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Abstract Rapid, accurate preoperative imaging diagnostics of appendicitis are critical in surgical decisions of emergency care. This study developed a fully automated diagnostic framework using a 3D convolutional neural network (CNN) to identify appendicitis and clinical information from patients with abdominal pain, including contrast-enhanced abdominopelvic computed tomography images. A deep learning model—Information of Appendix (IA)—was developed, and the volume of interest (VOI) region corresponding to the anatomical location of the appendix was automatically extracted. It was analysed using a two-stage binary algorithm with transfer learning. The algorithm predicted three categories: non-, simple, and complicated appendicitis. The 3D-CNN architecture incorporated ResNet, DenseNet, and EfficientNet. The IA model utilising DenseNet169 demonstrated 79.5% accuracy (76.4–82.6%), 70.1% sensitivity (64.7–75.0%), 87.6% specificity (83.7–90.7%), and an area under the curve (AUC) of 0.865 (0.862–0.867), with a negative appendectomy rate of 12.4% in stage 1 classification identifying non-appendicitis versus. appendicitis. In stage 2, the IA model exhibited 76.1% accuracy (70.3–81.9%), 82.6% sensitivity (62.9–90.9%), 74.2% specificity (67.0–80.3%), and an AUC of 0.827 (0.820–0.833), differentiating simple and complicated appendicitis. This IA model can provide physicians with reliable diagnostic information on appendicitis with generality and reproducibility within the VOI.

Abstract Genetic mutations in apoptosis-inducing factor (AIF) have a strong association with mitochondrial disorders; however, little is known about the aberrant splicing variants in affected patients and how these variants contribute to mitochondrial dysfunction and brain development defects. We identified pathologic AIF3/AIF3-like splicing variants in postmortem brain tissues of pediatric individuals with mitochondrial disorders. Mutations in AIFM1 exon-2/3 increase splicing risks. AIF3-splicing disrupts mitochondrial complexes, membrane potential, and respiration, causing brain development defects. Mechanistically, AIF is a mammalian NAD(P)H dehydrogenase and possesses glutathione reductase activity controlling respiratory chain functions and glutathione regeneration. Conversely, AIF3, lacking these activities, disassembles mitochondrial complexes, increases ROS generation, and simultaneously hinders antioxidant defense. Expression of NADH dehydrogenase NDI1 restores mitochondrial functions partially and protects neurons in AIF3-splicing mice. Our findings unveil an underrated role of AIF as a mammalian mitochondrial complex-I alternative NAD(P)H dehydrogenase and provide insights into pathologic AIF-variants in mitochondrial disorders and brain development.

Abstract T lymphocytes (T cells) are essential components of the adaptive immune system that play a vital role in identifying and eliminating infected and tumor cells. In tumor immunotherapy, T cells have emerged as a promising therapeutic strategy due to their high specificity, potent cytotoxic capability, long-lasting immune memory, and adaptability within immunotherapeutic approaches. However, tumors can evade the immune system by depleting T cells through various mechanisms, such as inhibitory receptor signaling, metabolic exhaustion, and physical barriers within the tumor microenvironment. This review provided an overview of the mechanisms underlying T-cell depletion in tumors and discussed recent advances in clinical research related to T-cell immunotherapy for tumors. It highlighted the need for in-depth studies on key issues such as indications, dosage, and sequencing of combined therapeutic strategies tailored to different patients and tumor types, providing practical guidance for individualized treatment. Future research on T-cell depletion would be necessary to uncover the fundamental mechanisms and laws of T-cell depletion, offering both theoretical insights and practical guidance for the selection and optimization of tumor immunotherapy. Furthermore, interdisciplinary, cross-disciplinary, and international collaborative innovations are necessary for developing more effective and safer treatments for tumor patients.

