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Abstract Knee osteoarthritis (KOA) has a high incidence among the elderly, significantly impacting their quality of life and overall health. Medial unicompartmental knee arthroplasty (UKA) is an excellent choice for treating knee single-compartment lesions, and lower limb alignment has a profound impact on medial UKA. To explore the influence of different lower limb alignments on medial UKA. In this study, we selected MR and CT data of healthy adult male knee joints to establish a complete finite element analysis (FEA) model of the knee joint. After validation, we established a finite element model of medial UKA. Subsequently, we created 60 sets of FEA models with different lower limb alignments to analyze the impact of different lower limb alignments on medial UKA. A vertical load of 1000 N was applied to the FEA models with different lower limb alignments. During the process of shifting the Mikulicz line from the midpoint of the knee joint towards the medial side, the lower limb load was primarily concentrated on the medial compartment. The stress values of the lateral meniscus, tibial cartilage, and femoral cartilage gradually decreased. ROI (region of interest) 1 and ROI 2 showed the maximum principal strain changes, while ROI 3 and ROI 4 exhibited less pronounced fluctuations, with the maximum principal strain roughly proportionally increased. During the process of shifting the Mikulicz line towards the lateral side from the midpoint of the knee joint, the stress on the lateral compartment increased observably. ROI 1, ROI 2, ROI 3, and ROI 4 showed decreased maximum principal strains, approximately inversely proportional changes, but the overall reduction was relatively small. Different lower limb alignments have a profound impact on the short- and long-term joint function after UKA. When the Mikulicz line is 10 mm inside the midpoint of the knee joint or slightly outside, there is a relatively lower risk of tibial component fractures, lower stress on the lateral compartment, and lower load on the prosthesis. During medial UKA, measures such as bone resection and prosthesis selection should be taken to ensure that the Mikulicz line is in the ideal position.

Abstract The mechanical interactions among integrated cellular structures in soft tissues dictate the mechanical behaviors and morphogenetic deformations observed in living organisms. However, replicating these multifaceted attributes in synthetic soft materials remains a challenge. In this work, we develop a smart hydrogel system featuring engineered stiff cellular patterns that induce strain-driven heterogeneous subdomains within the hydrogel film. These subdomains arise from the distinct mechanical responses of the pattern and film domains under applied mechanical forces. Unlike previous studies that incorporate reinforced inclusions into soft matrices to tailor material properties, our method manipulates the localization, integration, and interaction of these subdomain building blocks within the soft film. This enables extensive tuning of both local and global behaviors. Notably, we introduce a subdomain-interface mechanism that allows for the concurrent customization and decoupling of mechanical properties and shape transformations within a single material system—an achievement rarely accomplished with current synthetic soft materials. Additionally, our use of in-situ imaging characterizations, including full-field strain mapping via digital imaging correlation and reciprocal-space patterns through fast Fourier transform analysis of real-space pattern domains, provides rapid real-time monitoring tools to uncover the underlying principles governing tailored multiscale heterogeneities and intricate behaviors.

Abstract Background Teachers’ leadership styles have a significant impact on students’ academic performance, physical health and mental health. Authoritarian leadership, as a typical leadership style, is prevalent in the teacher community. The purpose of this study was to examine the mechanisms by which authoritarian leadership impacts students’ well-being. We also examined the mediating role of emotional exhaustion and the moderating role of narcissism. Methods This study is based on conservation of resources theory. We selected a sample of 369 students from a university in Sichuan province, collected data through two time points, and tested the data using SPSS 24.0 and AMOS 22.0. Results It was found that teachers’ authoritarian leadership negatively impacted students’ well-being and that emotional exhaustion mediated the relationship between authoritarian leadership and well-being. Narcissism not only moderated the effect of authoritarian leadership on emotional exhaustion, but also moderated the mediation role of emotional exhaustion. Conclusions Our findings enriched the research on authoritarian leadership and narcissism, and also had important practical implications for future teacher teaching in higher education.

Abstract The etiology of primary open angle glaucoma is constituted by both intraocular pressure-dependent and intraocular pressure-independent mechanisms. However, GWASs of traits affecting primary open angle glaucoma through mechanisms independent of intraocular pressure remains limited. Here, we address this gap by subtracting the genetic effects of a GWAS for intraocular pressure from a GWAS for primary open angle glaucoma to reveal the genetic contribution to primary open angle glaucoma via intraocular pressure-independent mechanisms. Seventeen independent genome-wide significant SNPs were associated with the intraocular pressure-independent component of primary open angle glaucoma. Of these, 7 are located outside known normal tension glaucoma loci, 11 are located outside known intraocular pressure loci, and 2 are novel primary open angle glaucoma loci. The intraocular pressure-independent genetic component of primary open angle glaucoma is associated with glaucoma endophenotypes, while the intraocular pressure-dependent component is associated with blood pressure and vascular permeability. A genetic risk score for the intraocular pressure-independent component of primary open angle glaucoma is associated with 26 different retinal micro-vascular features, which contrasts with the genetic risk score for the intraocular pressure-dependent component. Increased understanding of these intraocular pressure-dependent and intraocular pressure-independent components provides insights into the pathogenesis of glaucoma.

Abstract Source‐to‐sink analysis examines the effects of source areas and basin (sink) dynamics on the generation, transport, composition, distribution and deposition of sediment in modern and ancient sedimentary systems. Detrital zircon, as one of the most stable detrital minerals, its U–Pb geochronology and geochemistry is pivotal for sedimentary provenance analysis and reconstructing palaeogeography. The South China Sea (SCS), as the largest marginal sea in the Southeast Asia, is closely related to the uplift of the Tibetan Plateau and the evolution of Chinese rivers. In this study, we mainly collect published detrital zircon of Cenozoic sediments in the SCS (include Hainan and Taiwan Islands). These detrital zircon were concentrated on Cenozoic multiple episodic rift basins in the northern part of the SCS. A total of 21,760 detrital zircon U–Pb data from 293 samples and 995 detrital zircon Lu‐Hf isotope data from 22 samples were collected in this dataset, with the main study epochs being the Palaeogene and Neogene. Best ages of these grains are range from 4,691 to 10 Ma and more than half of them within age less than 500 Ma. The 176Hf/177Hf ratios of the SCS samples ranging from 0.280509 to 0.28306 and the εHf(t) values from −63.8 to 24.6. The main age group of the SCS Cenozoic sediments were at 130–95 Ma, 175–130 Ma and 265–230 Ma. The detrital zircon U–Pb age and Lu–Hf isotope data contained in this dataset is an important geological record of the sedimentary and tectonic evolution of the SCS and the evolution of rivers such as the ancient Pearl River and the ancient Red River, which can provide a basis and important clues or exploring the source of sediments in the SCS, the dynamical processes of basin evolution, the evolution of the coastal drainage system and the tectonic uplift of the Tibetan Plateau.

Abstract Complications of detrital zircons databases provide a means for statistically analysing a variety of significant geological problems. In this work, we tried to collect a database about the South China Phanerozoic detrital zircon geochronology data. The data statistics of this paper rely on the OneSediment Working Group of The Deep‐time Digital Earth program (DDE). By November 2022, the database contains a total of 699 samples with 55,532 U–Pb ages and 3,770 effective Hf isotope data, from 130 papers. Abundant information including reference title, sample ID, locality, rock type, research institution, GPS coordinates, U–Pb ages, εHf(t) values, etc., have been involved in our database, and all data can be downloaded from DDE Data Publish & Repository website, https://repository.deep‐time.org/. Through the integrated data, we can improve the previous studies and avoid the waste of resources caused by a large number of repeated studies.

