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In recent years, DNA origami-based nanocarriers have been extensively utilized for efficient cancer therapy. However, developing a nanocarrier capable of effectively protecting cargos such as RNA remains a challenge. In this study, we designed a compact and controllable DNA tubular origami (DTO) measuring 120 nm in length and 18 nm in width. The DTO exhibited appropriate structural characteristics for encapsulating and safeguarding cargo. Inside the DTO, we incorporated 20 connecting points to facilitate the delivery of cargoes to various ovarian and normal epithelial cell lines. Specifically, fluorescent-labeled DNA strands were attached to these sites as cargoes. The DTO was engineered to open upon encountering miR-21 through RNA/DNA strand displacement. Significantly, for the first time, we inhibited fluorescence using the compact DNA nanotube and observed dynamic fluorescent signals, indicating the controllable opening of DTO through live-cell imaging. Our results demonstrated that the DTO remained properly closed, exhibited effective internalization in ovarian cancer cells in vitro, showcasing marked differential expression of miR-21, and efficiently opened with short-term exposure to miR-21. Leveraging its autonomous behavior and compact design, the DTO emerges as a promising nanocarrier for various clinically relevant materials. It holds significant application prospects in anti-cancer therapy and the development of flexible biosensors.

TRIB3, a pseudokinase, was previously studied within only some specific cancer types, leaving its comprehensive functions in pan-cancer contexts largely unexplored. Here, we performed an integrated analysis of TRIB3 expression, prognosis, genetic alterations, functional enrichment and tumor immune-related characteristics in 33 cancer types. Our results showed that TRIB3 exhibits high expression levels across 24 different cancer types and correlates closely with unfavorable prognoses. Meanwhile, TRIB3 shows mutations in a wide spectrum of 22 distinct cancer types, with the predominant mutation types being missense mutations and gene amplifications, and significant changes in DNA methylation levels in 14 types of cancer. We further discovered that TRIB3 expression is significantly associated with cancer immune-related genome mutations, such as tumor mutational burden (TMB), microsatellite instability (MSI) and DNA mismatch repair (MMR), and infiltration of immunosuppressive cells, such as CD4+ Th2 cells and myeloid-derived suppressor cells (MDSCs), into the tumor microenvironment. These results indicated that the expression of TRIB3 might reshape the tumor immune microenvironment (TIME) and lead to immunosuppressive ''cold'' tumors. In addition, our results confirmed that the loss of function of TRIB3 inhibits cell proliferation, promotes apoptosis, and leads to significant enrichment of ''hot'' tumor-related immune pathways, at least in breast cancer cells, which further supports the important role of TRIB3 in cancer prognosis and TIME regulation. Together, this pan-cancer investigation provided a comprehensive understanding of the critical role of TRIB3 in human cancers, and suggested that TRIB3 might be a promising prognostic biomarker and a potential target for cancer immunotherapy.

Abstract Background Congenital heart disease (CHD) is a heterogeneous collection of structural abnormalities of the heart or great vessels that are present at birth. These birth defects are one of the leading causes of infant mortality and morbidity worldwide. The etiology and pathogenesis of CHD are unclear and largely considered to be multifactorial in nature. Since the chromosomal profile of CHD has not been analyzed in a large sample size, we aimed to summarize the clinical features, cytogenetics findings, and pregnancy outcomes of CHD to provide a clinical reference for prenatal diagnosis. Methods Among 21,152 pregnant women, 471 (2.23%) showed fetal CHD on cordocentesis or amniocentesis. The number of cases showing simple CHD, simple CHD with concomitant extracardiac structural abnormalities, complex CHD, and complex CHD with concomitant extracardiac structural abnormalities was 128, 124, 89, and 130, respectively. For prenatal genetic diagnosis, karyotyping was performed with single-nucleotide polymorphism array(SNP-array)-based chromosomal microarrays, fluorescence in situ hybridization (FISH), copy number variation sequencing (CNV-seq), and BACs-on-Beads™ (BoBs) analyses. The results of ultrasonography examinations, genetic analyses, and pregnancy outcomes were recorded in detail. Results Ventricular septal defects (VSDs) were observed in 245 (52.02%) cases of fetal CHD. Among the 471 cases of CHD, 258 (54.78%) showed other ultrasound abnormalities. The most common ultrasound abnormalities were abnormalities of the central nervous system. The 471 cases included 93 (19.75%) cases showing chromosomal abnormalities, and the incidence of these abnormalities increased with advanced maternal age or the presence of other ultrasound abnormalities. In eight cases, karyotype analysis showed normal results while SNP-array or CNV-seq results were abnormal. Among the 453 cases that were followed up, 166 (36.64%) involved pregnancy termination, 273 (60.26%) involved live births, 7 (1.55%) involved fetal death in utero, and 7 (1.55%) involved neonatal death after birth. Conclusions Fetuses with CHD showed higher rates of chromosomal abnormalities. In cases diagnosed with fetal CHD during fetal ultrasonic examination, the mothers should undergo a careful and comprehensive fetal ultrasound scan as well as prenatal genetic testing, including karyotype analysis and SNP-array or CNV-sequencing. The prognosis for simple fetal CHD is good, while the prognosis for complex fetal CHD and extracardiac anomalies is poor.

Abstract Objective To explore the cardiac structural and functional changes in obstructive sleep apnea-hypopnea syndrome (OSAHS) patients with heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF). Methods This retrospective study included 336 OSAHS patients with HFpEF. They were divided into Groups A (without an AF history and no AF episodes during cardiac color ultrasound examination), B (an AF history but no AF episodes), and C (an AF history and AF episodes). They all received cardiac color ultrasound examinations. Cardiac structural and functional changes in ultrasonic cardiograms were compared between the three groups. Results Compared with Groups A and B, Group C showed increased left atrial diameter (LAD), left atrial volume (LAV), right ventricular diameter at end-diastole (RV-D1), right ventricular diameter at end-systole (RV-D2), right ventricular outflow tract diameter (RVOT2), right atrial diameter at end-diastole (RA-D1), right atrial diameter at end-systole (RA-D2), and right atrial area (RAA) (p

Abstract Background With the ongoing prevalence of the emerging variant and global vaccination efforts, the optimal surgical timing for patients with resectable lung cancer in the Omicron-dominant period requires further investigation. Methods This prospective multicenter study involved patients who underwent radical surgery for lung cancer between January 29, 2023 and March 31, 2023. Patients were categorized into four groups based on the interval between SARS-CoV-2 infection and surgery. The main outcomes evaluated were 30-day mortality and 30-day morbidity. Results A total of 2081 patients were enrolled in the study, of which 1837 patients (88.3%) had a confirmed SARS-CoV-2 diagnosis before surgery. Notably, no instances of 30-day mortality were observed in any patient. Patients without prior infection had a 30-day morbidity rate of 15.2%, with postoperative pneumonia occurring in 7.0% of cases. In contrast, patients diagnosed with SARS-CoV-2 before surgery had significantly higher rates of 30-day morbidity and postoperative pneumonia when surgery was performed within 4–5 weeks (adjusted odds ratio (aOR) (95% CI):2.18 (1.29–3.71) and 2.39 (1.21–4.79), respectively) or within 6–7 weeks (aOR (95% CI):2.07 (1.36–3.20) and 2.10 (1.20–3.85), respectively). Conversely, surgeries performed ≥ 8 weeks after SARS-CoV-2 diagnosis exhibited similar risks of 30-day morbidity and pneumonia compared to those in the no prior infection group (aOR (95% CI):1.13 (0.77–1.70) and 1.12 (0.67–1.99), respectively). Conclusions Thoracic surgery for lung cancer conducted 4–7 weeks after SARS-CoV-2 infection is still associated with an increased risk of 30-day morbidity in the Omicron-dominant period. Therefore, surgeons should carefully assess the individual risks and benefits to formulate an optimal surgical strategy for patients with lung cancer with a history of SARS-CoV-2 infection.

