04, p = 0.035). The two-sample MR analysis further demonstrated that calcium levels were positively linked solely to endometriosis of uterus (i.e. adenomyosis, IVW: OR = 1.23, 95 % CI: 1.01–1.49, p = 0.038), with no evidence of a influence on other endometriosis categories. Conclusions: This study, employing various types of MR, offers some genetic evidence for the relationship between calcium homeostasis and endometriosis, augmenting the current comprehension of the complex association between the two and suggesting that calcium levels are a risk factor for endometriosis. These findings provide a unique genetic perspective that may spur further investigation and may inform future strategies for managing patients with endometriosis.

Abstract Background Root caries are prevalent issues that affect dental health, particularly among elderly individuals with exposed root surfaces. Fluoride therapy has shown effectiveness in preventing root caries, but limited studies have addressed its cost-effectiveness in elderly persons population. This study aimed to evaluate the cost-effectiveness of a fluoride treatment program for preventing root caries in elderly persons within the context of Chinese public healthcare. Methods A Markov simulation model was adopted for the cost-effectiveness analysis in a hypothetical scenario from a healthcare system perspective. A 60-year-old subject with 23 teeth was simulated for 20 years. A 5% sodium fluoride varnish treatment was compared with no preventive intervention in terms of effectiveness and cost. Tooth years free of root caries were set as the effect. Transition probabilities were estimated from the data of a community-based cohort and published studies, and costs were based on documents published by the government. The incremental cost-effectiveness ratio (ICER) was calculated to evaluate cost-effectiveness. Univariate and probabilistic sensitivity analyses were performed to evaluate the influence of data uncertainty. Results Fluoride treatment was more effective (with a difference of 10.20 root caries-free tooth years) but also more costly (with a difference of ¥1636.22). The ICER was ¥160.35 per root caries-free tooth year gained. One-way sensitivity analysis showed that the risk ratio of root caries in the fluoride treatment group influenced the result most. In the probabilistic sensitivity analysis, fluoride treatment was cost-effective in 70.5% of the simulated cases. Conclusions Regular 5% sodium fluoride varnish application was cost-effective for preventing root caries in the elderly persons in most scenarios with the consideration of data uncertainty, but to a limited extent. Improved public dental health awareness may reduce the incremental cost and make the intervention more cost-effective. Overall, the study shed light on the economic viability and impact of such preventive interventions, providing a scientific basis for dental care policies and healthcare resource allocation.

Abstract High drug development costs and the limited number of new annual drug approvals increase the need for innovative approaches for drug effect prediction. Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the cause of coronavirus disease 2019 (COVID‐19), led to a global pandemic with high morbidity and mortality. Although effective preventive measures exist, there are few effective treatments for hospitalized patients with SARS‐CoV‐2 infection. Drug repurposing and drug effect prediction are promising strategies that could shorten development time and reduce costs compared with de novo drug discovery. In this work, we present a machine learning framework to integrate a variety of target network features and physicochemical properties of compounds, and analyze their influence on the therapeutic effects for SARS‐CoV‐2 infection and on host cell cytotoxic effects. Random forest models trained on compounds with known experimental effects on SARS‐CoV‐2 infection and subsequent feature importance analysis based on Shapley values provided insights into the determinants of drug efficacy and cytotoxicity, which can be incorporated into novel drug discovery approaches. Given the complexity of molecular mechanisms of drug action and limited sample sizes, our models achieve a reasonable mean area under the receiver operating characteristic curve (ROC‐AUC) of 0.73 on an unseen validation set. To our knowledge, this is the first work to incorporate a combination of network and physicochemical features of compounds into a machine learning model to predict drug effects on SARS‐CoV‐2 infection. Our systems pharmacology–based machine learning framework can be used to classify other existing drugs for SARS‐CoV‐2 infection and can easily be adapted to drug effect prediction for future viral outbreaks.

Background and purpose: Acute kidney injury (AKI) is a common serious complication in sepsis patients with a high mortality rate. This study aimed to develop and validate a predictive model for sepsis associated acute kidney injury (SA-AKI). Methods: In our study, we retrospectively constructed a development cohort comprising 733 septic patients admitted to eight Grade-A tertiary hospitals in Shanghai from January 2021 to October 2022. Additionally, we established an external validation cohort consisting of 336 septic patients admitted to our hospital from January 2017 to December 2019. Risk predictors were selected by LASSO regression, and a corresponding nomogram was constructed. We evaluated the model’s discrimination, precision and clinical benefit through receiver operating characteristic (ROC) curves, calibration plots, decision curve analysis (DCA) and clinical impact curves (CIC) in both internal and external validation. Results: AKI incidence was 53.2% in the development cohort and 48.2% in the external validation cohort. The model included five independent indicators: chronic kidney disease stages 1 to 3, blood urea nitrogen, procalcitonin, D-dimer and creatine kinase isoenzyme. The AUC of the model in the development and validation cohorts was 0.914 (95% CI, 0.894–0.934) and 0.923 (95% CI, 0.895–0.952), respectively. The calibration plot, DCA, and CIC demonstrated the model’s favorable clinical applicability. Conclusion: We developed and validated a robust nomogram model, which might identify patients at risk of SA-AKI and promising for clinical applications.