Abstract Background The co-occurrence of Lemierre’s syndrome, primarily triggered by Fusobacterium necrophorum following oropharyngeal infection, with diabetic ketoacidosis (DKA) in diabetes mellitus (DM) patients, underscores a rare but life-threatening clinical scenario. Lemierre’s syndrome induced DKA is extremely rare, with only one case report in adult and no case yet reported in elderly. Case Presentation We reported a case of a 69-year-old female who presented with DKA triggered by deep neck space infection (DNSI), leading to rapid clinical deterioration within 6 h that necessitated high flow nasal cannula (HFNC) and antibiotic administration. Laboratory findings included leukocytosis, elevated serum C-reactive protein, hyperglycemia, ketonemia, and severe metabolic acidosis. Culture of the fluid from a neck mass puncture drainage and blood were positive for Klebsiella pneumoniae. The patient was further complicated by thrombosis of the left internal jugular vein with extension to the sigmoid and a neck abscess surrounding the carotid artery sheath, consistent with Lemierre’s syndrome. This condition was managed aggressively with fluid resuscitation, insulin therapy, surgical drainage, antibiotics, and anticoagulation led to a significant improvement in her condition. Following a 13-day hospitalization, there was significant clinical improvement, culminating in the patient’s discharge. Conclusions The case highlights the need for greater awareness and understanding of the interrelated and mutually promoting conditions of DKA and Lemierre’s syndrome among clinicians. Early recognition and treatment are crucial to prevent mortality in such complex cases.

Abstract Racial and ethnic minorities bear a disproportionate burden of type 2 diabetes (T2D) and its complications, with social determinants of health (SDoH) recognized as key drivers of these disparities. Implementing efficient and effective social needs management strategies is crucial. We propose a machine learning analytic pipeline to calculate the individualized polysocial risk score (iPsRS), which can identify T2D patients at high social risk for hospitalization, incorporating explainable AI techniques and algorithmic fairness optimization. We use electronic health records (EHR) data from T2D patients in the University of Florida Health Integrated Data Repository, incorporating both contextual SDoH (e.g., neighborhood deprivation) and person-level SDoH (e.g., housing instability). After fairness optimization across racial and ethnic groups, the iPsRS achieved a C statistic of 0.71 in predicting 1-year hospitalization. Our iPsRS can fairly and accurately screen patients with T2D who are at increased social risk for hospitalization.

Abstract The charge density wave (CDW), as a hallmark of vanadium-based kagome superconductor AV3Sb5 (A = K, Rb, Cs), has attracted intensive attention. However, the fundamental controversy regarding the underlying mechanism of CDW therein persists. Recently, the vanadium-based bi-layered kagome metal ScV6Sn6, reported to exhibit a long-range charge order below 94 K, has emerged as a promising candidate to further clarify this core issue. Here, employing micro-focusing angle-resolved photoemission spectroscopy (μ-ARPES) and first-principles calculations, we systematically studied the unique CDW order in vanadium-based bi-layered kagome metals by comparing ScV6Sn6 with its isostructural counterpart YV6Sn6, which lacks a CDW ground state. Combining ARPES data and the corresponding joint density of states (DOS), we suggest that the VHS nesting mechanism might be invalid in these materials. Besides, in ScV6Sn6, we identified multiple hybridization energy gaps resulting from CDW-induced band folding, along with an anomalous band dispersion, implying a potential electron-phonon coupling-driven mechanism underlying the formation of the CDW order. Our finding not only comprehensively maps the electronic structure of V-based bi-layer kagome metals but also provides constructive experimental evidence for the unique origin of CDW in this system.

Abstract The host limits Mycobacterium tuberculosis (Mtb) by enriching copper in high concentrations. This research investigates how Mtb escapes copper stress. The membrane protein encoded by Mtb Rv0102, when its homolog in M. smegmatis (MSMEG_4702) was knocked out, resulted in a fourfold decrease in intracellular copper levels and enhanced tolerance to elevated extracellular copper concentrations. Similarly, knockout mutants of its homolog in M. marinum (MMAR_0267) showed increased virulence in zebrafish and higher bacterial load within macrophages. In THP-1 cells infected with MMAR_0267 deletion mutants, the intracellular survival of these mutants increased, along with reduced THP-1 cell apoptosis. Deficiency in copper down-regulated the transcriptional level of the virulence factor CFP-10 in M. marinum, suppressed cytosolic signaling via the macrophage STING pathway, leading to decreased production of IFN-β and reduced cell apoptosis. In conclusion, these findings highlight the significant impact of copper on the survival and reproduction of mycobacteria, underscoring the importance of studying mycobacterial adaptation mechanisms in copper-rich environments.

Objective: To explore whether thrombopoietin can exert a protective effect against doxorubicin-induced cardiotoxicity by modulating the sirtuin 1 (SIRT1) signaling pathway. Methods: H9c2 cell viability was determined by CCK-8 and cardiomyocyte apoptosis was detected by TUNEL assay. The protein expressions of SIRT1 and p38 MAPK were measured by Western blot. RT-qPCR was also used to determine S1RT1 mRNA expression. In addition, intracellular reactive oxygen species levels and antioxidant enzyme activities were evaluated. Results: Thrombopoietin treatment reversed doxorubicin-induced decline in H9c2 cell viability. It also increased SIRT1 and decreased p-p38 MAPK protein expressions. In addition, thrombopoietin significantly attenuated doxorubicin-induced apoptosis and oxidative stress, and enhanced antioxidant enzyme activities. However, silencing S1RT1 abrogated the protective effects of thrombopoietin, as evidenced by reduced cell viability and increased oxidative stress and reactive oxygen species levels. Conclusions: Thrombopoietin alleviates doxorubicin-induced cardiomyocyte injury by reducing oxidative stress and apoptosis via the SIRT1/p38 MAPK pathway. However, its protective effects need to be further verified in animal tests.

Abstract Background Simulation-Based Learning (SBL) is increasingly adopted in medical education across various specialties, employing realistic simulations to significantly enhance learning experiences. However, a comprehensive evaluation of its effectiveness specifically in endocrinology has not yet been conducted. The study aims to systematically review and meta-analyze the impact of SBL versus Non-Simulation-Based Learning (NSBL) on knowledge acquisition, skills, satisfaction, and interest in learning among endocrinology trainees. Methods This systematic review and meta-analysis adhered to the PRISMA guidelines, searching PubMed, Web of Science, Embase, Cochrane library, China National Knowledge Infrastructure (CNKI), Wanfang Data, Weipu, and Chinese Biomedical Database (CBM) until March 2024. We included randomized controlled trials comparing SBL to NSBL in endocrinology education. The quality evaluation relied on the Cochrane risk-of-bias assessment tool. The main results included evaluations from both theoretical and practical assessments. Additional measures consisted of assessing satisfaction and interest in learning. Results We identified 22 studies suitable for systematic review and 21 for meta-analysis, involving a total of 2517 participants. SBL greatly enhanced theoretical knowledge [standardized mean difference (SMD) = 1.00, 95% confidence interval (CI): 0.68–1.32, P

Abstract Background This study aims to investigate the causal relationship of human plasma metabolites and metabolic ratios with schizophrenia (SCZ). Methods We employed Mendelian Randomization (MR) approach to comprehensively analyze two large-scale metabolomics and schizophrenia Genome-Wide Association Study (GWAS) datasets, incorporating a total of 1091 metabolites and 309 metabolic ratios, with 52017 schizophrenia patients and 75889 healthy controls. The inverse variance-weighted (IVW) method was utilized to estimate the causal relationship between exposure and outcome. To provide a more comprehensive evaluation, additional Mendelian Randomization (MR) approaches were employed, including MR-Egger regression, weighted median, simple mode, and weighted mode methods. These analyses assessed the causal effects between blood metabolites, metabolic ratios, and schizophrenia. Tests for pleiotropy and heterogeneity were conducted. False Discovery Rate (FDR) correction was applied to account for multiple comparisons and heterogeneity, ensuring the robustness and reliability of our findings. Consistent with previous studies, an FDR threshold of

Abstract Microbial fuel cells utilize exoelectrogenic microorganisms to directly convert organic matter into electricity, offering a compelling approach for simultaneous power generation and wastewater treatment. However, conventional microbial fuel cells typically require thick biofilms for sufficient metabolic electron production rate, which inevitably compromises mass and charge transport, posing a fundamental tradeoff that limits the achievable power density (

Abstract Objective This study aimed to evaluate the impact of adding 4 mg estradiol valerate to progesterone for luteal support on pregnancy rates in IVF cycles following a long protocol with reduced luteal serum estradiol levels post-hCG triggering. Design, setting, and participants The prospective randomized controlled trial was conducted at a public tertiary hospital reproductive center with 241 patients who experienced a significant decrease in serum estrogen levels post-oocyte retrieval. Interventions Participants received either a daily 4 mg dose of estradiol valerate in addition to standard progesterone or standard progesterone alone for luteal support. Results The ongoing pregnancy rate did not show a significant difference between the E2 group and the control group (56.6% vs. 52.2%, with an absolute rate difference (RD) of 4.4%, 95% CI -0.087 to 0.179, P = 0.262). Similarly, the live birth rate, implantation rate, clinical pregnancy rate, early abortion rate, and severe OHSS rate were comparable between the two groups. Notably, the E2 group had no biochemical miscarriages, contrasting significantly with the control group (0.0% vs. 10.7%, RD -10.7%, 95% CI -0.178 to -0.041, P = 0.000). In the blastocyst stage category, the clinical pregnancy rate was notably higher in the E2 group compared to the control group (75.6% vs. 60.8%, RD 14.9%, 95% CI 0.012 to 0.294, P = 0.016). Conclusion Adding 4 mg estradiol valerate to progesterone for luteal support does not affect the ongoing pregnancy rate in embryo transfer cycles using a long protocol with a significant decrease in serum estradiol levels after hCG triggering. However, it may reduce biochemical miscarriages and positively impact clinical pregnancy rates in blastocyst embryo transfer cycles. Trial registration ChiCTR1800020342.