Abstract Background There has been a significant surge in animal studies of stem cell-derived extracellular vesicles (EVs) therapy for the treatment of premature ovarian failure (POF) but its efficacy remains unknown and a comprehensive and up-to-date meta-analysis is lacking. Before clinical translation, it is crucial to thoroughly understand the overall impact of stem cell-derived EVs on POF. Methods PubMed, EMBASE, Cochrane Library, Web of Science were searched up to February 18, 2024. The risk of bias was evaluated according to Cochrane Handbook criteria, while quality of evidence was assessed using the SYRCLE system. The PRISMA guidance was followed. Trial sequential analysis was conducted to assess outcomes, and sensitivity analysis and publication bias analysis were performed using Stata 14. Results Data from 25 studies involving 339 animals were extracted and analyzed. The analysis revealed significant findings: stem cell-derived EVs increase ovary weight (SMD = 3.88; 95% CI: 2.50 ~ 5.25; P

BackgroundAs a key to economic and social development, occupational groups with low levels of occupational health literacy (OHL) are considered vulnerable groups with high risks of work-related diseases and injuries. Therefore, improving the OHL of these groups is of great significance in reducing the burden on public health. ObjectiveTo master the four dimensional OHL levels and influencing factors of the key groups in Fuling District, Chongqing, and provide a basis for formulating health education programs for occupational groups in the future. MethodsThe Occupational Health Literacy Questionnaire of Key Populations was distributed online to investigate the key occupational groups in Fuling District through stratified cluster sampling. The survey collected data on basic demographic information, legal knowledge of occupational health, basic knowledge of occupational health protection, basic skills of occupational health protection, and healthy working style and behavior. Univariate analysis, logistic regression, and nomogram were used to analyze the above data. ResultsThis survey distributed 4824 questionnaires, of which 4677 were valid, with a recovery rate of 97.0%. The dimensional OHL levels of key occupational groups in Fuling District from high to low were: healthy working style and behavior (79.1%), basic knowledge of occupational health protection (78.4%), legal knowledge of occupational health protection (43.3%), and basic skills of occupational health protection (37.6%). The results of logistic regression showed that the occupational health legal knowledge levels in the groups of high school/vocational high school/technical secondary school and above (reference: primary school and below) (OR=1.47, 95%CI: 1.05, 2.05), ≥3000 yuan of monthly income (reference:

Abstract Background Medical corporations, which are non-profit organizations that aim to operate hospitals, clinics, or long-term care facilities, account for more than half of all hospital beds and play a central role in the health care system in Japan. However, limited analysis of hospital integration has been performed. Examining the hospital integration trends of medical corporations can provide valuable insights for optimizing health care delivery and resource allocation in Japan. This study conducted a comprehensive analysis of trends in the hospital integration of medical corporations and market concentration in Japan using nationwide longitudinal data. Methods This longitudinal study evaluated the hospital integration of medical corporations in Japan between 2017 and 2021 using medical corporation financial data provided by the Neostage Company. The target population was medical corporations that own hospitals in Japan. The primary outcomes were the horizontal and vertical integration of medical corporation hospitals. Horizontal integration was defined as the integration of two or more hospitals within the same corporation, while vertical integration was defined as the integration of a hospital with different types of health care facilities, such as clinics or long-term care facilities, within a single medical corporation. The Herfindahl–Hirschman Index (HHI) was calculated to measure hospital market concentration using hospital bed data for medical corporations in all prefectures. Results The number of hospitals and hospital beds within medical corporations decreased from 5,670 to 848,174 in 2017 to 5,486 and 814,462 in 2021, respectively. Both horizontal and vertical integration among medical corporation facilities showed a gradual upward trend, increasing from 24.92% to 55.75% in 2017 to 26.92% and 59.42% in 2021, respectively. The mean (standard deviation [SD]) HHI increased slightly from 262.7 (178.6) in 2017 to 275.2 (187.9) in 2021, with rural areas being more concentrated than urban areas, although both remained unconcentrated. Conclusions This longitudinal study revealed a gradual downward trend in the number of hospitals and hospital beds owned by medical corporations, while horizontal and vertical integration gradually progressed without any particular medical corporation dominating the market. These findings are expected to contribute to policymaking efforts aimed at providing optimal health care services in Japan.

Abstract Background Atrial fibrillation (AF) is acknowledged as a disease continuum. Despite catheter ablation being recommended as a primary therapy for AF, the high recurrence rates have tempered the initial enthusiasm. Insulin resistance (IR) has been established as an independent predictor for the onset of AF. However, the correlation between non-insulin-based IR indices and late AF recurrence in patients undergoing radiofrequency catheter ablation remains unknown. Methods A retrospective cohort of 910 AF patients who underwent radiofrequency catheter ablation was included in the analysis. The primary endpoint was late AF recurrence during the follow-up period after a defined blank period. The relationship between non-insulin-based IR indices and the primary endpoint was assessed using multivariate Cox hazards regression models and restricted cubic splines (RCS). Additionally, the net reclassification improvement and integrated discrimination improvement index were calculated to further evaluate the additional predictive value of the four IR indices beyond established risk factors for the primary outcome. Results During a median follow-up period of 12.00 months, 189 patients (20.77%) experienced late AF recurrence, which was more prevalent among patients with higher levels of IR. The multivariate Cox hazards regression analysis revealed a significant association between these IR indices and late AF recurrence. Among the four indices, METS-IR provided the most significant incremental effect on the basic model for predicting late AF recurrence. Multivariable-adjusted RCS curves illustrated a nonlinear correlation between METS-IR and late AF recurrence. In subgroup analysis, METS-IR exhibited a significant correlation with late AF recurrence in patients with diabetes mellitus (HR: 1.697, 95% CI 1.397 − 2.063, P

Abstract In recent years, dental implants have become a trend in the treatment of human patients with missing teeth, which may also be an acceptable method for companion animal dentistry. However, there is a gap challenge in determining appropriate implant sizes for different dog breeds and human. In this study, we utilized skull computed tomography data to create three-dimensional models of the mandibles of dogs in different sizes. Subsequently, implants of various sizes were designed and subjected to biomechanical finite element analysis to determine the optimal implant size. Regression models were developed, exploring the relationship between the average weight of dogs and the size of premolar implants. Our results illustrated that the regression equations for mean body weight (x, kg) and second premolar (PM2), third premolar (PM3), and fourth premolar (PM4) implant length (y, mm) in dogs were: y = 0.2785x + 7.8209, y = 0.2544x + 8.9285, and y = 0.2668x + 10.652, respectively; the premolar implant diameter (mm) y = 0.0454x + 3.3506, which may provide a reference for determine suitable clinical implant sizes for dogs.

Tumor, as the second leading cause of death globally, following closely behind cardiovascular diseases, remains a significant health challenge worldwide. Despite the existence of various cancer treatment methods, their efficacy is still suboptimal, necessitating the development of safer and more efficient treatment strategies. Additionally, the advancement of personalized therapy offers further possibilities in cancer treatment. Nanomedicine, as a promising interdisciplinary field, has shown tremendous potential and prospects in the diagnosis and treatment of cancer. As an emerging approach in oncology, the application of nanomedicine in personalized cancer therapy primarily focuses on targeted drug delivery systems such as passive targeting drug delivery, active targeting drug delivery, and environmentally responsive targeting drug delivery, as well as imaging diagnostics such as tumor biomarker detection, tumor cell detection, and in vivo imaging. However, it still faces challenges regarding safety, biocompatibility, and other issues. This review aims to explore the advances in the use of nanomaterials in the field of personalized cancer diagnosis and treatment and to investigate the prospects and challenges of developing personalized therapies in cancer care, providing direction for the clinical translation and application.

Background: The Academic Research Consortium for High Bleeding Risk (ARC-HBR) criteria were proposed for predicting bleeding risk in patients undergoing percutaneous coronary intervention (PCI). However, there is a lack of research evaluating the risk of in-hospital bleeding following PCI for acute coronary syndrome (ACS) utilizing the ARC-HBR criteria. Methods and results: This study involved 1013 ACS patients who underwent PCI and dual antiplatelet therapy. There were 63 cases of in-hospital bleeding events (6.22 %). According to the ARC-HBR criteria, patients classified as HBR had a significantly greater bleeding rate than non-HBR patients (15.81 % vs. 1.99 %, p

Non-target fish are frequently present in crayfish aquaculture systems, yet limited research has explored their predatory impacts on crayfish larvae. To address this gap, three experiments were conducted to examine the predation dynamics of Rhodeus sinensis on Procambarus clarkii larvae, focusing on the effects of predator sizes, group sizes, and aquatic plant refuges. In experiment 1, Cox proportional hazards regression model revealed that P. clarkii larvae (8.40 mm and 11.30 mm) faced heightened predation risks from R. sinensis, particularly when the predator’s weight exceeded 2 g. Predation mortality significantly rose with increasing predator size. P. clarkii larvae primarily sought refuge in bottom corners and under heating rods, as indicated by Self-Organizing Map. Experiment 2, analyzed with Bayesian Additive Regression Tree, demonstrated that group predation of R. sinensis significantly enhanced predatory efficiency on larger crayfish larvae, resulting in reduced time to the first attack, increased total number of attacks and extended total attack duration. Experiment 3 disclosed that casualty and mortality rates of crayfish larvae markedly decreased when aquatic plants coverage exceeded 20 %, irrespective of plants types. Under predation pressure, crayfish larvae exhibited a preference for microhabitats on and under aquatic plants, indicating an adaptive behavior in response to predation. These findings underscore the susceptibility of P. clarkii larvae to predation by R. sinensis and suggest maintaining a 20 % aquatic plant coverage as an effective management strategy to mitigate predation risks and support juvenile crayfish survival in aquaculture systems.