ABSTRACTVaccination strategies that can induce a broad spectrum immune response are important to enhance protection against SARS-CoV-2 variants. We conducted a randomized, double-blind and parallel controlled trial to evaluate the safety and immunogenicity of the bivalent (5×1010viral particles) and B.1.1.529 variant (5×1010viral particles) adenovirus type-5 (Ad5) vectored COVID-19 vaccines administrated via inhalation. 451 eligible subjects aged 18 years and older who had been vaccinated with three doses inactivated COVID-19 vaccines were randomly assigned to inhale one dose of either B.1.1.529 variant Ad5 vectored COVID-19 vaccine (Ad5-nCoVO-IH group, N=150), bivalent Ad5 vectored COVID-19 vaccine (Ad5-nCoV/O-IH group, N=151), or Ad5 vectored COVID-19 vaccine (5×1010viral particles; Ad5-nCoV-IH group, N=150). Adverse reactions reported by 37 (24.67%) participants in the Ad5-nCoVO-IH group, 28 (18.54%) in the Ad5-nCoV/O-IH group, and 26 (17.33%) in the Ad5-nCoV-IH group with mainly mild to moderate dry mouth, oropharyngeal pain, headache, myalgia, cough, fever and fatigue. No serious adverse events related to the vaccine were reported. Investigational vaccines were immunogenic, with significant difference in the GMTs of neutralizing antibodies against Omicron BA.1 between Ad5-nCoV/O-IH (43.70) and Ad5-nCoV-IH (29.25) at 28 days after vaccination (P=0.0238). The seroconversion rates of neutralizing antibodies against BA.1 in Ad5-nCoVO-IH, Ad5-nCoV/O-IH, and Ad5-nCoV-IH groups were 56.00%, 59.60% and 48.67% with no significant difference among the groups. Overall, the investigational vaccines were demonstrated to be safe and well tolerated in adults, and was highly effective in inducing mucosal immunities in addition to humoral and cellular immune responses defending against SARS-CoV-2 variants.Trial registration: Chictr.org identifier: ChiCTR2200063996.

IntroductionThe research on plant leaf morphology is of great significance for understanding the development and evolution of plant organ morphology. As a relict plant, the G. biloba leaf morphology typically exhibits bifoliate and peltate forms. However, throughout its long evolutionary history, Ginkgo leaves have undergone diverse changes.MethodsThis study focuses on the distinct “trumpet” leaves and normal fan-shaped leaves of G. biloba for analysis of their phenotypes, photosynthetic activity, anatomical observations, as well as transcriptomic and metabolomic analyses.ResultsThe results showed that trumpet-shaped G. biloba leaves have fewer cells, significant morphological differences between dorsal and abaxial epidermal cells, leading to a significantly lower net photosynthetic rate. Additionally, this study found that endogenous plant hormones such as GA, auxin, and JA as well as metabolites such as flavonoids and phenolic acids play roles in the formation of trumpet-shaped G. biloba leaves. Moreover, the experiments revealed the regulatory mechanisms of various key biological processes and gene expressions in the trumpet-shaped leaves of G. biloba.DiscussionDifferences in the dorsal and abdominal cells of G. biloba leaves can cause the leaf to curl, thus reducing the overall photosynthetic efficiency of the leaves. However, the morphology of plant leaves is determined during the primordia leaf stage. In the early stages of leaf development, the shoot apical meristem (SAM) determines the developmental morphology of dicotyledonous plant leaves. This process involves the activity of multiple gene families and small RNAs. The establishment of leaf morphology is complexly regulated by various endogenous hormones, including the effect of auxin on cell walls. Additionally, changes in intracellular ion concentrations, such as fluctuations in Ca2+ concentration, also affect cell wall rigidity, thereby influencing leaf growth morphology.