The evaluation of urban underground space (UUS) suitability involves multiple indicators. Assigning weight to these indicators is crucial for accurate assessment. This paper presents a method for spatially variable weight assignment of indicators using the order relation analysis method (G1-method), the entropy weight method, an improved grey relational analysis (GRA) and a set of spatial weight adjustment coefficients. First, the subjective and objective weights of indicators for engineering geological and hydrogeological conditions were determined by the G1-method and entropy weight method, respectively, and their combined weights were then obtained using the principle of minimum discriminatory information. This study highlighted the impact of surface restrictions, such as buildings, on UUS, and the degree of the influence of these buildings gradually decreased with the increase in depth of the rock and soil mass in UUS, which resulted in changes in weights of indicators with depth. To address this issue, a coefficient was defined as the standardized value of the ratio of additional stress applied by restrictions to the self-weight stress of soil at the same depth to modify the combined weights so that all weights of indicators could vary in space. Finally, an improved GRA was used to determine the suitability level of each evaluation cell using the maximum correlation criterion. This method was applied to the 3D suitability evaluation of UUS in Sanlong Bay, Foshan City, Guangdong Province, China, including 16 evaluation indexes. This study comprehensively considered the influence of multiple factors, thereby providing reference for evaluating the suitability of UUS in big cities.

A new safety assessment framework has been proposed to address the operational risks of the integration of wind power and photovoltaic grid, which integrates the characteristics of distributed power sources with the dynamic reconfiguration requirements of the distribution grid. The framework comprehensively considers the impacts of wind power and photovoltaic output uncertainties, as well as load fluctuations, on the stability of the distribution grid. It also evaluates the safety under different operational states of the distribution grid. Using Halton sequence sampling technology to accurately simulate the output of distributed power sources and the status of system components, combined with CPLEX optimisation for solving, a dynamic reconfiguration model is constructed to address potential faults in the distribution grid. Introducing the combined weighting method, a comprehensive risk assessment system for voltage violations, power flow violations, and load shedding has been constructed. The effectiveness of this method has been validated through simulations on the IEEE33 bus and IEEE118 bus systems, providing new insights to improve the safety and reliability of distribution grids.

Abstract Land use and cover change (LUCC) significantly impacts global carbon cycles and land surface properties, accounting for 25% of the historical atmospheric CO2 increase. We explore a previously overlooked role of LUCC in driving the land carbon cycle by using a three-level meta-analysis and Land Use Harmonization data to drive an ecosystem model. Our findings reveal that a loss of 39.2% of soil organic carbon (SOC) change in China due to LUCC, mitigated by afforestation, doubles gross primary productivity at 0.02 Pg C yr−1, countering central China’s urbanization decline. Indirect climate effects, especially soil bulk density, significantly impact SOC compared to direct climate effects. LUCC has significantly increased the Chinese terrestrial carbon sink, with net ecosystem productivity reaching 0.02 ± 0.12 Pg C yr−1. Our study underscores the importance of reforestation and afforestation in addressing climate change and enhancing carbon sinks in future carbon management.

Abstract Background Brominated flame retardants (BFRs) are widely utilized to mitigate the flammability of various materials. Previous studies have revealed the impact of BFRs exposure on hormonal disruption and bone metabolism which are closely related to periodontitis. However, it remains unknown the potential relationship between BFRs and periodontitis. This study aimed to explore the association between BFRs exposure and periodontitis in US adults. Methods The data analyzed in this study were obtained from the National Health and Nutrition Examination Survey (NHANES) 2009–2014. Twelve serum BFRs were quantified using isotope dilution gas chromatography high-resolution mass spectrometry. Univariable and multivariable logistic regression was employed to evaluate the association between serum BFRs and periodontitis. Bayesian kernel machine regression (BKMR) analyses were utilized to assess the association between mixtures of BFRs and periodontitis. Results A total of 3311 eligible participants were included. Serum BFRs (PBDE-47, PBDE-99, and PBDE-154) were significantly associated with periodontitis, and the odds ratios (ORs) and corresponding 95% confidence intervals(CIs) were 1.15(1.01,1.29), 1.10(1.01,1.20), and 1.12(1.01,1.25), respectively. Notably, these three BFRs were also significantly associated with the severity of periodontitis. Additionally, the BKMR model revealed a significant association between the mixture of all twelve BFRs and periodontitis. Conclusions This preliminary study suggests a significant association between specific serum BFRs (PBDE-47, PBDE-99, and PBDE-154) and periodontitis and its severity. Further prospective and experimental studies are warranted to validate our findings.

Abstract Background Transposition of the great arteries (TGA) is the most common cyanotic congenital heart defect in neonates but with low prenatal detection rate. This study sought to review the prenatal diagnosis, associated abnormalities, and mid-term postnatal outcomes of fetuses with TGA and investigate the integrated prenatal and postnatal management for TGA neonates. Methods A total of 134 infants prenatally diagnosed with TGA in Guangdong Provincial People’s Hospital, China, from January 2009 to December 2022 were included in the study. The prenatal ultrasound data and neonatal records were reviewed to assess the accuracy of prenatal diagnosis. Univariate and multivariate logistic and Cox analyses were used to identify risk factors associated with prognosis in such individuals. Results The population originated from 40 cities in 10 provinces in China, with integrated antenatal and postnatal management rate reaching 94.0% (126/134) and a high accuracy rate (99.3%) of prenatal primary diagnosis. The median period of follow-up was 1.6 [interquartile range (IQR) 0.1–4.3] years. There were 3 (2.2%) postnatal deaths, 118 (88.1%) patients undergoing arterial switch operation (ASO), 3 (2.2%) undergoing Rastelli operations and 5 (3.7%) doing stage operations. Of 118 patients receiving ASO, the major morbidity occurred in 64 patients (54.2%), and right ventricular outflow tract obstruction (RVOTO) in 31 (26.3%). In the multivariate logistic analysis, gestational ages at birth (OR = 0.953, 95% CI 0.910–0.991; p = 0.025) and cardiopulmonary bypass (CPB) time (OR = 1.010, 95% CI 1.000–1.030; p = 0.038) were identified as independent risk factors associated with major morbidity. In the Cox multivariate analysis, aortic cross-clamping time (HR = 1.030, 95% CI 1.000–1.050; p = 0.017) was identified as independent risk factor associated with RVOTO. Conclusion Earlier gestational ages at birth and longer CPB time are significantly associated with increased morbidity. Integrated prenatal and postnatal management is recommended for patients with prenatal diagnosis of TGA.

Abstract Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a serious threat to global public health. Fluoroquinolones (FQs) are effective against M. tuberculosis; however, resistant strains have limited their efficacy. M ycobacterium fluoroquinolone resistance protein A (MfpA) confers intrinsic resistance to FQs; however, its regulatory mechanisms remain largely unknown. Using M. smegmatis as a model, we investigated whether MfpC is necessary for FQ susceptibility. MfpC mutants were sensitive to moxifloxacin, indicating that MfpC is involved in FQ susceptibility. By testing the mfpC inactivation phenotype in different mutants and using mycobacterial protein fragment complementation, we demonstrated that the function of MfpC depends on its interactions with MfpB. Guanine nucleotide exchange assays and site-directed mutagenesis confirmed that MfpC acts as a guanine nucleotide exchange factor to regulate MfpB. We propose that MfpB influences MfpA at the translational level. In summary, we reveal the role of MfpC in regulating the function of MfpA in FQ resistance.