Emeralds – the green colored variety of beryl – occur as gem-quality specimens in over fifty deposits globally. While digital traceability methods for emerald have limitations, sample-based approaches offer robust alternatives, particularly for determining the geographic origin of emerald. Three factors make emerald suitable for provenance studies and hence for developing models for origin determination. First, the diverse elemental chemistry of emerald at minor (

Degenerative musculoskeletal diseases are a class of diseases related to the gradual structural and functional deterioration of muscles, joints, and bones, including osteoarthritis (OA), osteoporosis (OP), sarcopenia (SP), and intervertebral disc degeneration (IDD). As the proportion of aging people around the world increases, degenerative musculoskeletal diseases not only have a multifaceted impact on patients, but also impose a huge burden on the medical industry in various countries. Therefore, it is crucial to find key regulatory factors and potential therapeutic targets. Recent studies have shown that irisin plays an important role in degenerative musculoskeletal diseases, suggesting that it may become a key molecule in the prevention and treatment of degenerative diseases of the musculoskeletal system. Therefore, this review provides a comprehensive description of the release and basic functions of irisin, and summarizes the role of irisin in OA, OP, SP, and IDD from a cellular and tissue perspective, providing comprehensive basis for clinical application. In addition, we summarized the many roles of irisin as a key information molecule in bone-muscle-adipose crosstalk and a regulatory molecule involved in inflammation, senescence, and cell death, and proposed the interesting possibility of irisin in degenerative musculoskeletal diseases.

The COVID-19 pandemic and large-scale administration of multiple SARS-CoV-2 vaccines have attracted global attention to the short-term and long-term effects on the human immune system. An analysis of the “traces” left by the body’s T-cell immune response is needed, especially for the prevention and treatment of breakthrough infections and long COVID-19 and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant infections. T-cell receptor complementarity determining region 3 (TCR CDR3) repertoire serves as a target molecule for monitoring the effects, mechanisms, and memory of the T-cell response. Furthermore, it has been extensively applied in the elucidation of the infectious mechanism and vaccine refinement of hepatitis B virus (HBV), influenza virus, human immunodeficiency virus (HIV), and SARS-CoV. Laboratories worldwide have utilized high-throughput sequencing (HTS) and scTCR-seq to characterize, share, and apply the TCR CDR3 repertoire in COVID-19 patients and SARS-CoV-2 vaccine recipients. This article focuses on the comparative analysis of the diversity, clonality, V&J gene usage and pairing, CDR3 length, shared CDR3 sequences or motifs, and other characteristics of TCR CDR3 repertoire. These findings provide molecular targets for evaluating T-cell response effects and short-term and long-term impacts on the adaptive immune system following SARS-CoV-2 infection or vaccination and establish a comparative archive of T-cell response “traces.”

Chimeric antigen receptor (CAR) T cell therapy has encountered limited success in solid tumors. The lack of dependable antigens and the immunosuppressive tumor microenvironment (TME) are major challenges. Within the TME, tumor cells along with immunosuppressive cells employ an immune-evasion mechanism that upregulates programmed death ligand 1 (PD-L1) to deactivate effector T cells; this makes PD-L1 a reliable, universal target for solid tumors. We developed a novel PD-L1 CAR (MC9999) using our humanized anti-PD-L1 monoclonal antibody, designed to simultaneously target tumor and immunosuppressive cells. The antigen-specific antitumor effects of MC9999 CAR T cells were observed consistently across four solid tumor models: breast cancer, lung cancer, melanoma, and glioblastoma multiforme (GBM). Notably, intravenous administration of MC9999 CAR T cells eradicated intracranially established LN229 GBM tumors, suggesting penetration of the blood-brain barrier. The proof-of-concept data demonstrate the cytolytic effect of MC9999 CAR T cells against immunosuppressive cells, including microglia HMC3 cells and M2 macrophages. Furthermore, MC9999 CAR T cells elicited cytotoxicity against primary tumor-associated macrophages within GBM tumors. The concept of targeting both tumor and immunosuppressive cells with MC9999 was further validated using CAR T cells derived from cancer patients. These findings establish MC9999 as a foundation for the development of effective CAR T cell therapies against solid tumors.

Fibrous plants with higher biomass, particularly industrial hemp, have ability to withstand and accumulate significant quantities of heavy metals from contaminated environments. The present study aimed to evaluate the dynamics of different levels (ratios) of macronutrients nitrogen, phosphorus and potassium (NPK) viz., NPK1NPK (1:1:1); NPK2NPK (2:1:1); NPK3NPK (3:1:2); NPK4NPK (4:1:2) on hemp growth and Cu contents under various levels of Cu stress (100, 400 and 800 mg kg−1 on dry soil basis using CuSO4·5H2O). Results revealed that by increasing the Cu stress, growth and biomass decreased linearly and lipid per oxidation and enzymatic antioxidants increased. Balanced application of NPK improved the biomass and decreased the membrane damage by the modulation of malonaldehyde contents. Maximum concentration of Cu in roots (377.47 ± 4.90 mg kg−1), shoots (137.45 ± 5.60 mg kg−1) and (150.07 ± 3.57 mg kg−1) was recorded at Cu3NPK2 treatment as compared to control. Maximum translocation factor (TF) and bioaccumulation coefficients (BAC) in the shoots and leaves of hemp plant were noticed where Cu stress was applied at the rate of 100 mg kg−1. However, BAC and TF were below 1. The NPK2 treatment enhanced biomass and increase Cu content both in leaves and stems, rather than the roots. Our study suggests that balanced application of NPK is a practicable approach to alleviate Cu stress and improve biomass production of industrial hemp plant. These findings indicate that optimum nutrient supply, under Cu stress, can maximize the growth potential and overall health of industrial hemp, making it a viable option for phytoremediation and sustainable agriculture on contaminated soils.

Objective To explore the effect of CD5-like molecule (CD5L) on rheumatoid arthritis (RA) fibroblast-like synoviocytes (RA-FLS) and the relative molecular mechanism of CD5L in it.Methods Recombinant protein CD5L was used to stimulate the cultured RA-FLS cells. The inflammation-related cytokines were determined by real time-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). The signal molecules and apoptosis-related molecules were detected by western blot assay (WB), and cell counting kit-8 (CCK-8) was used to detect the proliferation.Results CD5L can increase the production of IL-6, IL-8, and TNF-α and this effect can be inhibited by signal pathway inhibitor. At the same time, CD5L activated ERK1/2 MAPK signal, inhibitor treatment can weaken the intensity of phosphorylation. In addition, CD5L can enhance the proliferation ability of RA-FLS.Conclusion CD5L induces the production of inflammatory cytokines in RA-FLS through the ERK1/2 MAPK pathway and increases cell survival.