Background and aimsRoot-knot nematodes (RKN; Meloidogyne spp.) are among the highly prevalent and significantly detrimental pathogens that cause severe economic and yield losses in crops. Currently, control of RKN primarily relies on the application of chemical nematicides but it has environmental and public health concerns, which open new doors for alternative methods in the form of biological control.MethodsIn this study, we investigated the nematicidal and attractive activities of an endophytic strain WF01 against Meloidogyne incognita in concentration-dependent experiments. The active nematicidal metabolite was extracted in the WF01 crude extract through the Sephadex column, and its structure was identified by nuclear magnetic resonance and mass spectrometry data.ResultsThe strain WF01 was identified as Aspergillus tubingensis based on morphological and molecular characteristics. The nematicidal and attractive metabolite of A. tubingensis WF01 was identified as oxalic acid (OA), which showed solid nematicidal activity against M. incognita, having LC50 of 27.48 μg ml–1. The Nsy-1 of AWC and Odr-7 of AWA were the primary neuron genes for Caenorhabditis elegans to detect OA. Under greenhouse, WF01 broth and 200 μg ml–1 OA could effectively suppress the disease caused by M. incognita on tomatoes respectively with control efficiency (CE) of 62.5% and 70.83%, and promote plant growth. In the field, WF01-WP and 8% OA-WP formulations showed moderate CEs of 51.25%–61.47% against RKN in tomato and tobacco. The combined application of WF01 and OA resulted in excellent CEs of 66.83% and 69.34% toward RKN in tomato and tobacco, respectively. Furthermore, the application of WF01 broth or OA significantly suppressed the infection of J2s in tomatoes by upregulating the expression levels of the genes (PAL, C4H, HCT, and F5H) related to lignin synthesis, and strengthened root lignification.ConclusionAltogether, our results demonstrated that A. tubingensis WF01 exhibited multiple weapons to control RKN mediated by producing OA to lure and kill RKN in a concentration-dependent manner and strengthen root lignification. This fungus could serve as an environmental bio-nematicide for managing the diseases caused by RKN.

Background: Recently, male fertility preservation before cancer treatment has become more prevalent. The research in this field has progressed over time, with some studies having a major impact and providing guidance for further research. However, the trends and hotspots of research on fertility preservation in male cancer patients may have changed; exploring them is essential for relevant research progress. Design: We extracted relevant studies from the Web of Science Core Collection database, capturing information on the countries of study, affiliations, authors, keywords, as well as co-citations of references and journals. To identify publication trends, research strengths, key subjects, prominent topics, and emerging areas, we conducted a bibliometric analysis using CiteSpace. Results: We included 3201 articles on fertility preservation in male cancer patients published over January 1999 to December 2023 were included. Although the relevant research growth rate was slow initially, the number of publications increased annually. Of all study countries, the United States, Germany, and Japan reported the earliest studies; the United States published the highest number of relevant studies. The US institutions remained at the forefront for all 25 years, and the US researcher Ashok Agarwal published the most articles. Literature co-citation analyses indicated a transformation in the study participants; they comprised a younger demographic (i.e., a large number of adolescent male patients underwent fertility preservation); moreover, fertility preservation techniques evolved from sperm cryopreservation to testicular tissue cryopreservation. Research on reproductive outcomes of sperm cryopreservation was the recent hotspot in male fertility preservation research, and the impact of immunotherapy and checkpoint inhibitors on male fertility requires further research. Conclusions: Male fertility preservation will be a major future research focus, with closer connections and collaborations between countries and organizations. Our results present the historical data on the development of research on male fertility preservation in cancer patients, providing relevant insights for future research and development in this study area.

ABSTRACT Numerous studies have supported that nonalcoholic fatty liver disease (NAFLD) is highly associated with gut microbiota dysbiosis. Ling-Gui-Zhu-Gan decoction (LG) has been clinically used to treat NAFLD, but the underlying mechanism remains unknown. This study investigated the therapeutic effect and mechanisms of LG in mice with NAFLD induced by a high-fat diet (HD). An HD-induced NAFLD mice model was established to evaluate the efficacy of LG followed by biochemical and histopathological analysis. Metagenomics, metabolomics, and transcriptomics were used to explore the structure and metabolism of the gut microbiota. LG significantly improved hepatic function and decreased lipid droplet accumulation in HD-induced NAFLD mice. LG reversed the structure of the gut microbiota that is damaged by HD and improved intestinal barrier function. Meanwhile, the LG group showed a lower total blood bile acids (BAs) concentration, a shifted BAs composition, and a higher fecal short-chain fatty acids (SCFAs) concentration. Furthermore, LG could regulate the hepatic expression of genes associated with the primary BAs biosynthesis pathway and peroxisome proliferator-activated receptor (PPAR) signaling pathway. Our study suggested that LG could ameliorate NAFLD by altering the structure and metabolism of gut microbiota, while BAs and SCFAs are considered possible mediating substances.IMPORTANCEUntil now, there has still been no study on the gut microbiota and metabolomics of Ling-Gui-Zhu-Gan decoction (LG) in nonalcoholic fatty liver disease (NAFLD) mouse models. Our study is the first to report on the reshaping of the structure and metabolism of the gut microbiota by LG, as well as explore the potential mechanism underlying the improvement of NAFLD. Specifically, our study demonstrates the potential of gut microbial-derived short-chain fatty acids (SCFAs) and blood bile acids (BAs) as mediators of LG therapy for NAFLD in animal models. Based on the results of transcriptomics, we further verified that LG attenuates NAFLD by restoring the metabolic disorder of BAs via the up-regulation of Fgf15/FXR in the ileum and down-regulation of CYP7A1/FXR in the liver. LG also reduces lipogenesis in NAFLD mice by mediating the peroxisome proliferator-activated receptor (PPAR) signaling pathway, which then contributes to reducing hepatic inflammation and improving intestinal barrier function to treat NAFLD.