Abstract Background Hepatocellular carcinoma (HCC) constitutes an important contributor to fatalities. Coronavirus disease 2019 (COVID-19) frequently presents with complications such as respiratory distress, systemic inflammatory responses, and damage to various organs. Several studies have investigated the relationship between COVID-19 and mortality in patients with liver cancer, but there are few research on the relationship between them. This study is to explore the correlation between the two diseases and drugs treating them. Methods The Gene Expression Omnibus (GEO) database provides gene datasets of COVID-19 patients and HCC patients. Through differential gene analysis and weighted gene co-expression network analysis, we determined 223 genes represented in HCC and COVID-19. We then used functional annotation, protein–protein interaction network construction, predictive model development and verification, prognostic value analysis, and miRNA–gene network construction. Besides, we created a drug–hub–gene network by predicting possible medications that interact with hub genes using the Drug–Gene Interaction Database (DGIdb). Ultimately, we applied immunohistochemistry to ascertain the hub genes expression. Results This study revealed that eight core genes (RRM2, TPX2, DTL, CDT1, TYMS, CDCA5, CDC25C, and HJURP) co-existed in both HCC and COVID-19 and were differentially expressed in both HCC and normal tissues.CDC25C, RRM2, CDCA5, and HJURP had diagnostic value (AUC > 0.8) and prognostic value (adjusted P-value

Abstract Background A comprehensive understanding of the genetic basis of rare diseases and their regulatory mechanisms is essential for human molecular genetics. However, the genetic mutant spectrum of pathogenic genes within the Chinese population remains underrepresented. Here, we reported previously unreported functional ABHD12 variants in two Chinese families and explored the correlation between genetic polymorphisms and phenotypes linked to PHARC syndrome. Methods Participants with biallelic pathogenic ABHD12 variants were recruited from the Chinese Deafness Genetics Cohort. These participants underwent whole-genome sequencing. Subsequently, a comprehensive literature review was conducted. Results Two Han Chinese families were identified, one with a compound heterozygous variant and the other with a novel homozygous variant in ABHD12. Among 65 PHARC patients, including 62 from the literature and 3 from this study, approximately 90% (57 out of 63) exhibited hearing loss, 82% (50 out of 61) had cataracts, 82% (46 out of 56) presented with retinitis pigmentosa, 79% (42 out of 53) experienced polyneuropathy, and 63% (36 out of 57) displayed ataxia. Seventeen different patterns were observed in the five main phenotypes of PHARC syndrome. A total of 33 pathogenic variants were identified in the ABHD12. Compared with other genotypes, individuals with biallelic truncating variants showed a higher incidence of polyneuropathy (p = 0.006), but no statistically significant differences were observed in the incidence of hearing loss, ataxia, retinitis pigmentosa and cataracts. Conclusions The diagnosis of PHARC syndrome is challenging because of its genetic heterogeneity. Therefore, exploring novel variants and establishing genotype-phenotype correlations can significantly enhance gene diagnosis and genetic counseling for this complex disease.

【Objective】In October 2023, skin ulceration, subcutaneous hemorrhage and enteritis appeared in a breeding base of Epinephelus coioides in Shenzhen, China. We clarified the causative organisms that triggered the sudden death of E. coioides and their biological characteristics, and screened the disinfectant that effectively inhibited the causative organisms, with an aim to provide theoretical guidance for the scientific prevention and control of E. coioides infected with Vibrio alginolyticus.【Method】The pathogen of V. alginolyticus was isolated from the diseased tissues of the dying E. coioides by streak plate method, the morphological characteristics, physiological and biochemical properties, phylogenetic tree, virulence genes and resistance genes as well as drug sensitivity of the pathogen were investigated, and regression infection tests were carried out.【Result】A dominant strain was isolated from the diseased tissues of E. coioides and named as strain SZGP226. The results of phylogenetic analysis showed that, the sequence of strain SZGP226 was homologous to V. alginolyticus HH101307, IB1 and Xmb015, with a similarity of 99.72%. The strain was identified as positive in physiological and biochemical indexes such as sucrose, mannitol, glucose, urea, oxidase activity and V-P, and it also carried five virulence genes, namely, tlh, toxR, ctsA, sto and vpi. The results of drug sensitivity showed that strain SZGP226 was resistant to 9 antibiotics like ampicillin and benzoxacillin, and carried 9 resistance genes including qnrB, floR, tetC, tetM, qnrD, gyrA, Sul1, SHV, and Oxa-24. The screening results of disinfectants showed that, sodium hydroxide had the best bactericidal effect, and its minimal inhibition concentration (MIC) was 8 mg/mL. The regression infection test showed that strain SZGP226 was strongly pathogenic to the E. coioides, with a LC50 of 1.63×107 CFU/mL, and it could cause obvious pathological damage to the liver, kidney and spleen of the E. coioides.【Conclusion】V. alginolyticus was the main pathogenic bacterium for the sudden death of the E. coioides, and its causative genes included tlh, toxR, ctsA, sto and vpi, and the LC50 was 1.63×107 CFU/mL. Sodium hydroxide (3 mg/mL) showing the best bactericidal effect on strain bactericidal effect could be selected to clean up the culture environment before aquaculture was carried out.

【Objective】The study was conducted to investigate the causes of sudden death of largemouth bass (Micropterus salmoides) in a bass culture base in Shenzhen-Shanwei Special Cooperation Zone, and reveal the biological characteristics of the Pathogen, with an aim to provide theoretical reference for disease prevention, treatment and prevention in breeding largemouth bass.【Method】A dominant bacterial strain, named SZNH-S20230817, was isolated from the liver, spleen, intestine and lesion tissues of the diseased largemouth bass, and the isolate was subsequently subjected to morphological characteristics observation, physiological and biochemical characteristics identification, artificial infection experiment, drug sensitivity test, MIC and MBC determination, 16S rRNA sequencing, identification of resistance genes and virulence genes to analyse its drug resistance and pathology.【Result】The results showed that the extended 16S rRNA sequence of SZNH-S20230817 had a 99.38% homology with Aeromonas caviae AP019195, and also carried four virulence genes, including aer, act, lip and fla. The results of physiological and biochemical identification showed that, indole, oxidase, phenylalanine, mannitol, xylose, arginine dihydrolysate and glucose acid production of the strain were positive, and the strain SZNH-S20230817 was identified as Aeromonas caviae. Regression infection revealed that the strain SZNH-S20230817 was highly pathogenic, with an LC50 of 1.39×107 CFU/mL for largemouth bass. The results of drug sensitivity tests showed that the bacterium was resistant to 12 antibiotics such as cefazolin, kanamycin, tetracycline and vancomycin, ampicillin, and clindamycin, and also carried 13 resistance genes such as qnrS, catI, emrB, Sul1, rmtB and etc. Histopathological analysis showed that infection with the strain SZNH-S20230817 could cause swelling and freeing of splenocytes, fracture and rupture of intestinal mucosa, shedding of villi, necrosis of renal cells, infiltration of inflammatory cells and vacuolisation of hepatic cells in the fish. The results of in vitro bacterial inhibition tests showed that the bacterium had low MIC and MBC against rheum officinale and gallnut, and the remaining seven herbs had weak inhibition against the bacterium.【Conclusion】Aeromonas caviae is the pathogen that causes the sudden death of largemouth bass, which carries four virulence genes of aer, act, lip and fla, and has an LC50 of 1.39×107 CFU/mL against largemouth bass. It is resistant to antibiotics such as cefazolin, kanamycin and tetracycline. Low dose of rheum officinale and gallnut can inhibit the growth of the bacterium effectively, with good preventive and inhibitory effects.