AimTo evaluate the capability of strain elastography (SE) in assessing the degree of testicular injury after torsion.Material and methodsIn total, 50 rabbits were divided into four groups according to different degrees of testicular torsion (TT) at 0°, 180°, 360°, and 720°. For each animal, according to the tissue stiffness distribution, an SE score and strain ratio (SR) were obtained. With the histopathological results as the reference, the correlation coefficients of the apoptotic index and SE score or SR were calculated, and the receiver operating characteristic (ROC) curves were created to assess the capability of SE in assessing the degree of testicular injury.ResultsA significant positive correlation was found between the apoptotic index and SE score, as well as the SR, with corresponding correlation coefficients of 0.70 (

BackgroundPorcine Reproductive and Respiratory Syndrome Virus (PRRSV) is a single-stranded positive-sense RNA virus that severely impacts the global swine industry. Recently, variation and recombination of this pathogen have led to more recombinant strains. However, commercial PRRSV vaccines provide limited protection, and no effective therapeutic drugs are available in clinical settings. Astragalus membranaceus (AM) has anti-inflammatory and immune-enhancing properties, while Curcuma zedoaria (CZ) possesses anti-inflammatory, antibacterial, and antitumor effects. The combination of AM and CZ, originating from the “Lichong Tang” recorded in the “Intergrating Chinese and Western Medicine” offers complementary and synergistic benefits.MethodsIn this study, the AM extract, CZ extract, and various ratios of CZ-AM extracts were prepared using the decoction method. The NADC30-like PRRSV strain SCCD22 was used for viral challenge. The optimal ratio and mode of action of the CZ-AM extract on Pams-163 were assessed by measuring viral copies and mRNA expression of cytokines. Subsequently, the optimal ratio of combined extracts identified in vitro was used as an adjuvant for the PRRSV inactivated vaccine in 28-day-old piglets. Clinical symptom observations, peripheral blood lymphocyte proliferation assays, levels of PRRSV antibody, cytokine secretion, and NLRP3 inflammasome mRNA were conducted to evaluate the potential of the CZ-AM extract as an adjuvant for the PRRSV inactivated vaccine.ResultsResults showed that the CZ-AM extract inhibited PRRSV in vitro, with the best ratio of CZ to AM being 1:4. Animal experiments demonstrated that using the CZ-AM extract as an adjuvant for the PRRSV inactivated vaccine significantly increased the body weight of piglets, elevated serum PRRSV antibody levels, and enhanced the piglets’ inflammatory response. mRNA analysis indicated that the CZ-AM extract inhibited key inflammatory pathways (TLR4/NLRP3/IL-1β), reducing the expression of inflammatory factors. Lymphocyte proliferation assays indicated that the CZ-AM extract significantly stimulated T and B lymphocyte proliferation.ConclusionThis study not only deepens the understanding of the pharmacological effects of AM and CZ but also expands the application of traditional Chinese medicine in the prevention and control of animal diseases. Furthermore, it provides new insights and methods for optimizing PRRSV vaccines, offering significant scientific value and broad application prospects.

Rich in flavonoids and phenolic compounds, walnut shells have lipid-lowering, antioxidant, and anti-inflammatory properties; however, their impact on blood lipids has not been widely documented. We investigated the effects of walnut shell extract (WSE) on the lipid metabolism and serum metabolomics of rats with obesity. The results showed that WSE reduced the body weight and serum TC、TG and LDL-c levels and increased the HDL-c levels in obese rats (p

BackgroundImmune-related adverse events (irAEs) typically occur within 3 months of initiating immune-checkpoint inhibitors (ICIs), which has been extensively documented. But the clinical profiles of late-onset irAEs remain inadequately characterized. Therefore, this study aims to quantify the correlation between delayed irAEs and ICIs, and to delineate the profiles of delayed toxicities associated with ICIs using data from the Food and Drug Administration Adverse Event Reporting System (FAERS).MethodsData from the January 2011 to December 2023 in FAERS database were extracted. Four signal detection indices, reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN) and multi-item gamma Poisson shrinker (MGPS), were employed to evaluate the associations between ICIs and delayed irAEs.ResultsA total of 147,854 cases were included in this study, of which 3,738 cases related to delayed irAEs were identified. Generally, 8 signals at System Organ Class (SOC) level were found to be associated with ICIs. Males had a slightly higher reporting frequencies for respiratory disorders (ROR975 = 0.95) and blood and lymphatic system disorders (ROR025 = 1.22), but lower reporting frequencies for immune system disorders (ROR025 = 1.16). Three monotherapy (anti-PD-1, anti-PD-L1 and anti-CTLA-4) were all associated with significant increasing gastrointestinal disorders (ROR025 = 1.66, 1.16, 1.99) and metabolism disorders (ROR025 = 2.26, 1.74, 3.13). Anti-PD-1 therapy exhibited higher rates of respiratory toxicities (ROR025 = 1.46 versus 0.82) and skin toxicities (ROR025 = 1.27 versus 0.94) compared with anti-CTLA-4 therapy. At PT levels, pneumonitis (ROR025: from 11.85 to 29.27) and colitis (ROR025: from 2.11 to 24.84) were the most notable PT signals associated with all three ICI regimens. For outcomes of delayed irAEs, gastrointestinal disorders showed the highest proportion (51.06%) of death.ConclusionOur pharmacovigilance analysis indicates that a small percentage of patients receiving ICIs therapy experience delayed irAEs, which are challenging to manage and may result in severe consequences. Prompt identification and intervention of these delayed irAEs are crucial in clinical practice.

ABSTRACT Pathogen infections remain a significant public health problem worldwide. Accumulating evidence regarding the crosstalk between bile acid (BA) metabolism and immune response reveals that BA metabolism regulates host immunity and microbial pathogenesis, making it an attractive target for disease prevention and infection control. However, the effect of infection on circulating BA profiles, the biosynthesis-related enzymes, and their receptors remains to be depicted. Here, we investigated the effect of viral (vesicular stomatitis virus, VSV) and bacterial (lipopolysaccharide, LPS) infections on BA metabolism and signaling. Infection models were successfully established by intraperitoneally injecting VSV and LPS, respectively. VSV and LPS injection significantly changed the circulating BA profiles, with highly increased levels of taurine-conjugated BAs and significant decreases in unconjugated BAs. Consistent with the decreased levels of circulating cholic acid (CA) and chenodeoxycholic acid (CDCA), the expression of BA biosynthesis-related rate-limiting enzymes (Cyp7a1, Cyp27a1, Cyp8b1, and Hsd3b7) were significantly reduced. Furthermore, hepatic and pulmonary BA receptors (BARs) expression varied in different infection models. LPS treatment had an extensive impact on tested hepatic and pulmonary BARs, resulting in the upregulation of TGR5, S1PR2, and VDR, while VSV infection only promoted VDR expression. Our study provides insights into the involvement of BA metabolism in the pathophysiology of infection, which may provide potential clues for targeting BA metabolism and BAR signaling to boost innate immunity and control infection.IMPORTANCEThis study focuses on the crosstalk between bile acid (BA) metabolism and immune response in VSV infection and LPS treatment models and depicts the effect of infection on circulating BA profiles, the biosynthesis-related enzymes, and their receptors. These findings provide insights into the effect of infection on BA metabolism and signaling, adding a more comprehensive understanding to the relationship between infection, BA metabolism and immune responses.

Abstract Background The pathogenesis of acute lung injury (ALI) involves a severe inflammatory response, leading to significant morbidity and mortality. N6-methylation of adenosine (m6A), an abundant mRNA nucleotide modification, plays a crucial role in regulating mRNA metabolism and function. However, the precise impact of m6A modifications on the progression of ALI remains elusive. Methods ALI models were induced by either intraperitoneal injection of lipopolysaccharide (LPS) into C57BL/6 mice or the LPS-treated alveolar type II epithelial cells (AECII) in vitro. The viability and proliferation of AECII were assessed using CCK-8 and EdU assays. The whole-body plethysmography was used to record the general respiratory functions. M6A RNA methylation level of AECII after LPS insults was detected, and then the “writer” of m6A modifications was screened. Afterwards, we successfully identified the targets that underwent m6A methylation mediated by METTL3, a methyltransferase-like enzyme. Last, we evaluated the regulatory role of METTL3-medited m6A methylation at phosphatase and tensin homolog (Pten) in ALI, by assessing the proliferation, viability and inflammation of AECII. Results LPS induced marked damages in respiratory functions and cellular injuries of AECII. The m6A modification level in mRNA and the expression of METTL3, an m6A methyltransferase, exhibited a notable rise in both lung tissues of ALI mice and cultured AECII cells subjected to LPS treatment. METTL3 knockdown or inhibition improved the viability and proliferation of LPS-treated AECII, and also reduced the m6A modification level. In addition, the stability and translation of Pten mRNA were enhanced by METTL3-mediated m6A modification, and over-expression of PTEN reversed the protective effect of METTL3 knockdown in the LPS-treated AECII. Conclusions The progression of ALI can be attributed to the elevated levels of METTL3 in AECII, as it promotes the stability and translation of Pten mRNA through m6A modification. This suggests that targeting METTL3 could offer a novel approach for treating ALI.

The uninterrupted operation of the distribution network is crucial for enhancing the security of power supply. However, factors such as environmental and line conditions may impede uninterrupted operation of overhead lines. Hence, this study conducts an analysis of factors that influence the uninterrupted operation of 10 kV overhead lines in distribution networks. To accomplish this, the Interpretative Structural Model (ISM) is employed to establish a hierarchical structure of the factors. Important factors are selected from this structure for the demand analysis of uninterrupted operation, and an optimization scheme for the design of overhead lines is proposed based on technical requirements for uninterrupted operation. Finally, the model is applied to optimize a real overhead line in a distribution network, thus validating the applicability of the proposed model.