Abstract Background Tigecycline is widely used to treat a variety of bacterial infections despite concerns regarding increased mortality in severe infections. Previous case reports have documented breakthrough bloodstream infections (BSI) during tigecycline therapy. This study aimed to investigate the incidence of, and risk factors for, breakthrough BSI during tigecycline monotherapy. Methods A retrospective matched case–control study was conducted in a 2700-bed tertiary referral center, involving patients who received tigecycline monotherapy. Patients with breakthrough BSI (1:1) were matched with controls without breakthrough BSI based on age, sex, and date of tigecycline therapy. Results Of 4505 patients treated with tigecycline, 115 (2.6%, 95% confidence interval 2.1 to 3.1%) developed breakthrough BSI. The most frequently identified pathogen in breakthrough BSI was Klebsiella pneumoniae (22.8%), followed by Candida species (17.1%), Pseudomonas aeruginosa (16.3%), and Acinetobacter baumannii (14.6%). Of the K. pneumoniae and A. baumannii isolates for which tigecycline susceptibility results were available, 50% and 23%, respectively, were tigecycline-resistant (MIC > 2 mg/L). Intraabdominal (33.9%), catheter-related (30.4%), and hepatobiliary (19.1%) infections were the main sources of breakthrough BSI. In multivariable analysis, independent risk factors for breakthrough BSI during tigecycline therapy were liver cirrhosis (adjusted odds ratio [aOR], 3.09), indwelling catheter (aOR, 3.42), previous Candida colonization (aOR, 14.95), and previous multi-drug resistant bacteria colonization (aOR, 10.30). Conclusion In cases where there is a high suspicion of breakthrough BSI during tigecycline therapy, meticulous management and prudent selection of empirical antibiotics are crucial due to the diverse range of causative microorganisms involved.

Abstract Background Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with poor prognosis, nomogram model for its prognosis and acute exacerbation was constructed. Methods Two hundred and sixty eight patients with IPF were grouped with different severity according to fibrosis area, serum Club cell secretory protein 16(CC16) was compared between these groups. All patients were randomly divided into training and testing sets. COX regression and LASSO algorithm were used to screen featured characteristics. Then nomogram models were constructed, ROC curve, calibration curve and decision curve analysis(DCA) were conducted to evaluate the performance of model. Expression of CC16 were detected in fibrotic human lung tissues, bronchoalveolar lavage fluid (BALF) and Bleomycin(BLM)-treated mouse lung tissues and serums. Results Serum CC16 gradually increased with the severity of fibrosis, and was especially high in AE-IPF group. CC16 and diffusion capacity for carbon monoxide (DLCO) were screened as characteristic variables to construct nomogram model for IPF prognosis. The survival was significantly lower in high-risk group scored by the model. The area under ROC curves(AUCs) for 1-year and 2-year mortality prediction were 0.866 and 0.916, respectively. This model performed better than gender-age-physiology (GAP) index for predicting 2-year and 3-year mortality. Another nomogram model for acute exacerbation of IPF based on CC16, Krebs von den Lungen-6(KL-6) and DLCO was developed, the AUC was 0.815. Expression of CC16 obviously up-regulated in fibrotic lung tissues, BALF and BLM-treated mice lung tissues and serums. Conclusions The nomogram model based on CC16 performed good predictive ability for prognosis and acute exacerbation of IPF.

Abstract K2P (two-pore domain potassium) channels, a diversified class of K+-selective ion channels, have been found to affect a wide range of physiological processes in the body. Despite their established significance in regulating proliferation and differentiation in multiple cell types, K2P channels’ specific role in adipogenic differentiation (adipogenesis) remains poorly understood. In this study, we investigated the engagement of K2P channels, specifically KCNK2 (also known as TREK-1), in adipogenesis using primary cultured adipocytes and TREK-1 knockout (KO) mice. Our findings showed that TREK-1 expression in adipocytes decreases substantially during adipogenesis. This typically causes an increased Ca2+ influx and alters the electrical potential of the cell membrane in 3T3-L1 cell lines. Furthermore, we observed an increase in differentiation and lipid accumulation in both 3T3-L1 cell lines and primary cultured adipocytes when the TREK-1 activity was blocked with Spadin, the specific inhibitors, and TREK-1 shRNA. Finally, our findings revealed that mice lacking TREK-1 gained more fat mass and had worse glucose tolerance when fed a high-fat diet (HFD) compared to the wild-type controls. The findings demonstrate that increase of the membrane potential at adipocytes through the downregulation of TREK-1 can influence the progression of adipogenesis.