【Objective】In recent years, probiotics have been widely used in aquaculture, but the probiotics derived from Trachinotus ovatus been rarely reported. In the study, a strain was isolated from the intestine of Trachinotus ovatus and its biological characteristics were analyzed, which provided a theoretical basis its application in T. ovatus culture.【Method】The bacteria were isolated and identified through the sterile collection of intestinal contents from the healthy T. ovatus. And the morphological observation, gram staining, biochemical identification, 16S rRNA gene sequence analysis, drug sensitivity test, salt tolerance test, acid production ability, growth curve determination, and virulence gene identification of the typical bacterial colonies were performed.【Result】Based on the morphological characteristics, gram staining results biochemical characteristics, and 16S rRNA gene sequence alignment of the isolated bacterium, the results showed that it shared 100% similarities with Enterococcus faecalis, therefore, the isolated bacterium was identified as E. faecalis. The colony of the isolated strain was light grayish white, and Gram-positive. The biochemical indicators including esculin, cellobios, maltose, mannose and salicylic acid were tested positive. The results of the drug sensitivity test showed that the isolated bacterium exhibited varying degrees of resistance to drugs such as piperacillin, polymyxin B, penicillin, trimethoprim-sulfamethoxazole and oxacillin, exhibited intermediate sensitivity to ciprofloxacin, medemycin and ceftriaxone and sensitive to 11 drugs such as vancomycin, cefoperazone, ofloxacin and etc. The results of the salt tolerance test showed that the isolated strain could grow at 0%-8% NaCl concentrations, showing salt tolerance to some extent. The results of acid production capacity and growth curve measurements indicated that the pH of the culture media rapidly decreased and the acid production capacity was enhanced as the proliferation of the strain. The identification results of virulence genes showed that the isolated strains possessed four virulence genes including efaA, agg, as and fsrA.【Conclusion】A potential probiotic strain was successfully isolated from the intestine of T. ovatus and identified as E. faecalis. The isolated strain has good salt tolerance and acid production capability, and it contains functional genes associated with intestinal adhesion, which will provide a theoretical basis for further application of the strain.

Abstract Circulating cell-free DNA (cfDNA) in the peripheral blood is a promising biomarker for cancer diagnosis and prognosis. Somatic mutations identified in cancers have been used to detect therapeutic targets for clinical transformation and individualize drug selection, while germline variants can predict a patient’s risk of developing cancer and drug sensitivity. However, no platform has been developed to analyze, calculate, integrate, and friendly visualize these pan-cancer cfDNA mutations deeply. In this work, we performed panel sequencing encompassing 1,115 cancer-related genes across 16,659 cancer patients, spanning 27 cancer types. We detected 496 germline variants in leukocytes and 11,232 somatic mutations in the cfDNA of all patients. CPGV (Cancer Peripheral blood Gene Variations), a database constructed from this dataset, is the first pan-cancer cfDNA database that encompasses somatic mutations, germline variants, and further comparative analyses of mutations across different cancer types. It bears great promise to serve as a valuable resource for cancer research.

Abstract The metabolic profile predating the onset of Parkinson’s disease (PD) remains unclear. We aim to investigate the metabolites associated with incident and prevalent PD and their predictive values in the UK Biobank participants with metabolomics and genetic data at the baseline. A panel of 249 metabolites was quantified using a nuclear magnetic resonance analytical platform. PD was ascertained by self-reported history, hospital admission records and death registers. Cox proportional hazard models and logistic regression models were used to investigate the associations between metabolites and incident and prevalent PD, respectively. Area under receiver operating characteristics curves (AUC) were used to estimate the predictive values of models for future PD. Among 109,790 participants without PD at the baseline, 639 (0.58%) individuals developed PD after one year from the baseline during a median follow-up period of 12.2 years. Sixty-eight metabolites were associated with incident PD at nominal significance (P

Abstract The comprehensive understanding of propagation patterns of extreme precipitation events (EPEs) is essential for early warning of associated hazards such as floods and landslides. In this study, we utilize climate networks based on an event synchronization measure to investigate the propagation patterns of EPEs over the global land masses, and identify 16 major propagation pathways. We explain them in association with regional weather systems, topographic effects, and travelling Rossby wave patterns. We also demonstrate that the revealed propagation pathways carry substantial EPE predictability in certain areas, such as in the Appalachian, the Andes mountains. Our results help to improve the understanding of key propagation patterns of EPEs, where the global diversity of the propagated patterns of EPEs and corresponding potential predictability provide prior knowledge for predicting EPEs, and demonstrate the power of climate network approaches to study the spatiotemporal connectivity of extreme events in the climate system.

Abstract This paper utilizes the theory of quantum diffusion to analyze the electron probability and spreading width of a wavepacket on each layer in a two-dimensional (2D) coupled system with edge disorder, aiming to clarify the effects of edge disorder on the stability of the electron periodic oscillations in 2D coupled systems. Using coupled 2D square lattices with edge disorder as an example, we show that, the electron probability and wavepacket spreading width exhibit periodic oscillations and damped oscillations, respectively, before and after the wavepacket reaches the boundary. Furthermore, these electron oscillations exhibit strong resistance against disorder perturbation with a longer decay time in the regime of large disorder, due to the combined influences of ordered and disordered site energies in the central and edge regions. Finally, we numerically verified the universality of the results through bilayer graphene, demonstrating that this anomalous quantum oscillatory behavior is independent of lattice geometry. Our findings are helpful in designing relevant quantum devices and understanding the influence of edge disorder on the stability of electron periodic oscillations in 2D coupled systems.

【Objective】The study aims to screen the formula of vacuum freeze-drying protective agent for Vibrio alginolyticus, optimize the freeze-drying process conditions, and explore the influence of freeze-drying on the virulence and drug sensitivity of the strains, with a view to providing a theoretical basis for the application of freeze-drying in the preservation of the strains.【Method】With Vibrio alginolyticus HY9901 as the research object, the vacuum freeze-drying technology was used to freeze-dry the strains. Through single factor test and orthogonal test, the effects of six single cryoprotectants (L-glutamate sodium, trehalose, skim milk, glucose, mannitol and glycine) on the activity of the strains were investigated, and the optimal formula of cryoprotectants was selected. The influences of four factors, namely, concentration of bacterial solution, pre-freezing time, pre-freezing temperature and rehydration medium, on the freeze-drying process of strains were studied, and the freeze-drying process conditions for Vibrio alginolyticus were optimized. At the same time, storage test, LD50 test and antimicrobial susceptibility test were used to investigate the changes in the activity of lyophilized strains and their of biological characteristics.【Result】There were significant differences in the protective effects of 6 cryoprotectants on lyophilized Vibrio alginolyticus, and the effects from strongest to weakest showed as: L-glutamate sodium, trehalose, skim milk, glucose, mannitol and glycine. The optimum freeze-drying compound formula of cryoprotectants was trehalose 50 g/L+ L-glutamate sodium 50 g/L+ skim milk 50 g/L, with a survival rate of 62.12%, which was significantly different from that of single cryoprotectant. The optimal conditions of freeze-drying process were as follows: bacterial solution concentration 1×108-109 CFU/mL, pre-freezing time 3 h, pre-freezing temperature -80 ℃, rehydration medium PBS or 50 g/L skim milk, under which the activity of the strains could reach the maximum of 63.72%. There was no significant difference in the activity of the strains during 60 days of storage under optimal freeze-drying conditions. The LD50 values of the strains before and after freeze-drying were 1.22×108 CFU/mL and 1.20×108 CFU/mL, respectively, with no significant difference in LD50. There was no significant difference in the diameter of the antimicrobial inhibition zone before and after freeze-drying, and the strains were sensitive to florfenicol, chloramphenicol, ciprofloxacin and other drugs. They were moderately sensitive to neomycin and kanamycin, and resistant to drugs like amimcana and piperacillin.【Conclusion】The freeze-drying formula for Vibrio alginolyticus HY9901 is trehalose 50 g/L+ L-glutamate sodium 50 g/L+ skim milk 50 g/L, and the freeze-drying process conditions are: bacterial solution concentration 1×108-109 CFU/mL, pre-freezing time 3 h, pre-freezing temperature -80 ℃, rehydration medium PBS or 50 g/L skim milk. The fomula and process for this strain are reasonable and feasible, with good storage and stability of biological characteristics.