Abstract Background Oxford Nanopore provides high throughput sequencing platforms able to reconstruct complete bacterial genomes with 99.95% accuracy. However, even small levels of error can obscure the phylogenetic relationships between closely related isolates. Polishing tools have been developed to correct these errors, but it is uncertain if they obtain the accuracy needed for the high-resolution source tracking of foodborne illness outbreaks. Results We tested 132 combinations of assembly and short- and long-read polishing tools to assess their accuracy for reconstructing the genome sequences of 15 highly similar Salmonella enterica serovar Newport isolates from a 2020 onion outbreak. While long-read polishing alone improved accuracy, near perfect accuracy (99.9999% accuracy or ~ 5 nucleotide errors across the 4.8 Mbp genome, excluding low confidence regions) was only obtained by pipelines that combined both long- and short-read polishing tools. Notably, medaka was a more accurate and efficient long-read polisher than Racon. Among short-read polishers, NextPolish showed the highest accuracy, but Pilon, Polypolish, and POLCA performed similarly. Among the 5 best performing pipelines, polishing with medaka followed by NextPolish was the most common combination. Importantly, the order of polishing tools mattered i.e., using less accurate tools after more accurate ones introduced errors. Indels in homopolymers and repetitive regions, where the short reads could not be uniquely mapped, remained the most challenging errors to correct. Conclusions Short reads are still needed to correct errors in nanopore sequenced assemblies to obtain the accuracy required for source tracking investigations. Our granular assessment of the performance of the polishing pipelines allowed us to suggest best practices for tool users and areas for improvement for tool developers.

Abstract Background There is sufficient evidence that women with atrial fibrillation (AF) have a greater symptom burden than men with AF and are more likely to experience recurrence after catheter ablation. However, the mechanisms underlying these sex differences are unclear. Methods We prospectively enrolled 125 consecutive patients, including 40 non-AF patients and 85 AF patients, who underwent high-density voltage mapping during sinus rhythm and AF patients who underwent first ablation. Results Overall, 37 (44%) female patients with AF and 24 (60%) female non-AF patients with a mean age of 61.7 ± 11.6 years and 53.6 ± 16.7 years, respectively, were enrolled in this study. The results showed that the atrial voltage of female AF patients was significantly lower than that of male AF patients (1.11 ± 0.58 mV vs. 1.53 ± 0.65 mV; P = 0.003), while there were no significant sex differences in non-AF patients (3.02 ± 0.86 mV vs. 3.21 ± 0.84 mV; P = 0.498). Multiple linear regression analysis revealed that female sex (− 0.29, 95% confidence interval [CI] − 0.64 to − 0.13, P = 0.004) and AF type (− 0.32, 95% CI − 0.69 to − 0.13, P = 0.004) were the only factors independently associated with voltage. Compared with men, women in the paroxysmal AF group had a 3.5-fold greater incidence of recurrence (adjusted hazard ratio 4.49; 95% CI 1.101–18.332, P = 0.036). Both globally and regionally, the results showed that sex-related differences in voltage values occurred prominently in paroxysmal AF patients but not in nonparoxysmal AF patients. Conclusion Sex-related differences in atrial substrates and arrhythmia-free survival were found in paroxysmal AF patients, suggesting the existence of sex-related pathophysiological factors.

ObjectiveTo understand the incidence of carotid atherosclerosis (CAS) and the association of CAS with stroke incidence in an occupational population of the Jinchang Cohort, and to provide an evidence for the prevention and treatment of CAS and stroke. MethodsThe analysis included 6 262 employees of a nonferrous metal company who participated in the Jinchang Cohort Study and had complete information from the baseline examination, including carotid color Doppler ultrasound, from June 2011 to December 2013 and two rounds of follow-up in 2015 and 2017. The cumulative incidence rates of CAS, carotid intima-media thickening, carotid atherosclerotic plaque, and stroke were calculated among the employees during the follow-up period. A multivariate unconditional logistic regression model was used to analyze the factors associated with CAS, carotid intima-media thickening, and carotid atherosclerotic plaque. A multivariate Cox proportional hazards regression model was used to analyze the risk of stroke incidence and its influencing factors in individuals with CAS, carotid intima-media thickening, and carotid atherosclerotic plaque. ResultsDuring the initial follow-up of a mean of 1.71 ± 0.55 years (ranging from 0.08 to 3.75 years), a total of 1 147 cases of CAS, 287 cases of carotid intima-media thickening, and 860 cases of carotid atherosclerotic plaque were observed, with cumulative incidence rates of 18.32%, 4.58%, and 13.73%, respectively. The results of multivariate unconditional logistic regression analysis showed that age ≥ 45 years, smoking, hypertension, diabetes, abnormal total cholesterol (TC), working as a cadre or technical personnel, and internal staff were risk factors for CAS in the occupational population; whereas education level of college or above was a protective factor; age ≥ 45 years, working as a cadre or technical personnel, smoking, having high-sugar diet, and hypertension were risk factors for carotid intima-media thickening, whereas female gender was a protective factor; females, age ≥ 45 years, working as internal staff, hypertension, diabetes, and abnormal TC were risk factors for carotid atherosclerotic plaque, whereas college education or higher was a protective factor. At the second follow-up of a mean of 2.67 ± 0.55 years (ranging from 0.06 to 4.37 years), a total of 240 stroke cases were identified, with a cumulative incidence of 3.83%. The numbers of stroke cases in subjects with CAS, carotid intima-media thickening, and carotid atherosclerotic plaque were 104, 19, and 85, with cumulative stroke incidences of 9.07%, 6.62%, and 9.88%, respectively. The results of the multivariate Cox proportional hazards regression model analysis showed that after adjusting for gender, age, education level, occupation, smoking, alcohol consumption, physical activity, high-salt diet, high-fat diet, high-sugar diet, hypertension, diabetes, hyperuricemia, body mass index (BMI), abnormal TC, abnormal triglycerides (TG), abnormal high-density lipoprotein cholesterol (HDL-C), abnormal low-density lipoprotein cholesterol (LDL-C), and reduced glomerular filtration rate, the risk of stroke was significantly increased in the individuals with CAS (hazard ratio [HR] = 1.421, 95% confidence interval [95%CI]: 1.030 – 1.961) compared with those without CAS. The results also showed that, age ≥ 45 years, high-salt diet, and overweight were risk factors for stroke incidence in the individuals with CAS; females and hyperuricemia were risk factors for stroke incidence in individuals with carotid intima-media thickening; and high school or technical secondary school education, high-salt diet, and overweight were risk factors for stroke incidence in individuals with carotid atherosclerotic plaque. ConclusionThe cumulative incidence of both CAS and stroke was high during follow-up in the occupational population of the Jinchang Cohort Study and in the occupational population, the individuals with CAS had a higher risk of stroke, and older age, high-salt diet, and overweight were the main risk factors for stroke in the individuals with CAS.

Abstract Radio-immunotherapy exploits the immunostimulatory features of ionizing radiation (IR) to enhance antitumor effects and offers emerging opportunities for treating invasive tumor indications such as melanoma. However, insufficient dose deposition and immunosuppressive microenvironment (TME) of solid tumors limit its efficacy. Here we report a programmable sequential therapeutic strategy based on multifunctional fusogenic liposomes (Lip@AUR-ACP-aptPD-L1) to overcome the intrinsic radio-immunotherapeutic resistance of solid tumors. Specifically, fusogenic liposomes are loaded with gold-containing Auranofin (AUR) and inserted with multivariate-gated aptamer assemblies (ACP) and PD-L1 aptamers in the lipid membrane, potentiating melanoma-targeted AUR delivery while transferring ACP onto cell surface through selective membrane fusion. AUR amplifies IR-induced immunogenic death of melanoma cells to release antigens and damage-associated molecular patterns such as adenosine triphosphate (ATP) for triggering adaptive antitumor immunity. AUR-sensitized radiotherapy also upregulates matrix metalloproteinase-2 (MMP-2) expression that combined with released ATP to activate ACP through an “and” logic operation-like process (AND-gate), thus triggering the in-situ release of engineered cytosine-phosphate-guanine aptamer-based immunoadjuvants (eCpG) for stimulating dendritic cell-mediated T cell priming. Furthermore, AUR inhibits tumor-intrinsic vascular endothelial growth factor signaling to suppress infiltration of immunosuppressive cells for fostering an anti-tumorigenic TME. This study offers an approach for solid tumor treatment in the clinics.