Purpose: This study aimed to explore the trends in research keywords and topics in the field of urology based on text mining over the recent decades. The investigation looked into changes in frequent subject keywords and the trends in prevailing research topics, as reflected in representative urology journals over recent decades. Materials and Methods: A total of 27,129 bibliographic documents were collected from four urology journals, including European Urology, Journal of Urology, BJU International, and World Journal of Urology. The study then examined the changes in the most frequent author keywords over the decades. Moreover, structured topic modeling was employed to identify twenty prevailing research topics in urology and to examine their trends across different periods. Results: The study observed consistently increasing patterns in author keywords and topics related to the prostate and oncology. Conversely, research fields such as pediatrics, male infertility, voiding dysfunction, and cancer biology exhibited a downward trend in urology. Potential factors or reasons underlying these trends were further discussed in this study. Conclusions: This exploratory study uncovered major research topics in the discipline of urology. The findings of this study depict the domain of urology research in recent decades, providing insights for both researchers and clinicians seeking to better understand the research trends in the discipline.

Abstract Background Impairment of the inner blood-retinal barrier (iBRB) leads to various blinding diseases including diabetic retinopathy (DR). The cGAS-STING pathway has emerged as a driving force of cardiovascular destruction, but its impact on the neurovascular system is unclear. Here, we show that cGAMP, the endogenous STING agonist, causes iBRB breakdown and retinal degeneration thorough P2RX7-mediated transport into microglia. Methods Extracellular cGAMP and STING pathway were determined in tissue samples from patients with proliferative DR (PDR) and db/db diabetic mice. Histological, molecular, bioinformatic and behavioral analysis accessed effects of cGAMP on iBRB. Single-cell RNA sequencing identified the primary retinal cell type responsive to cGAMP. Specific inhibitors and P2RX7-deficienct mice were used to evaluate P2RX7’ role as a cGAMP transporter. The therapeutic effects of P2RX7 inhibitor were tested in db/db mice. Results cGAMP was detected in the aqueous humor of patients with PDR and elevated in the vitreous humor with STING activation in db/db mouse retinas. cGAMP administration led to STING-dependent iBRB breakdown and neuron degeneration. Microglia were the primary cells responding to cGAMP, essential for cGAMP-induced iBRB breakdown and visual impairment. The ATP-gated P2RX7 transporter was required for cGAMP import and STING activation in retinal microglia. Contrary to previous thought that mouse P2RX7 nonselectively transports cGAMP only at extremely high ATP concentrations, human P2RX7 directly binds to cGAMP and activates STING under physiological conditions. Clinically, cGAMP-induced microglial signature was recapitulated in fibrovascular membranes from patients with PDR, with P2RX7 being predominantly expressed in microglia. Inhibiting P2RX7 reduced cGAMP-STING activation, protected iBRB and improved neuron survival in diabetic mouse retinas. Conclusions Our study reveals a mechanism for cGAMP-mediated iBRB breakdown and suggests that targeting microglia and P2RX7 may mitigate the deleterious effects of STING activation in retinal diseases linked to iBRB impairment.

Grain-boundary diffusion process (GBDP) emerges as a crucial technology of high-coercivity Nd-Fe-B permanent magnets for the efficient utilization of heavy rare-earths (HREs) Tb and Dy. However, besides the formation of preferred Tb/Dy-rich shell surrounding Tb/Dy-lean core (shell/core structure), the anti-shell/core structure also occurs and causes excessive Tb/Dy consumption. In present work, to gain a deeper verification on the evolution of shell/core and anti-shell/core structure, the multi-main-phase (MMP) Nd-Dy-Fe-Ga-B base magnets were subjected to Tb diffusion over a wide range of duration from 0 h to 36 h. The time-dependent formation of shell/core and anti-shell/core structure with corresponding magnetic responses was unveiled. Before the depletion of deposited Tb film (diffusion time