Microalgae has great potential in carbon sequestration and production of biofuel even with a low concentrations of CO2. In this paper, an Andrews based microalgae growth kinetic model and a novel and multiple nutrient supplementary scheme that significantly extends the carbon sequestration period and enhances growth rates of microalgae are proposed. First, the correlation between nutrient concentration and microalgal growth is constructed experimentally. The advanced growth kinetic model incorporating nitrogen and phosphorus consumption is developed. Then, the optimum cultivation conditions including initial nutrients concentration, nutrients supplementary interval and daily nutrients supplementary quantities are obtained in the conical flask reactor. The findings led to a novel nutrient supplementation strategy that initiates with a 0.2BC concentration, followed by a 0.3BC addition at 100 h, with subsequent supplements every 72 h. After adopting this supplementary strategy, the microalgae growth rate is increased by 42.9 % and the carbon sequestration rate is increased by 56.2 % compared with that of the original microalgae cultivation method in one cultivation cycle. Finally, the universal microalgae nutrients supplementary model is proposed in a piecewise model. It can be concluded from the model that in the first cultivation period, microalgae needs a higher affinity for nutrients and after nutrients supplementary, the sensitivity to nutrient inhibition is reduced. The paper is significantly helpful to improve the sustainability of the microalgae growth rate and the carbon sequestration rate.

Background Clinical trials repurposing pulmonary arterial hypertension (PAH) therapies to patients with lung disease- or hypoxia-pulmonary hypertension (PH) (classified as World Health Organization Group 3 PH) have failed to show a consistent benefit. However, Group 3 PH clinical heterogeneity suggests robust phenotyping may inform detection of treatment-responsive subgroups. We hypothesised that cluster analysis would identify subphenotypes with differential responses to oral PAH therapy. Methods Two k-means analyses were performed on a national cohort of US veterans with Group 3 PH; an inclusive model (I) of all treated patients (n=196) and a haemodynamic model (H) limited to patients with right heart catheterisations (n=112). The primary outcome was organ failure or all-cause mortality by cluster. An exploratory analysis evaluated within-cluster treatment effects. Results Three distinct clusters of Group 3 PH patients were identified. In the inclusive model (C1I n=43, 21.9%; C2I n=102, 52.0%; C3I n=51, 26.0%), lung disease and spirometry drove cluster assignment. By contrast, in the haemodynamic model (C1H n=44, 39.3%; C2H n=43, 38.4%; C3H n=25, 22.3%), right heart catheterisation data surpassed the importance of lung disease and spirometry. In the haemodynamic model, compared to C3H, C1H experienced the greatest hazard for respiratory failure or death (HR 6.1, 95% CI 3.2–11.8). In an exploratory analysis, cluster determined treatment response (p=0.006). Conclusions regarding within-cluster treatment responses were limited by significant differences between select variables in the treated and untreated groups. Conclusions Cluster analysis identifies novel real-world subphenotypes of Group 3 PH patients with distinct clinical trajectories. Future studies may consider this methodological approach to identify subgroups of heterogeneous patients that may be responsive to existing pulmonary vasodilatory therapies.

This study performs a series of mechanical tests, quasi-static and dynamic, on CuCoCrFeNi high-entropy alloys (HEAs) using an experimental setup to explore the performance of Cu-based HEAs in shaped charges. It derives the parameters for the Johnson–Cook constitutive model through fitting. A static penetration test is conducted with a small cone angle and a thin-walled liner. The outcomes are then compared to simulation data generated by AUTODYN software. They indicated that the CuCoCrFeNi HEA liner can produce a shaped-charge jet that achieves both penetration and reaming effects when driven by explosives. In a C45 steel target, the diameter of the penetration hole is 46.43% of the charge diameter. The experimental findings align closely with the simulations, indicating discrepancies of less than 12.13% in the diameters of the penetration holes and ∼2.56% in penetration depths. Hence, the numerical simulation approach and its parameters can be utilized to investigate the penetration characteristics of Cu-based HEA jets, providing a groundwork for future optimization of HEA-shaped charge designs.