Summary: Intraocular pressure (IOP) is closely correlated with blood pressure (BP), and while BP has been linked to brain volumes, the effect of IOP on brain volumes remains unclear. This study analyzed participants from the UK Biobank with MRI-measured brain volumes. Observational analyses included 8,634 participants for IOP and 36,069 for BP, followed by Mendelian randomization (MR) analyses of 37,410 participants. Observational analyses revealed that each 10-mmHg increase in diastolic BP was linked to a 0.13 mL larger white matter hyperintensity (WMH) after adjusting for covariates. Associations between IOP and brain volumes were more pronounced in younger individuals or those without hypertension. MR analyses confirmed significant relationships between diastolic BP and WMH, and each 5-mmHg increase in IOP reduced gray matter volumes by 3.24 mL. The study suggests that targeting IOP and BP could help prevent brain volume reduction.

ABSTRACT The widespread prevalence and dissemination of antibiotic-resistant bacteria, coupled with the diminishing supply of new antibiotics, emphasize the pressing necessity for the exploration of innovative antibacterial agents. Previously, we detailed the impact of the small-molecule compound CY-158-11 on S. aureus biofilm. By hindering adhesion and PIA-mediated biofilm formation, subinhibitory concentrations of CY-158-11 exhibit antibiofilm activity toward S. aureus. Here, we sought to elucidate the antibacterial activity and mode of action of this compound. Upon CY-158-11 treatment in culture, the inhibition of bacterial growth, coupled with MBC to MIC of >4, indicated that CY-158-11 exerted a bacteriostatic effect. Particularly, CY-158-11 showed strong antibacterial activity against a wide variety of S. aureus, including multidrug-resistant bacteria. We found that CY-158-11 promoted the permeability of cell membrane and propidium iodide absorption as well as caused the dissipation of membrane potential. The effect of CY-158-11 on the mammalian cytoplasmic membrane was measured using hemolytic and cytotoxicity assays, and the skin irritation and systemic toxicity of the drug were measured by injecting the compound into the skin and tail vein of mice. Moreover, CY-158-11 exhibited considerable efficacy in a subcutaneous abscess mouse model of S. aureus infection. In conclusion, CY-158-11 possesses antibacterial properties, including inhibition of bacterial growth, damage to cell membranes, and treatment of skin abscesses, which can be a promising therapeutic option for combating S. aureus.IMPORTANCEThe combination of the rising incidence of antibiotic resistance and the shrinking antibiotic pipeline has raised concern about the postantibiotic era. New antibacterial agents and targets are required to combat S. aureus-associated infections. In this study, we identified a maleimide-diselenide hybrid compound CY-158-11 exhibiting antibacterial activity against S. aureus in vitro and in vivo at relatively low concentrations. Furthermore, the investigation of its mode of action revealed that CY-158-11 can selectively perturb the cytoplasmic membrane of bacteria without harming mammalian cells or mouse organs. Thus, CY-158-11 is a compelling novel drug for development as a new therapy for S. aureus infections.

Abstract High‐efficiency non‐doped deep‐blue organic light‐emitting diodes (OLEDs) meeting the standard of BT.2020 color gamut is desired but rarely reported. Herein, an asymmetric structural engineering based on crossed long‐short axis (CLSA) strategy is developed to obtain three new deep‐blue emitters (BICZ, PHDPYCZ, and PHPYCZ) with a hot‐exciton characteristic. Compared to 2BuCz‐CNCz featuring a symmetric single hole‐transport framework, these asymmetric emitters with the introduction of different electron‐transport units show the enhancement of photoluminescence efficiency and improvement of bipolar charge transport capacity. Further combined with high radiative exciton utilization efficiency and light outcoupling efficiency, the non‐doped OLED based on PHPYCZ exhibits the best performance with an excellent current efficiency of 3.49%, a record‐high maximum external quantum efficiency of 9.5%, and a CIE y coordinate of 0.049 approaching the BT.2020 blue point. The breakthrough obtained in this work can inspire the molecular design of deep‐blue emitters for high‐performance non‐doped BT.2020 blue OLEDs.

IntroductionRecently, a novel type of metabolic-regulated cell demise titled disulfidptosis has been discovered. Studies have demonstrated its importance in immune responses against cancer and its impact on the proliferation of cancer cells. Nonetheless, the precise mechanism and roles of disulfidptosis are not fully understood, particularly regarding the prognosis for individuals with uterine corpus endometrial carcinoma (UCEC).MethodsIn this research, a distinctive disulfidptosis pattern was developed in UCEC, and by utilizing Non-negative Matrix Factorization (NMF) on 23 disulfidptosis related genes within the TCGA database, 3 distinct subgroups were distinguished. To collect data, we acquired gene expression profiles, somatic mutation information, copy number variation data, and corresponding clinical data from the TCGA and GEO database, specifically from UCEC patients. Cell line experiments and immunohistochemical (IHC) staining were conducted to validate the role of the LRPPRC in proliferation, migration and invasion.ResultsThe genetic features and immune microenvironment of these subgroups were examined. It is worth mentioning that these subgroups offer important insights into comprehending the tumor microenvironment (TME) and the response of patients to immunotherapy and chemotherapy. Moreover, a disulfidptosis model was developed and validated, demonstrating a high level of accuracy in predicting the prognosis and outcomes of immunotherapy in UCEC patients. Additionally, a novel biomarker, LRPPRC, was identified, which can server as a promising predictor for forecasting prognosis in UCEC patients, with validation through tissue microarray staining and cell line experiments.DiscussionThis study has designed a classification system and a disulfidptosis model for UCEC, in addition to identifying a new biomarker, LRPPRC, for UCEC. These advancements serve as reliable and positive indicators for predicting outcomes and the efficacy of immunotherapy for each UCEC patient.

PurposeLong-term post-stroke cognitive impairment (PSCI) exhibits an accelerated rate of long-term cognitive decline, which can impair communication, limit social engagement, and increase rate of institutional dependence. The aim of this case report is to provide evidence for the potential of home-based transcutaneous auricular vagus nerve stimulation (taVNS) for home-bound patients with severe, long-term PSCI.MethodsA 71-year-old male suffered a stroke two and a half years ago, which imaging reported foci of cerebral infarction visible in the left temporal and parietal lobes. The patient was performed taVNS twice a day for 30 min, 5 times a week for 8 weeks. The patient was evaluated the changes of cognitive function and brain white matter at 4 time points: baseline (t0), 4 weeks without taVNS after baseline (t1), 4 weeks of intervention (t2), and 8 weeks of intervention (t3). The effect of taVNS on white matter changes was visualized by DTI.ResultsAfter 8 weeks of taVNS treatment, the scores of Montreal cognitive assessment improved and the time to complete the shape trails test decreased. The DTI results showed that white matter in bilateral dorsal lateral prefrontal cortex remodeled after taVNS.ConclusionEight-week home-based taVNS may be beneficial to long-term PSCI. Further studies of home-based taVNS treating patients with long-term PSCI are needed.

Summary: Background: While many patients seem to recover from SARS-CoV-2 infections, many patients report experiencing SARS-CoV-2 symptoms for weeks or months after their acute COVID-19 ends, even developing new symptoms weeks after infection. These long-term effects are called post-acute sequelae of SARS-CoV-2 (PASC) or, more commonly, Long COVID. The overall prevalence of Long COVID is currently unknown, and tools are needed to help identify patients at risk for developing long COVID. Methods: A working group of the Rapid Acceleration of Diagnostics-radical (RADx-rad) program, comprised of individuals from various NIH institutes and centers, in collaboration with REsearching COVID to Enhance Recovery (RECOVER) developed and organized the Long COVID Computational Challenge (L3C), a community challenge aimed at incentivizing the broader scientific community to develop interpretable and accurate methods for identifying patients at risk of developing Long COVID. From August 2022 to December 2022, participants developed Long COVID risk prediction algorithms using the National COVID Cohort Collaborative (N3C) data enclave, a harmonized data repository from over 75 healthcare institutions from across the United States (U.S.). Findings: Over the course of the challenge, 74 teams designed and built 35 Long COVID prediction models using the N3C data enclave. The top 10 teams all scored above a 0.80 Area Under the Receiver Operator Curve (AUROC) with the highest scoring model achieving a mean AUROC of 0.895. Included in the top submission was a visualization dashboard that built timelines for each patient, updating the risk of a patient developing Long COVID in response to clinical events. Interpretation: As a result of L3C, federal reviewers identified multiple machine learning models that can be used to identify patients at risk for developing Long COVID. Many of the teams used approaches in their submissions which can be applied to future clinical prediction questions. Funding: Research reported in this RADx® Rad publication was supported by the National Institutes of Health. Timothy Bergquist, Johanna Loomba, and Emily Pfaff were supported by Axle Subcontract: NCATS-STSS-P00438.