Abstract Benzodiazepines, commonly used for anxiolytics, hinder conditioned fear extinction, and the underlying circuit mechanisms are unclear. Utilizing remimazolam, an ultra-short-acting benzodiazepine, here we reveal its impact on the thalamic nucleus reuniens (RE) and interconnected hippocamposeptal circuits during fear extinction. Systemic or RE-specific administration of remimazolam impedes fear extinction by reducing RE activation through A type GABA receptors. Remimazolam enhances long-range GABAergic inhibition from lateral septum (LS) to RE, underlying the compromised fear extinction. RE projects to ventral hippocampus (vHPC), which in turn sends projections characterized by feed-forward inhibition to the GABAergic neurons of the LS. This is coupled with long-range GABAergic projections from the LS to RE, collectively constituting an overall positive feedback circuit construct that promotes fear extinction. RE-specific remimazolam negates the facilitation of fear extinction by disrupting this circuit. Thus, remimazolam in RE disrupts fear extinction caused by hippocamposeptal intermediation, offering mechanistic insights for the dilemma of combining anxiolytics with extinction-based exposure therapy.

Abstract Background The disputed phylogenetic position of Aerides flabellata Rolfe ex Downie, due to morphological overlaps with related species, was investigated based on evidence of complete chloroplast (cp) genomes. The structural characterization of complete cp genomes of A. flabellata and A. rosea Lodd. ex Lindl. & Paxton were analyzed and compared with those of six related species in “Vanda-Aerides alliance” to provide genomic information on taxonomy and phylogeny. Results The cp genomes of A. flabellata and A. rosea exhibited conserved quadripartite structures, 148,145 bp and 147,925 bp in length, with similar GC content (36.7 ~ 36.8%). Gene annotations revealed 110 single-copy genes, 18 duplicated in inverted regions, and ten with introns. Comparative analysis across related species confirmed stable sequence identity and higher variation in single-copy regions. However, there are notable differences in the IR regions between two Aerides Lour. species and the other six related species. The phylogenetic analysis based on CDS from complete cp genomes indicated that Aerides species except A. flabellata formed a monophyletic clade nested in the subtribe Aeridinae, being a sister group to Renanthera Lour., consistent with previous studies. Meanwhile, a separate clade consisted of A. flabellata and six Vanda R. Br. species was formed, as a sister taxon to Holcoglossum Schltr. Conclusions This research was the first report on the complete cp genomes of A. flabellata. The results provided insights into understanding of plastome evolution and phylogenetic relationships of Aerides. The phylogenetic analysis based on complete cp genomes showed that A. flabellata should be placed in Vanda rather than in Aerides.

Abstract Cross-modal analysis of the same whole brain is an ideal strategy to uncover brain function and dysfunction. However, it remains challenging due to the slow speed and destructiveness of traditional whole-brain optical imaging techniques. Here we develop a new platform, termed Photoacoustic Tomography with Temporal Encoding Reconstruction (PATTERN), for non-destructive, high-speed, 3D imaging of ex vivo rodent, ferret, and non-human primate brains. Using an optimally designed image acquisition scheme and an accompanying machine-learning algorithm, PATTERN extracts signals of genetically-encoded probes from photobleaching-based temporal modulation and enables reliable visualization of neural projection in the whole central nervous system with 3D isotropic resolution. Without structural and biological perturbation to the sample, PATTERN can be combined with other whole-brain imaging modalities to acquire the whole-brain image with both high resolution and morphological fidelity. Furthermore, cross-modal transcriptome analysis of an individual brain is achieved by PATTERN imaging. Together, PATTERN provides a compatible and versatile strategy for brain-wide cross-modal analysis at the individual level.

Abstract During cell differentiation, growth, and development, cells can respond to extracellular stimuli through communication channels. Pannexin (Panx) family and connexin (Cx) family are two important types of channel-forming proteins. Panx family contains three members (Panx1-3) and is expressed widely in bone, cartilage and muscle. Although there is no sequence homology between Panx family and Cx family, they exhibit similar configurations and functions. Similar to Cxs, the key roles of Panxs in the maintenance of physiological functions of the musculoskeletal system and disease progression were gradually revealed later. Here, we seek to elucidate the structure of Panxs and their roles in regulating processes such as osteogenesis, chondrogenesis, and muscle growth. We also focus on the comparison between Cx and Panx. As a new key target, Panxs expression imbalance and dysfunction in muscle and the therapeutic potentials of Panxs in joint diseases are also discussed.

Fertilization or atmospheric deposition of nitrogen (N) and phosphorus (P) to terrestrial ecosystems can alter soil N (P) availability and the nature of nutrient limitation for plant growth. Changing the allocation of leaf P fractions is potentially an adaptive strategy for plants to cope with soil N (P) availability and nutrient-limiting conditions. However, the impact of the interactions between imbalanced anthropogenic N and P inputs on the concentrations and allocation proportions of leaf P fractions in forest woody plants remains elusive. We conducted a meta-analysis of data about the concentrations and allocation proportions of leaf P fractions, specifically associated with individual and combined additions of N and P in evergreen forests, the dominant vegetation type in southern China where the primary productivity is usually considered limited by P. This assessment allowed us to quantitatively evaluate the effects of N and P additions alone and interactively on leaf P allocation and use strategies. Nitrogen addition (exacerbating P limitation) reduced the concentrations of leaf total P and different leaf P fractions. Nitrogen addition reduced the allocation to leaf metabolic P but increased the allocation to other fractions, while P addition showed opposite trends. The simultaneous additions of N and P showed an antagonistic (mutual suppression) effect on the concentrations of leaf P fractions, but an additive (summary) effect on the allocation proportions of leaf P fractions. These results highlight the importance of strategies of leaf P fraction allocation in forest plants under changes in environmental nutrient availability. Importantly, our study identified critical interactions associated with combined N and P inputs that affect leaf P fractions, thus aiding in predicting plant acclimation strategies in the context of intensifying and imbalanced anthropogenic nutrient inputs.

Monocrotaline (MCT), a major pyrrolizidine alkaloid, is well-known for its high liver toxicity. Dysregulation of autophagy induced apoptosis can lead to various liver diseases, including those induced by chemical compounds. Therefore, we aim to explore whether autophagy might serve as a potential strategy for addressing liver apoptosis caused by MCT. In primary rat hepatocytes (PRHs), MCT significantly increased the number of autophagosomes and the expression levels of LC3II, Becline-1, and Atg5, while it decreased the expression of p62 in a concentration-dependent manner at doses of 100, 200, 300, and 400 μM. Western blot assays revealed MCT inhibited the phosphorylation levels of the PI3K/AKT/mTOR pathway. To elucidate the role of autophagy in mediating MCT-induced apoptosis, we further pretreated PRHs with the autophagy agonist Rapamycin and the inhibitors Bafilomycin A1 and Chloroquine, respectively, and assessed the apoptosis of PRHs induced by MCT. The results displayed that Rapamycin increased the apoptosis rate and the expression of cleaved caspase-3, whereas Bafilomycin A1 and Chloroquine reduced the apoptosis and the expression of cleaved caspase-3 in PRHs. This study confirms that autophagy enhances PRHs apoptosis induced by MCT. In summary, this study demonstrates that MCT-induced autophagy via inhibition of the PI3K/AKT/mTOR pathway can lead to apoptosis in PRHs.

Abstract BackgroundInternet-based cognitive behavioral therapy (iCBT) shows promise in the prevention of depression. However, the specific iCBT components that contribute to its effectiveness remain unclear. ObjectiveWe aim to evaluate the effects of iCBT components in preventing depression among university students. MethodsUsing a smartphone cognitive behavioral therapy (CBT) app, we randomly allocated university students to the presence or absence of 5 different iCBT components: self-monitoring, behavioral activation, cognitive restructuring, assertiveness training, and problem-solving. The active intervention lasted 8 weeks but the app remained accessible through the follow-up. The primary outcome was the onset of a major depressive episode (MDE) between baseline and the follow-up after 52 weeks, as assessed with the computerized World Health Organization Composite International Diagnostic Interview. Secondary outcomes included changes in the 9-item Patient Health Questionnaire, 7-item General Anxiety Disorder, and CBT Skills Scale. ResultsDuring the 12-month follow-up, 133 of 1301 (10) participants reported the onset of an MDE. There were no significant differences in the incidence of MDEs between the groups with or without each component (hazard ratios ranged from 0.85, 95% CI 0.60‐1.20, for assertiveness training to 1.26, 95% CI 0.88‐1.79, for self-monitoring). Furthermore, there were no significant differences in the changes on the 9-item Patient Health Questionnaire, 7-item General Anxiety Disorder, or for CBT Skills Scale between component allocation groups. However, significant reductions in depression and anxiety symptoms were observed among all participants at the 52-week follow-up. ConclusionsIn this study, we could not identify any specific iCBT components that were effective in preventing depression or the acquisition of CBT skills over the 12-month follow-up period, but all participants with and without intervention of each iCBT component demonstrated significant improvements in depressive and anxiety symptoms. Further research is needed to explore the potential impact of frequency of psychological assessments, nonspecific intervention effects, natural change in the mental state, and the baseline depression level.