Abstract Lipid metabolism, particularly fatty acid oxidation dysfunction, is a major driver of renal fibrosis. However, the detailed regulatory mechanisms underlying this process remain unclear. Here we demonstrated that acyl-CoA thioesterase 12 (Acot12), an enzyme involved in the hydrolysis of acyl-CoA thioesters into free fatty acids and CoA, is a key regulator of lipid metabolism in fibrotic kidneys. A significantly decreased level of ACOT12 was observed in kidney samples from human patients with chronic kidney disease as well as in samples from mice with kidney injuries. Acot12 deficiency induces lipid accumulation and fibrosis in mice subjected to unilateral ureteral obstruction (UUO). Fenofibrate administration does not reduce renal fibrosis in Acot12 −/− mice with UUO. Moreover, the restoration of peroxisome proliferator-activated receptor α (PPARα) in Acot12 −/− Pparα −/− kidneys with UUO exacerbated lipid accumulation and renal fibrosis, whereas the restoration of Acot12 in Acot12 −/− Pparα −/− kidneys with UUO significantly reduced lipid accumulation and renal fibrosis, suggesting that, mechanistically, Acot12 deficiency exacerbates renal fibrosis independently of PPARα. In Acot12 −/− kidneys with UUO, a reduction in the selective autophagic degradation of peroxisomes and pexophagy with a decreased level of ACBD5 was observed. In conclusion, our study demonstrates the functional role and mechanistic details of Acot12 in the progression of renal fibrosis, provides a preclinical rationale for regulating Acot12 expression and presents a novel means of preventing renal fibrosis.

Abstract Background Premature ventricular complexes (PVCs) are generally benign in healthy children, but in some cases, a persistent high PVC burden may be observed, potentially related to ventricular tachycardia or left ventricular dysfunction. This study explores the natural history of PVCs in children with structurally normal hearts and identifies factors associated with unresolved PVCs. Methods We retrospectively analyzed demographic and clinical data from children

The design of commercial spaces is a critical factor affecting the modern consumer experience, and the visual interactions within these spaces are one of the significant metrics of purchasing behavior. This study aims to explore the influence of spatial layout in commercial spaces on visitors’ visual perception and behavior. The study uses a glasses-type eye-tracking and behavior-tracking observation experiment to record consumers’ reactions to salient stimuli within the visual system as encountered in the space. Because of the specific characteristics of the experimental site, the study was conducted exclusively with female participants, each of whom participated in two distinct types of experiments. The results reveal a clear correlation between visual concentration and behavioral patterns during product exploration in the commercial space. Notably, it was found that direct interaction with the product increased visual concentration and is a significant factor in explaining behavioral changes within the space and the differences in stages of visual perception. This study is significant in that it establishes a research framework that aligns the human visual system with behavior types by examining variations in gaze data values and pupil sizes associated with selective focus as behavior changes to analyze the emergence of specific behaviors during the decision-making stages related to visual perception and cognition.

Abstract This paper systemically assesses the performances of two assimilation methods, i.e., the Offline Ensemble Kalman Filter (OEnKF) and the Hybrid Gain Analog Offline EnKF (HGAOEnKF) with three proxy databases, on reconstructing the temperature and precipitation during the last two millennia. The results show that, among three databases, increasing the number of proxy records significantly improves the reconstruction skill for both assimilation methods, with a larger improvement in HGAOEnKF. In the instrumental era, six reconstructions have comparable skill (similar correlation coefficients, CEs, and RMSEs) when validated against out-of-sample proxy records and instrumental reanalyses. During the pre-industrial era, HGAOEnKF shows better assimilation performance by improving the background field of assimilation when the number of proxy records is limited. Compared with the temperature reconstruction, the skill of precipitation reconstruction is relatively lower. The proxy records from the ocean contribute more to the temperature reconstruction skill with both assimilation methods. Finally, a new reanalysis product (NNU-2ka Reanalysis) is generated through the HGAOEnKF with the expanded proxy database.