Background and aims: Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world and the sixth leading cause of cancer death worldwide, and it is urgent to find safe and effective drugs for treatment. As an important therapeutic method, small-molecule drugs are continually being updated to achieve improved therapeutic effects. The purpose of this study was to investigate the structural effects of various FDA-listed small-molecule drugs sorafenib, cabozantinib, lenvatinib, and regorafenib on the corresponding HCC targets and possible structural optimization methods, and to explore the mechanism for identifying potential therapeutic drugs that offer better efficacy and fewer side effects. Methods: The structure-activity relationship, pharmacological actions, and clinical applications of small-molecule drugs were reviewed by referencing MEDLINE, Web of Science, CNKI, and other databases, summarizing and integrating the relevant content. Results: The results showed that small-molecule drugs can inhibit HCC primarily by forming hydrogen bonds with Glu885, Asp1046, and Cys919 on the HCC target. HCC can be targeted by inhibiting the activation of multiple pathways, blocking the conduction of downstream signaling, and reducing the formation of tumor blood vessels. In general, small-molecule drugs primarily target four key receptors in HCC: VEGFR, PDGFR, EGFR, and FGFR, to achieve effective treatment. Conclusions: By revealing their structure-activity relationships, pharmacological actions, and clinical trials, small-molecule drugs can offer broad prospects for the development of new medications.

ABSTRACT: Duck hepatitis A virus type 3 (DHAV-3) is an infectious virus that is highly fatal to ducklings and causes significant economic losses in the duck industry worldwide. Biosecurity and vaccination are required to control the pathogen. In the present study, we attenuated a lowly pathogenic DHAV-3 clinical isolate, named as HB, by serial passaging in duck embryos, and followed by several adaptive proliferations in specific-pathogen-free (SPF) chicken embryos. The virulence of DHAV-3 at different passages was assessed by infecting 3-day-old ducklings. We found that the HB strain lost pathogenicity to ducklings from the 55th passage onwards. The 80th passage strain (HB80), which achieved good growth capacity in duck embryos with a viral titer of 108.17 50% egg lethal dose per milliliter (ELD50/mL), was selected as a live attenuated vaccine candidate. The HB80 strain did not induce clinical symptoms or pathological lesions in 3-day-old ducklings and showed no virulence reversion after 5 rounds of in vivo back-passage. The minimum effective dose of HB80 was determined to be 104.5 ELD50 by hypodermic inoculation of the neck. Importantly, a single dose of HB80 elicited good immune responses and provided complete protection against challenge with the lethal DHAV-3 strain. Compared with the genomic sequence of the parental HB strain, HB80 had 7 amino acid substitutions, two of them are in the hypervariable region of the VP1 and polymerase-encoding 3D regions, which may play a role in virulence attenuation. Our data suggest that the attenuated HB80 strain is a promising vaccine candidate for the prevention of DHAV-3 infections in China. HB80 has been registered as a New Veterinary Drug Registration Certificate by the Chinese Ministry of Agriculture and Rural Affairs (MARA), and is the first live attenuated DHAV-3 vaccine strain to be officially licensed in China.

Today’s increasing demand for aquaculture production is accompanied by various challenges such as diseases, broodstock improvement, domestication, development of suitable pellets and feeding methods, hatchery technology, and water quality management. Thus, probiotic usage has been reported as the ideal alternative to antibiotics, other chemotherapeutics, and additional supplements to other alternative ingredients. The main beneficial roles of probiotics include the enhancement of disease and stress resistance, immunity, promotion of growth and reproduction, improvement of digestion, provide several nutrients, and enhancement of water microbial composition. To guarantee safety, the probiotics provided must be non-invasive and non-pathogenic. The use of probiotics in aquaculture, either directly or in combination with alternative materials such as plant protein diets, vitamins, microalgae, fermented products, and so on, has been shown to improve the health and growth of aquatic animals and offer significant benefits to the sustainability of the industry. There is advocacy for a systematic approach to conducting innovative research to unearth new putative strains, which is substantial in ensuring sustainable probiotic usage and, thus, can help in the continuous development of the aquaculture industry especially in China. Some examples of the probiotics found in China are mainly photosynthetic bacteria (PSB) which are autotroph bacteria capable of photosynthesis, antagonistic bacteria (Pseudoalteromonas sp., Flavobacterium sp., Alteromonas sp., Phaeobacter sp., Bacillus sp., etc.), bacteria that contribute nutrients and enzymes during digestion (lactic acid bacteria, yeasts, etc.), bacteria that improve water quality (nitrifying bacteria, denitrifying bacteria, etc.), Bdellovibrio, and other probiotics. This review also focuses on the potential use of probiotics in aquaculture, especially in China, and probiotics’ prospective future role.

Different sampling strategies produce varying sample data, serve as the primary input data and directly affect the accuracy of predictions in data-driven grid-based susceptibility models. This study analyzes the accuracy and variation of debris flow susceptibility maps (DFSMs) generated by various sampling strategies. The study area is the Yingxiu region in China, where six sampling strategies were applied, including three sampling locations (deposition area, runout area, and source area) and two sampling types (centroid and polygon) for the debris flow inventory. The effectiveness of 10 conditioning factors used to build the model was assessed by using Pearson correlation coefficient, variance inflation factor, and information gain ratio (IGR) techniques. We then used Weight of Evidence (WofE), Logistic Regression (LR), and Deep Neural Network (DNN) models to produce DFSMs and quantify their performance using the receiver operating characteristic curve (ROC), Accuracy (ACC), Precision, F1 score, and Recall. The results show that the WofE (AUC: 0.754–0.960), LR (AUC: 0.761–0.965), and DNN (AUC: 0.786–0.976) models all perform well, but the DFSMs and dominant factors depend strongly on sampling strategies, especially on sampling location. If the sample areas are excessively large and span across different factor class labels, or if there is a concentration of either large or small sample areas within a specific region, the results of centroid and polygon sampling strategies may differ or even be contradictory.We recommend: (1) determining sampling locations based on the research objectives to provide more accurate evaluation results; (2) selecting the sampling type by first considering the sample size. If the aforementioned conditions are not present, the quicker and more convenient centroid sampling strategy can be chosen; and (3) determining an appropriate sampling strategy and ensuring the accuracy of initial samples are paramount before producing DFSMs.

Karst areas are often characterized by fragile ecological systems, and environmental pollution has increased the pressures on people living in such regions. This study aimed to investigate the status of pollution caused by heavy metals (Pb, Cd, Hg, As, and Cu) in soils based on different land uses in Changshun County, a karst area in southwestern China. Soil samples were collected from natural forestlands (NFLs), natural brush lands (NBLs), natural pasture lands (NPLs), artificial forestlands (AFLs), artificial brush lands (ABLs), and artificial pasture lands (APLs) for evaluation. The results suggest that the soil profile characteristics of the heavy metals studied herein vary significantly among different land uses. The heavy metal concentrations in all soil samples collected from NFLs were lower than those in samples from other land uses. Forest trees can protect soil from heavy metal pollution caused by atmospheric deposition; this is especially true for Hg. In cultivated forestlands and brush lands, special attention should be devoted to Cd pollution in the soil, which may be caused by the use of fertilizers. Changing both natural and artificial pastoral lands to forestlands could benefit the local ecosystems as it may reduce Hg contamination.