Abstract Social insects are prone to pathogen infection because of high exposure rates from social interactions. However, it remains unclear whether queens have enhanced pathogen resistance, because reproduction is largely confined to queens. Here, we used a natural host–pathogen system, the subterranean termite Reticulitermes chinensis and the entomopathogenic fungus Metarhizium anisopliae, to investigate the differences in allogrooming, locomotion, and immune gene expression between queens and workers against pathogen infection. We found that fungal infection significantly reduced survival in both queens and workers. Infected queens received significantly more grooming time from sanitary nestmates than infected workers, but they returned much less grooming time to sanitary nestmates than infected workers. Infection resulted in a reduction in the average locomotion speed and distance of queens but had no effect on worker locomotion. Infection resulted in upregulated expression of two immune genes (termicin and transferrin), two antioxidant genes (CAT and SOD), and phosphate genes CYP450 in queens but not in workers. Our results indicated that eusocial termites evolved strategies that prioritize the reproductive castes' welfare in defending against the pathogen infection to ensure continued reproduction and colony persistence.

Abstract Leprosy and psoriasis rarely coexist, the specific molecular mechanisms underlying their mutual exclusion have not been extensively investigated. This study aimed to reveal the underlying mechanism responsible for the mutual exclusion between psoriasis and leprosy. We obtained leprosy and psoriasis data from ArrayExpress and GEO database. Differential expression analysis was conducted separately on the leprosy and psoriasis using DEseq2. Differentially expressed genes (DEGs) with opposite expression patterns in psoriasis and leprosy were identified, which could potentially involve in their mutual exclusion. Enrichment analysis was performed on these candidate mutually exclusive genes, and a protein–protein interaction (PPI) network was constructed to identify hub genes. The expression of these hub genes was further validated in an external dataset to obtain the critical mutually exclusive genes. Additionally, immune cell infiltration in psoriasis and leprosy was analyzed using single-sample gene set enrichment analysis (ssGSEA), and the correlation between critical mutually exclusive genes and immune cells was also examined. Finally, the expression pattern of critical mutually exclusive genes was evaluated in a single-cell transcriptome dataset. We identified 1098 DEGs in the leprosy dataset and 3839 DEGs in the psoriasis dataset. 48 candidate mutually exclusive genes were identified by taking the intersection. Enrichment analysis revealed that these genes were involved in cholesterol metabolism pathways. Through PPI network analysis, we identified APOE, CYP27A1, FADS1, and SOAT1 as hub genes. APOE, CYP27A1, and SOAT1 were subsequently validated as critical mutually exclusive genes on both internal and external datasets. Analysis of immune cell infiltration indicated higher abundance of 16 immune cell types in psoriasis and leprosy compared to normal controls. The abundance of 6 immune cell types in psoriasis and leprosy positively correlated with the expression levels of APOE and CYP27A1. Single-cell data analysis demonstrated that critical mutually exclusive genes were predominantly expressed in Schwann cells and fibroblasts. This study identified APOE, CYP27A1, and SOAT1 as critical mutually exclusive genes. Cholesterol metabolism pathway illustrated the possible mechanism of the inverse association of psoriasis and leprosy. The findings of this study provide a basis for identifying mechanisms and therapeutic targets for psoriasis.

Abstract N-methyl-D-aspartate receptors (NMDARs) are ligand-gated, voltage-dependent channels of the ionotropic glutamate receptor family. The present study explored whether NMDAR activation induced ferroptosis in vascular endothelial cells and its complicated mechanisms in vivo and in vitro. Various detection approaches were used to determine the ferroptosis-related cellular iron content, lipid reactive oxygen species (LOS), siRNA molecules, RNA-sequence, MDA, GSH, and western blotting. The AMPK activator Acadesine (AICAR), HMGB1 inhibitor glycyrrhizin (GLY), PP2A inhibitor LB-100, and NMDAR inhibitor MK801 were used to investigate the involved in vivo and in vitro pathways. The activation of NMDAR with L-glutamic acid (GLU) or NMDA significantly promoted cellular ferroptosis, iron content, MDA, and the PTGS2 expression, while decreasing GPX4 expression and GSH concentration in human umbilical vein endothelial cells (HUVECs), which was reversed by ferroptosis inhibitors Ferrostatin-1(Fer-1), Liproxstatin-1 (Lip-1), or Deferoxamine (DFO). RNA-seq revealed that ferroptosis and SLC7A11 participate in NMDA or GLU-mediated NMDAR activation. The PP2A-AMPK-HMGB1 pathway was majorly associated with NMDAR activation-induced ferroptosis, validated using the PP2A inhibitor LB-100, AMPK activator AICAR, or HMGB1 siRNA. The role of NMDAR in ferroptosis was validated in HUVECs induced with the ferroptosis activator errasin or RSL3 and counteracted by the NMDAR inhibitor MK-801. The in vivo results showed that NMDA- or GLU-induced ferroptosis and LOS production was reversed by MK-801, LB-100, AICAR, MK-801, and GLY, confirming that the PP2A-AMPK-HMGB1 pathway is involved in NMDAR activation-induced vascular endothelium ferroptosis. In conclusion, the present study demonstrated a novel role of NMDAR in endothelial cell injury by regulating ferroptosis via the PP2A-AMPK-HMGB1 pathway.