Dilated cardiomyopathy (DCM) remains an enigmatic myocardial disorder characterized either by enlargement of either the left or right ventricle or both and reduced contractility, posing a significant burden on pediatric populations as a leading cause of cardiac-related mortality and morbidity. This paper presents a compelling case of DCM in a Han Chinese child whose genomic analysis unveiled a novel LMNA-C.185G>C (p.Arg62Pro) variant. Over a meticulous 3-year clinical follow-up, spanning ten outpatient consultations and hospital admissions since the initial diagnosis, the patient exhibited a progressive emergence of various cardiac conduction anomalies closely mirroring LMNA-associated phenotypes. Delving into a comprehensive review of the patient's 14-year medical journey and familial history, antecedent signs of muscular dystrophy (MD) predated DCM onset. Familial scrutiny revealed a lineage marred by muscular atrophy, with the patient's maternal grandmother having a history of muscular dystrophy and an episode of DCM, necessitating cardiac transplantation in the patient's uncle at age 37. This scenario illuminates the intricate interplay between LMNA-associated diseases and genetic predisposition. Timely identification of etiological triggers stands paramount in DCM management. Beyond conventional genetic scrutiny, leveraging novel serum biomarkers such as anti-heart muscle antibodies (AHA) remarkably enhanced diagnostic precision. Notably, personalized therapeutic interventions comprising prednisolone regimens and intravenous immunoglobulin infusions precipitated marked amelioration in heart failure symptoms and serum biomarker profiles. It is noteworthy to identify this novel genetic locus within the Han Chinese populace, underscoring the imperative of expanding the LMNA mutation repository within this demographic cohort. Early recognition of clinical manifestations and etiological cues in pediatric DCM heralds a paradigm shift in risk prognostication and individualized therapeutic interventions, underscoring the profound significance of precision medicine in combating rare familial cardiomyopathies.

BackgroundSevere acute pancreatitis (SAP) is accompanied with acute onset, rapid progression, and complicated condition. Sepsis is a common complication of SAP with a high mortality rate. This research aimed to identify the shared hub genes and key pathways of SAP and sepsis, and to explore their functions, molecular mechanism, and clinical value.MethodsWe obtained SAP and sepsis datasets from the Gene Expression Omnibus (GEO) database and employed differential expression analysis and weighted gene co-expression network analysis (WGCNA) to identify the shared differentially expressed genes (DEGs). Functional enrichment analysis and protein–protein interaction (PPI) was used on shared DEGs to reveal underlying mechanisms in SAP-associated sepsis. Machine learning methods including random forest (RF), least absolute shrinkage and selection operator (LASSO) and support vector machine recursive feature elimination (SVM-RFE) were adopted for screening hub genes. Then, receiver operating characteristic (ROC) curve and nomogram were applied to evaluate the diagnostic performance. Finally, immune cell infiltration analysis was conducted to go deeply into the immunological landscape of sepsis.ResultWe obtained a total of 123 DEGs through cross analysis between Differential expression analysis and WGCNA important module. The Gene Ontology (GO) analysis uncovered the shared genes exhibited a significant enrichment in regulation of inflammatory response. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that the shared genes were primarily involved in immunoregulation by conducting NOD-like receptor (NLR) signaling pathway. Three machine learning results revealed that two overlapping genes (ARG1, HP) were identified as shared hub genes for SAP and sepsis. The immune infiltration results showed that immune cells played crucial part in the pathogenesis of sepsis and the two hub genes were substantially associated with immune cells, which may be a therapy target.ConclusionARG1 and HP may affect SAP and sepsis by regulating inflammation and immune responses, shedding light on potential future diagnostic and therapeutic approaches for SAP-associated sepsis.

Abstract The challenge of disease relapsed/refractory (R/R) remains a therapeutic hurdle in chimeric antigen receptor (CAR) T‐cell therapy, especially for hematological diseases, with chronic lymphocytic leukemia (CLL) being particularly resistant to CD19 CAR T cells. Currently, there is no approved CAR T‐cell therapy for CLL patients. In this study, we aimed to address this unmet medical need by choosing the B‐cell activating factor receptor (BAFF‐R) as a promising target for CAR design against CLL. BAFF‐R is essential for B‐cell survival and is consistently expressed on CLL tumors. Our research discovered that BAFF‐R CAR T‐cell therapy exerted the cytotoxic effects on both CLL cell lines and primary B cells derived from CLL patients. In addition, the CAR T cells exhibited cytotoxicity against CD19‐knockout CLL cells that are resistant to CD19 CAR T therapy. Furthermore, we were able to generate BAFF‐R CAR T cells from small blood samples collected from CLL patients and then demonstrated the cytotoxic effects of these patient‐derived CAR T cells against autologous tumor cells. Given these promising results, BAFF‐R CAR T‐cell therapy has the potential to meet the long‐standing need for an effective treatment on CLL patients.

Disease-related malnutrition is a prevalent issue among cancer patients, affecting approximately 40–80% of those undergoing treatment. This condition is associated with numerous adverse outcomes, including extended hospitalization, increased morbidity and mortality, delayed wound healing, compromised muscle function and reduced overall quality of life. Moreover, malnutrition significantly impedes patients’ tolerance of various cancer therapies, such as surgery, chemotherapy, and radiotherapy, resulting in increased adverse effects, treatment delays, postoperative complications, and higher referral rates. At present, numerous countries and regions have developed objective assessment models to predict the risk of malnutrition in cancer patients. As advanced technologies like artificial intelligence emerge, new modeling techniques offer potential advantages in accuracy over traditional methods. This article aims to provide an exhaustive overview of recently developed models for predicting malnutrition risk in cancer patients, offering valuable guidance for healthcare professionals during clinical decision-making and serving as a reference for the development of more efficient risk prediction models in the future.

Abstract Cadmium (Cd) is a neurotoxic contaminant that induces cognitive decline similar to that observed in Alzheimer's disease (AD). Autophagic flux dysfunction is attributed to the pathogenesis of AD, and this study aimed to investigate the effect of autophagy on environmental Cd‐induced AD progression and the underlying mechanism. Here, Cd exposure inhibited autophagosome‐lysosome fusion and impaired lysosomal function, leading to defects in autophagic clearance and then to APP accumulation and nerve cell death. Proteomic analysis coupled with Ingenuity Pathway Analysis (IPA) identified SIRT5 as an essential molecular target in Cd‐impaired autophagic flux. Mechanistically, Cd exposure hampered the expression of SIRT5, thus increasing the succinylation of RAB7A at lysine 31 and inhibiting RAB7A activity, which contributed to autophagic flux blockade. Importantly, SIRT5 overexpression led to the restoration of autophagic flux blockade, the alleviation of Aβ deposition and memory deficits, and the desuccinylation of RAB7A in Cd‐exposed FAD4T mice. Additionally, SIRT5 levels decrease mainly in neurons but not in other cell clusters in the brains of AD patients according to single‐nucleus RNA sequencing data from the public dataset GSE188545. This study reveals that SIRT5‐catalysed RAB7A desuccinylation is an essential adaptive mechanism for the amelioration of Cd‐induced autophagic flux blockade and AD‐like pathogenesis.