IntroductionSemen Cuscutae is a traditional Chinese medicine (TCM) that tonifies the kidneys and prevents miscarriage. According to Chinese medicine theory, kidney deficiency is one of the main causes of recurrent spontaneous abortion (RSA). The previous studies showed that raw product of Semen Cuscutae (SP) and Semen Cuscutae processed with salt solution (YP) have ameliorative effects on RSA, and that YP is superior to SP. However, the active components of YP to ameliorate RSA remain unclear and require further studies. The objective of this study is to investigate the active components of YP in ameliorating RSA.MethodsFirst, a rat model of RSA was established using hydroxyurea in combination with mifepristone. Aqueous decoction of YP was given by gavage to rats. Second, pregnant rats were sampled on days 5, 7, 9, 10 and 12 during the modelling period. The content of Hyperin (HY), astragalin (AS) and kaempferol-3-O-β-D-glucuronide (KA) in blood and liver, heart, spleen, lung and kidney tissues were detected by liquid chromatography-mass spectrometry (LC-MS). The pharmacodynamic indicators including progesterone (P), chorionic gonadotropin β (β-HCG), estradiol (E2), tumor necrosis factor-α (TFN-α), interleukin 4 (IL-4), and tryptophan (TRP) were measured by enzyme-linked immunosorbent assay (ELISA) Pearson's correlation analysis and grey relational analysis were used to establish the relationship between the pharmacodynamic indexes and chemical constituents.ResultsThe pharmacokinetic results showed that the area under curve (AUC) value of KA was the largest. The tissue distribution results showed that astragalin was widely distributed in liver, heart, spleen, lung and kidney in the RSA model rats, while HY was detected only in the uterus, and KA was detected only in the kidney. The pearson correlationl analysis showed that KA was significantly and positively correlated with the contents of E2, P, β-HCG and TRP. Both AS and HY were significantly negatively correlated with the content of TNF-α, respectively.DiscussionThis study reveals the pharmacokinetics and tissue distribution of KA, AS and HY in rats with RSA. It was elucidated that all three were involved in the regulation of progesterone levels and immune function. It initially revealed the mechanism of action of YP in enhancing the improvement of RSA, and it provided a theoretical basis for the quality assessment of YP.

BackgroundBenign tumors of the spleen are rare compared to those of other parenchymal organs, accounting for less than 0.007% of all tumors, and are often found incidentally. Splenolymphangiomas are much rarer, commonly occur in children, and tend to have multiple foci. Splenic lymphangiomas are rare in adults, and fewer than 20 adult patients with isolated splenic lymphangiomas have been reported. In this article, we report the case of a middle-aged female patient with isolated splenic lymphangioma who underwent laparoscopic anatomical hypophysectomy of the lower pole of the spleen. We also summarize the existing literature on splenic lymphangioma diagnosis and available treatment options.Case presentationA 58-year-old middle-aged woman was found to have a mass approximately 60 mm in diameter at the lower pole of the spleen during a health checkup that was not accompanied by other symptoms or examination abnormalities. After completing a preoperative examination with no contraindications to surgery, the patient underwent laparoscopic anatomical splenectomy of the lower extremity of the spleen. The patient recovered well without complications and was discharged from the hospital on the 7th postoperative day. Histopathological and immunohistochemical results confirmed the diagnosis of splenic lymphangioma. Prompt surgical intervention is safe and necessary when splenic lymphangiomas are large or associated with a risk of bleeding.ConclusionSplenic lymphangiomas are rare and require early surgical intervention in patients with large tumor diameters or those at risk of rupture and bleeding. After rigorous preoperative evaluation and preparation, laparoscopic anatomical partial splenectomy is safe and feasible for surgeons with experience in laparoscopic surgery.

Primary adrenal tuberculosis is an extremely rare benign lesion that typically presents with no clinical symptoms in its early stages, making it prone to clinical misdiagnosis. We report a case of a middle-aged man initially thought to have adrenal nodules, which further examination revealed to be adrenal tuberculosis accompanied by Addison's disease. This report discusses the diagnostic approach, progressive features, and treatment options for this rare disease.

Abstract Background Dysregulation of immune surveillance is tightly linked to the development of metabolic dysfunction-associated steatohepatitis (MASH)-driven hepatocellular carcinoma (HCC); however, its underlying mechanisms remain unclear. Herein, we aimed to determine the role of interleukin-21 receptor (IL-21R) in MASH-driven HCC. Methods The clinical significance of IL-21R was assessed in human HCC specimens using immunohistochemistry staining. Furthermore, the expression of IL-21R in mice was assessed in the STAM model. Thereafter, two different MASH-driven HCC mouse models were applied between IL-21R-deficient mice and wild type controls to explore the role of IL-21R in MASH-driven HCC. To further elucidate the potential mechanisms by which IL-21R affected MASH-driven HCC, whole transcriptome sequencing, flow cytometry and adoptive lymphocyte transfer were performed. Finally, flow cytometry, enzyme-linked immunosorbent assay, immunofluorescent staining, chromatin immunoprecipitation assay and western blotting were conducted to explore the mechanism by which IL-21R induced IgA+ B cells. Results HCC patients with high IL-21R expression exhibited poor relapse-free survival, advanced TNM stage and severe steatosis. Additionally, IL-21R was demonstrated to be upregulated in mouse liver tumors. Particularly, ablation of IL-21R impeded MASH-driven hepatocarcinogenesis with dramatically reduction of lipid accumulation. Moreover, cytotoxic CD8+ T lymphocyte activation was enhanced in the absence of IL-21R due to the reduction of immunosuppressive IgA+ B cells. Mechanistically, the IL-21R-STAT1-c-Jun/c-Fos regulatory axis was activated in MASH-driven HCC and thus promoted the transcription of Igha, resulting in the induction of IgA+ B cells. Conclusions IL-21R plays a cancer-promoting role by inducing IgA+ B cells in MASH-driven hepatocarcinogenesis. Targeting IL-21R signaling represents a potential therapeutic strategy for cancer therapy.

Abstract Age-related cataract and hearing difficulties are major sensory disorders that often co-exist in the global-wide elderly and have a tangible influence on the quality of life. However, the epidemiologic association between cataract and hearing difficulties remains unexplored, while little is known about whether the two share their genetic etiology. We first investigated the clinical association between cataract and hearing difficulties using the UK Biobank covering 502,543 individuals. Both unmatched analysis (adjusted for confounders) and a matched analysis (one control matched for each patient with cataract according to confounding factors) were undertaken and confirmed that cataract was associated with hearing difficulties (OR, 2.12; 95% CI, 1.98–2.27; OR, 2.03; 95% CI, 1.86–2.23, respectively). Furthermore, we explored and quantified the shared genetic architecture of these two complex sensory disorders at the common variant level using the bivariate causal mixture model (MiXeR) and conditional/conjunctional false discovery rate method based on the largest available genome-wide association studies of cataract (N = 585,243) and hearing difficulties (N = 323,978). Despite detecting only a negligible genetic correlation, we observe polygenic overlap between cataract and hearing difficulties and identify 6 shared loci with mixed directions of effects. Follow-up analysis of the shared loci implicates candidate genes QKI, STK17A, TYR, NSF, and TCF4 likely contribute to the pathophysiology of cataracts and hearing difficulties. In conclusion, this study demonstrates the presence of epidemiologic association between cataract and hearing difficulties and provides new insights into the shared genetic architecture of these two disorders at the common variant level.

Abstract Dissolved organic matter (DOM) as critical redox active soil carbon plays a crucial role in shuttling electrons between bacteria and solid electron acceptors, such as iron oxides. However, research on DOM as an electron shuttle has traditionally focused on its impact on typical iron-reducing bacteria, namely strong exoelectrogens, like Geobacter. Besides these strong exoelectrogens, there is a significant presence of weak exoelectrogens in the soil, but studies examining how DOM affects their survival and competitiveness are lacking. This study focused on exploring the influence of DOM on weak exoelectrogens like Bacillus in the soil. By utilizing soil-bioelectrochemical systems (s-BESs) to enrich soil electroactive microorganisms, it investigated the relationship between the abundance of strong and weak exoelectrogens under conditions rich in DOM and conditions lacking DOM. The results showed that in the rich DOM treatment, the abundance of Geobacter was relatively lower (12 ± 0.5% vs. 41 ± 3%), and there was a significant negative correlation between the abundance changes of 18 weak exoelectrogens and Geobacter. This suggests that DOM caused a decrease in the population of strong exoelectrogens (e.g., Geobacter) while simultaneously promoting the growth of weak exoelectrogens (e.g., Bacillus and Sedimentibacter). Based on this, we propose that DOM, acting as an electron shuttle, creates favorable ecological niches for the thriving and propagation of weak exoelectrogens, enhancing their competitiveness within the microbial community. This new understanding provides deeper insights into the significance of DOM electron shuttling in soil microbial ecology, and raises the question: is the role of weak exoelectrogens in soil iron cycling underestimated due to the existence of DOM? Graphical Abstract