Abstract Background Sarcopenia has received increasing attention in non-small cell lung cancer (NSCLC). Red blood cell distribution width (RDW) is a significant component of the complete blood count and indicates the heterogeneity of erythrocyte volume. Little information is known about RDW in relation to sarcopenia in early-stage (IA-IIIA) NSCLC. The purpose of the present study was to investigate the association between RDW and sarcopenia risk in early-stage NSCLC patients. Methods This study included 378 patients with pathologically confirmed stage IA-IIIA NSCLC. Sarcopenia was defined by measuring the skeletal muscle index (SMI) at the eleventh thoracic vertebra level. The maximum Youden index on the receiver operating characteristic (ROC) curve was used to estimate the cutoff value for RDW to predict sarcopenia. Logistic regression analyses were carried out to assess the independent risk factors for sarcopenia in NSCLC. Results The ROC curve indicated that the best cutoff point for RDW to predict sarcopenia was 12.9 (sensitivity of 43.80% and specificity of 76.76%, respectively). Moreover, there were significant differences in hemoglobin (p

Abstract Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease worldwide. Basement membranes (BMs) are ubiquitous extracellular matrices which are affected in many diseases including DKD. Here, the authors aimed to identify BM‐related markers in DKD and explored the immune cell infiltration in this process. The expression profiles of three datasets were downloaded from the Gene Expression Omnibus database. BM‐related differentially expression genes (DEGs) were identified and Kyoto encyclopaedia of genes and genomes pathway enrichment analysis were applied to biological functions. Immune cell infiltration and immune function in the kidneys of patients with DKD and healthy controls were evaluated and compared using the ssGSEA algorithm. The association of hub genes and immune cells and immune function were explored. A total of 30 BM‐related DEGs were identified. The functional analysis showed that BM‐related DEGs were notably associated with basement membrane alterations. Crucially, BM‐related hub genes in DKD were finally identified, which were able to distinguish patients with DKD from controls. Moreover, the authors observed that laminin subunit gamma 1(LAMC1) expression was significantly high in HK2 cells treated with high glucose. Immunohistochemistry results showed that, compared with those in db/m mouse kidneys, the levels of LAMC1 in db/db mouse kidneys were significantly increased. The biomarkers genes may prove crucial for DKD treatment as they could be targeted in future DKD treatment protocols.

Abstract Background Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Unhealthy dietary habit is one of major risk factors of NAFLD. However, the associations between specific types of fish and meat consumption and NAFLD remain inconclusive. We explored the associations of fish and meat consumption with NAFLD risk in middle-aged and older Chinese. Methods We collected information on 1,862 participants aged 50 years or older from Guangzhou Biobank Cohort Study in 2009 to 2010. Fish and meat consumption was assessed using a validated food-frequency questionnaire. NAFLD was diagnosed by ultrasound. Multivariable logistic regression was used to examine the associations of fish and meat consumption with the presence of NAFLD. Results The average age was 61.0 (standard deviation = 6.5) years for the participants, 50.2% were women, and 37.2% were diagnosed with NAFLD. After adjusting for age, sex, education, family income, occupation, smoking status, drinking status, physical activity and several metabolic traits, compared with 0 serving/week (one serving = 50 g), fatty fish consumption of ≥ 3 servings/week showed higher odds of NAFLD (odds ratio (OR) and 95% confidence interval (CI): 1.64 (1.12, 2.39)). The highest (≥ 11 servings/week of red meat and poultry; ≥ 3 servings/week of processed meat) versus the lowest (0–3 servings/week of red meat and poultry; 0 serving/week of processed meat) consumption of all other types of meats, including red meat, poultry and processed meat, showed no association with NAFLD (1.17 (0.75, 1.81), 1.02 (0.42, 2.50) and 0.85 (0.50, 1.45), respectively). Aquatic and sea food, and red meat had negative indirect effects on NAFLD via systolic blood pressure and/or high-density lipoprotein cholesterol. Processed meat had positive indirect effects on NAFLD via body mass index, waist circumference, fasting plasma glucose and triglycerides. Conclusion High consumption of fatty fish was associated with higher NAFLD risk. Our results, if causal, provide evidence that limiting consumption of fatty fish can be considered as part of NAFLD lifestyle prevention and treatment.