Human apolipoprotein E (ApoE) was first identified as a polymorphic gene in the 1970s; however, the genetic association of ApoE genotypes with late-onset sporadic Alzheimer’s disease (sAD) was only discovered 20 years later. Since then, intensive research has been undertaken to understand the molecular effects of ApoE in the development of sAD. Despite three decades’ worth of effort and over 10,000 papers published, the greatest mystery in the ApoE field remains: human ApoE isoforms differ by only one or two amino acid residues; what is responsible for their significantly distinct roles in the etiology of sAD, with ApoE4 conferring the greatest genetic risk for sAD whereas ApoE2 providing exceptional neuroprotection against sAD. Emerging research starts to point to a novel and compelling hypothesis that the sialoglycans posttranslationally appended to human ApoE may serve as a critical structural modifier that alters the biology of ApoE, leading to the opposing impacts of ApoE isoforms on sAD and likely in the peripheral systems as well. ApoE has been shown to be posttranslationally glycosylated in a species-, tissue-, and cell-specific manner. Human ApoE, particularly in brain tissue and cerebrospinal fluid (CSF), is highly glycosylated, and the glycan chains are exclusively attached via an O-linkage to serine or threonine residues. Moreover, studies have indicated that human ApoE glycans undergo sialic acid modification or sialylation, a structural alteration found to be more prominent in ApoE derived from the brain and CSF than plasma. However, whether the sialylation modification of human ApoE has a biological role is largely unexplored. Our group recently first reported that the three major isoforms of human ApoE in the brain undergo varying degrees of sialylation, with ApoE2 exhibiting the most abundant sialic acid modification, whereas ApoE4 is the least sialylated. Our findings further indicate that the sialic acid moiety on human ApoE glycans may serve as a critical modulator of the interaction of ApoE with amyloid β (Aβ) and downstream Aβ pathogenesis, a prominent pathologic feature in AD. In this review, we seek to provide a comprehensive summary of this exciting and rapidly evolving area of ApoE research, including the current state of knowledge and opportunities for future exploration.

Microwave ablation (MWA) is a potent cancer treatment tool, but its effectiveness can be hindered by the lack of visual feedback. This paper validates the feasibility of using microwave-induced thermoacoustic imaging (TAI) technique to monitor the MWA process. A feasibility analysis was conducted at the principle level and a high-performance real-time TAI system was introduced. To address the interference caused by MWA, a robust principal component analysis (RPCA)-based method for TAI was proposed. This method leverages the correlation between multiple signal frames to eliminate interference. RPCA’s effectiveness in TAI was demonstrated through three sets of different experiments. Experiments demonstrated that TAI can effectively monitors the MWA process. This work represents the first application of RPCA-related matrix decomposition methods in TAI, paving the way for the application of TAI in more complex clinical scenarios. By providing rapid and accurate visual feedback, this research advances MWA technology.

Lipid-coated perfluorocarbon nanodroplets (lp-NDs) hold great promise in bio-medicine as vehicles for drug delivery, molecular imaging and vaccine agents. However, their clinical utility is restricted by limited targeted accumulation, attributed to the innate immune system (IIS), which acts as the initial defense mechanism in humans. This study aimed to optimize lp-ND formulations to minimize non-specific clearance by the IIS. Ginsenosides (Gs), the principal components of Panax ginseng, possessing complement inhibition ability, structural similarity to cholesterol, and comparable fat solubility to phospholipids, were used as promising candidate IIS inhibitors. Two different types of ginsenoside-based lp-NDs (Gs lp-NDs) were created, and their efficacy in reducing IIS recognition was examined. The Gs lp-NDs were observed to inhibit the adsorption of C3 in the protein corona (PC) and the generation of SC5b-9. Adding Gs to lp-NDs reduced complement adsorption and phagocytosis, resulting in a longer blood circulation time in vivo compared to lp-NDs that did not contain Gs. These results suggest that Gs can act as anti-complement and anti-phagocytosis adjuvants, potentially reducing non-specific clearance by the IIS and improving lifespan.

Abstract Radix Fici Simplicissimae (RFS) is widely studied, and is in demand for its value in medicines and food products, with increased scientific focus on its cultivation and breeding. We used ultra-high-performance liquid chromatography quadrupole-orbitrap mass spectrometry-based metabolomics to elucidate the similarities and differences in phytochemical compositions of wild Radix Fici Simplicissimae (WRFS) and cultivated Radix Fici Simplicissimae (CRFS). Untargeted metabolomic analysis was performed with multivariate statistical analysis and heat maps to identify the differences. Eighty one compounds were identified from WRFS and CRFS samples. Principal component analysis and orthogonal partial least squares discrimination analysis indicated that mass spectrometry could effectively distinguish WRFS from CRFS. Among these, 17 potential biomarkers with high metabolic contents could distinguish between the two varieties, including seven phenylpropanoids, three flavonoids, one flavonol, one alkaloid, one glycoside, and four organic acids. Notably, psoralen, apigenin, and bergapten, essential metabolites that play a substantial pharmacological role in RFS, are upregulated in WRFS. WRFS and CRFS are rich in phytochemicals and are similar in terms of the compounds they contain. These findings highlight the effects of different growth environments and drug varieties on secondary metabolite compositions and provide support for targeted breeding for improved CRFS varieties.

Acute pancreatitis (AP) is one of the most common acute abdomen diseases with increasing incidence and substantial healthcare burden. Gut microbiota disturbance, mucosal barrier failure, and bacterial translocation are identified as the dominant cause of infected pancreatic necrosis and high mortality. With the advance of high-throughput sequencing, imbalance between beneficial and facultative pathogenic microorganisms with their metabolic activities in the development of AP has been increasingly recognized, whereas it remains unclear whether dysbacteriosis is the dominant cause of aggravating AP, or merely reflecting different epidemiological or environmental factors at the individual level. This review discussed the alterations of the gut microbiota and their metabolites during AP with detailed molecular mechanisms. Importantly, it highlights microbiome-based medical therapies which influence gut barrier function and immune homeostasis to mitigate inflammatory responses in AP. Our review will provide a novel roadmap of gastrointestinal microecology in AP progression, and contribute to the future development of microbiome-based diagnostic and therapeutic strategies in clinical practice.

Abstract Background Ultrasound three-dimensional visualization, a cutting-edge technology in medical imaging, enhances diagnostic accuracy by providing a more comprehensive and readable portrayal of anatomical structures compared to traditional two-dimensional ultrasound. Crucial to this visualization is the segmentation of multiple targets. However, challenges like noise interference, inaccurate boundaries, and difficulties in segmenting small structures exist in the multi-target segmentation of ultrasound images. This study, using neck ultrasound images, concentrates on researching multi-target segmentation methods for the thyroid and surrounding tissues. Method We improved the Unet++ to propose PA-Unet++ to enhance the multi-target segmentation accuracy of the thyroid and its surrounding tissues by addressing ultrasound noise interference. This involves integrating multi-scale feature information using a pyramid pooling module to facilitate segmentation of structures of various sizes. Additionally, an attention gate mechanism is applied to each decoding layer to progressively highlight target tissues and suppress the impact of background pixels. Results Video data obtained from 2D ultrasound thyroid serial scans served as the dataset for this paper.4600 images containing 23,000 annotated regions were divided into training and test sets at a ratio of 9:1, the results showed that: compared with the results of U-net++, the Dice of our model increased from 78.78% to 81.88% (+ 3.10%), the mIOU increased from 73.44% to 80.35% (+ 6.91%), and the PA index increased from 92.95% to 94.79% (+ 1.84%). Conclusions Accurate segmentation is fundamental for various clinical applications, including disease diagnosis, treatment planning, and monitoring. This study will have a positive impact on the improvement of 3D visualization capabilities and clinical decision-making and research in the context of ultrasound image.

Abstract. Background:. Copper and zinc are involved in the development of multiple malignancies; yet, epidemiological evidence on hepatocellular carcinoma (HCC) is limited. This study aimed to investigate the association between dietary intake and serum levels of copper and zinc with the risk of HCC. Methods:. A total of 434 case-control pairs matched for sex and age (±1 year) were included in this study. Cases with newly diagnosed HCC were from the Guangdong Liver Cancer Cohort (GLCC) study, and healthy controls were from the Guangzhou Nutrition and Health Study (GNHS). A semi-quantitative 79-item food frequency questionnaire (FFQ) was used to assess habitual dietary intakes of copper and zinc. Serum levels of copper and zinc were measured by using inductively coupled plasma mass spectrometry. The copper (Cu)/ zinc (Zn) ratio was computed by dividing copper levels by zinc levels. Conditional logistic regression models were performed to calculate the odds ratio (OR) and 95% confidence intervals (CI) for per 1 standard deviation increase (per-SD increase) in copper and zinc levels. Results:. Higher dietary intake (ORper-SD increase = 0.65, 95% CI: 0.44, 0.96, Ptrend = 0.029) and serum levels of zinc (ORper-SD increase = 0.11, 95% CI: 0.04, 0.30, Ptrend