Background The certification of immunogenicity consistency at different production scales is indispensable for the quality control of vaccines. Research design and methods A randomized, double-blind immunobridging trial in healthy adults aged 18–59 was divided into Scale A (50 L and 800 L) and Scale B (50 L and 500 L) based on vaccine manufacturing scales. Eligible participants in Scale A were randomly assigned to receive the single-dose recombinant adenovirus type-5 vectored COVID-19 vaccine (Ad5-nCoV) of different scales at a 1:1 ratio, as was Scale B. The primary endpoint was the geometric mean titer (GMT) of anti-live SARS-CoV-2-specific neutralizing antibodies (NAb) 28 days post-vaccination. Results 1,012 participants were enrolled, with 253 (25%) per group. The post-vaccination GMTs of NAb were 10.72 (95% CI: 9.43, 12.19) and 13.23 (11.64, 15.03) in Scale A 50 L and 800 L, respectively; 11.64 (10.12, 13.39) and 12.09 (10.48, 13.95) in Scale B 50 L and 500 L, respectively. GMT ratios in Scale A and B have a 95% CI of 0.67–1.5. Most adverse reactions were mild or moderate. 17 of 18 participants reported non-vaccination-related serious adverse reactions. Conclusions The Ad5-nCoV in the scale-up production of 500 L and 800 L showed consistent immunogenicity with the original 50 L production scale, respectively.

Abstract The major histocompatibility complex (MHC) genes are the most polymorphic genes in vertebrates, and their proteins play a critical role in adaptive immunity for defense against a variety of pathogens. MHC diversity was lost in many species after experiencing a decline in size. To understand the variation and evolution of MHC genes in the Siberian ibex, Capra sibirica, which has undergone a population decline, we analyzed the variation of the second exon of MHC class II DRB genes in samples collected from five geographic localities in Xinjiang, China, that belong to three diverged mitochondrial clades. Consequently, we identified a total of 26 putative functional alleles (PFAs) with 260 bp in length from 43 individuals, and found one (for 27 individuals) to three (for 5 individuals) PFAs per individual, indicating the presence of one or two DRB loci per haploid genome. The Casi-DRB1*16 was the most frequently occurring PFA, Casi-DRB1*22 was found in only seven individuals, 14 PFAs occurred once, 7 PFAs twice, implying high frequency of rare PFAs. Interestingly, more than half (15) of the PFAs were specific to clade I, only two and three PFAs were specific to clades II and III, respectively. So, we assume that the polygamy and sexual segregation nature of this species likely contributed to the allelic diversity of DRB genes. Genetic diversity indices showed that PFAs of clade II were lower in nucleotide, amino acid, and supertype diversity compared to those of the other two clades. The pattern of allele sharing and F ST values between the three clades was to some extent in agreement with the pattern observed in mitochondrial DNA divergence. In addition, recombination analyses revealed no evidence for significant signatures of recombination events. Alleles shared by clades III and the other two clades diverged 6 million years ago, and systematic neighbor grids showed Trans-species polymorphism. Together with the PAML and MEME analyses, the results indicated that the DRB gene in C. sibirica evolved under balancing and positive selection. However, by comparison, it can be clearly seen that different populations were under different selective pressures. Our results are valuable in understanding the diversity and evolution of the DRB gene in a mountain living C. sibirica and in making decisions on future long-term protection strategies.

Abstract The Omicron variant of the severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infected a substantial proportion of Chinese population, and understanding the factors underlying the severity of the disease and fatality is valuable for future prevention and clinical treatment. We recruited 64 patients with invasive ventilation for COVID-19 and performed metatranscriptomic sequencing to profile host transcriptomic profiles, plus viral, bacterial, and fungal content, as well as virulence factors and examined their relationships to 28-day mortality were examined. In addition, the bronchoalveolar lavage fluid (BALF) samples from invasive ventilated hospital/community-acquired pneumonia patients (HAP/CAP) sampled in 2019 were included for comparison. Genomic analysis revealed that all Omicron strains belong to BA.5 and BF.7 sub-lineages, with no difference in 28-day mortality between them. Compared to HAP/CAP cohort, invasive ventilated COVID-19 patients have distinct host transcriptomic and microbial signatures in the lower respiratory tract; and in the COVID-19 non-survivors, we found significantly lower gene expressions in pathways related viral processes and positive regulation of protein localization to plasma membrane, higher abundance of opportunistic pathogens including bacterial Alloprevotella, Caulobacter, Escherichia-Shigella, Ralstonia and fungal Aspergillus sydowii and Penicillium rubens. Correlational analysis further revealed significant associations between host immune responses and microbial compositions, besides synergy within viral, bacterial, and fungal pathogens. Our study presents the relationships of lower respiratory tract microbiome and transcriptome in invasive ventilated COVID-19 patients, providing the basis for future clinical treatment and reduction of fatality.

Abstract Previous studies have shown that the Hawking effect always destroys quantum correlations and the fidelity of quantum teleportation in the Schwarzschild black hole. Here, we investigate the fidelity of quantum teleportation of Dirac fields between users in Schwarzschild spacetime. We find that, with the increase of the Hawking temperature, the fidelity of quantum teleportation can monotonically increase, monotonically decrease, or non-monotonically increase, depending on the choice of the initial state, which means that the Hawking effect can create net fidelity of quantum teleportation. This striking result banishes the extended belief that the Hawking effect of the black hole can only destroy the fidelity of quantum teleportation. We also find that quantum steering cannot fully guarantee the fidelity of quantum teleportation in Schwarzschild spacetime. This new unexpected source may provide a new idea for the experimental evidence of the Hawking effect.

Abstract Quantum key distribution (QKD) holds the potential to establish secure keys over long distances. The distance of point-to-point QKD secure key distribution is primarily impeded by the transmission loss inherent to the channel. In the quest to realize a large-scale quantum network, increasing the QKD distance under current technology is of great research interest. Here we adopt the 3-intensity sending-or-not-sending twin-field QKD (TF-QKD) protocol with the actively-odd-parity-pairing method. The experiment demonstrates the feasibility of secure QKD over a 1002 km fibre channel considering the finite size effect. The secure key rate is 3.11 × 10 − 12 $3.11\times 10^{-12}$ per pulse at this distance. Furthermore, by optimizing parameters for shorter fiber distances, we conducted performance tests on key distribution for fiber lengths ranging from 202 km to 505 km. Notably, the secure key rate for the 202 km, the normal distance between major cities, reached 111.74 kbps.

Dendritic cells (DCs) are crucial in initiating and shaping both innate and adaptive immune responses. Clinical studies and experimental models have highlighted their significant involvement in various autoimmune diseases, positioning them as promising therapeutic targets. Nicotinamide (NAM), a form of vitamin B3, with its anti-inflammatory properties, has been suggested, while the involvement of NAM in DCs regulation remains elusive. Here, through analyzing publicly available databases, we observe substantial alterations in NAM levels and NAM metabolic pathways during DCs activation. Furthermore, we discover that NAM, but not Nicotinamide Mononucleotide (NMN), significantly inhibits DCs over-activation in vitro and in vivo. The suppression of DCs hyperactivation effectively alleviates symptoms of psoriasis. Mechanistically, NAM impairs DCs activation through a Poly (ADP-ribose) polymerases (PARPs)-NF-κB dependent manner. Notably, phosphoribosyl transferase (NAMPT) and PARPs are significantly upregulated in lipopolysaccharide (LPS)-stimulated DCs and psoriasis patients; elevated NAMPT and PARPs expression in psoriasis patients correlates with higher psoriasis area and severity index (PASI) scores. In summary, our findings underscore the pivotal role of NAM in modulating DCs functions and autoimmune disorders. Targeting the NAMPT-PARP axis emerges as a promising therapeutic approach for DC-related diseases.

Abstract Hyperkeratosis of the nipples and areolae (HNA) is an uncommon skin disorder with no definite aetiology. We report a case of a 16‐year‐old boy, who presented with bilateral pigmentation and thickening of the nipples and areolae, accompanied with linear brown protrusions on the anterior neck and a velvet like appearance with pigmentation on the axillary bilaterlly. Based on clinical and histopathological, and dermatoscopic findings, the diagnosis of bilateral HNA accompanied by linear nevus and acanthosis nigricans was made. The skin lesions were improved by treatment with topical calcipotriol gel.

BackgroundSystemic inflammation and glucose metabolism have been closely related to the survival of cancer patients. Therefore, we aimed to evaluate whether preoperative glucose-to-lymphocyte ratio (GLR) can be used to predict the survival of cancer patients.MethodsWe retrospectively examined 2172 cancer patients who underwent surgery from January 1, 2014, to December 31, 2016. There were 240 patients with non-small cell lung cancer (NSCLC), 378 patients with colorectal cancer (CRC), 221 patients with breast cancer (BC), 335 patients with gastric cancer (GC), 270 patients with liver cancer, 233 patients with esophageal cancer (EC), 295 patients with renal cancer, and 200 patients with melanoma. The formula for preoperative GLR calculation was as follows: GLR=glucose/lymphocyte count. The overall survival (OS) was estimated using the Kaplan-Meier method. The predictive factors for OS were determined using multivariate analysis.ResultsThe Kaplan-Meier analysis showed that the median survival time in the high-GLR group was much shorter than that of those in the low-GLR group for different cancers. Cox multivariate regression analysis reveals that preoperative GLR was an independent factor for predicting overall survival in different tumor types.ConclusionElevated preoperative GLR was remarkably associated with a poorer prognosis in patients with NSCLC, CRC, breast cancer, gastric cancer, kidney cancer, liver cancer, esophageal cancer, and melanoma. Preoperative GLR promises to be an essential predictor of survival for cancer patients.