Abstract Lipopolysaccharide (LPS) exacerbates liver injury by activating various inflammatory pathways. Clusterin, a glycoprotein involved in lipid transport, and cytoprotection, is known to have inhibitory effects on liver steatosis and fibrosis. In this study, we investigated the role of clusterin in regulating LPS-induced liver injury and its effects on liver injury in C57BL/6 mice and clusterin knockout mice injected with LPS for 3 h. Primary Kupffer cells (KCs) and hepatocytes (HCs) were isolated from these mice and examined using immunohistochemistry, real-time RT-PCR, ELISA, and western blot analysis to assess the effects of clusterin. Clusterin deficiency significantly exacerbated LPS-induced liver injury, as evidenced by increased inflammatory cell infiltration, elevated serum alanine aminotransferase and aspartate aminotransferase levels, and upregulated expression of pro-inflammatory cytokines and components of the NLRP3 inflammasome. By contrast, overexpression of clusterin in primary Kupffer cells and hepatocytes significantly reduced these inflammatory markers. Furthermore, the protective mechanism of clusterin involved inhibition of the STAT3 signaling pathway. These findings suggest that clusterin is a useful therapeutic target to modulate cytokine production and key inflammatory signaling pathways in inflammatory liver diseases.

Abstract Breast cancer is a prevalent malignancy worldwide, and its treatment has increasingly shifted towards precision medicine, with immunotherapy emerging as a key therapeutic strategy. Deubiquitination, an essential epigenetic modification, is regulated by deubiquitinating enzymes (DUBs) and plays a critical role in immune function and tumor progression. Ubiquitin-specific proteases (USPs), a prominent subgroup of DUBs, are involved in regulating immune cell functions, antigen processing, and T cell development in the context of breast cancer. Certain USPs also modulate the differentiation of immune cells, such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), within the breast cancer immune microenvironment. Furthermore, several USPs influence the expression of PD-L1, thus affecting the efficacy of immune checkpoint inhibitors. The overexpression of USPs may promote immune evasion, contributing to the development of treatment resistance. This review elucidates the role of USPs in modulating the immune microenvironment and immune responses in breast cancer. Additionally, it discusses effective strategies for combining USP inhibitors with other therapeutic agents to enhance treatment outcomes. Therefore, targeting USPs presents the potential to enhance the efficacy of immunotherapy and overcome drug resistance, offering a more effective treatment strategy for breast cancer patients.

Highlights The layered arrangement and gradient distribution of magnetic MXene are firstly combined to improve the electromagnetic wave (EMW) RL min and broaden effective absorption bandwidth. Absorption, reflection, and transmission (A–R–T) power coefficient analysis is firstly used to guide the gradient distribution, so as to realize EMW incidence at low-concentration surface, loss at middle concentration interlayer and reflection at high-concentration bottom. The layered gradient composite (LG5-10-15) achieves complete absorption coverage of X-band at thickness of 2.00-2.20 mm with RL min of -68.67 dB.

Abstract We evaluated the diagnostic performance of the newly developed MoiM Dx Candida 9-plex (MoiM) assay for the detection of Candida species from positive blood cultures and compared the results with those obtained from the BIOFIRE Blood Culture Identification 2 (BCID2) Panel. This study included 39 candidaemia cases and 40 cases of non-Candida bloodstream infections as negative controls. Routine culture results, which were identified via matrix-assisted laser desorption/ionization time‒of‒flight mass spectrometry (MALDI‒TOF MS), were used as the reference standard for analysis. The performance of the MoiM assay was evaluated using positive percent agreement (PPA) and negative percent agreement (NPA). The MoiM assay demonstrated a PPA of 97.1% and an NPA of 100% for detecting the five most common Candida species (C. albicans, C. glabrata, C. tropicalis, C. parapsilosis, and C. krusei) in candidaemia cases. In comparison, the BCID2 panel yielded a PPA of 67.6% and an NPA of 100.0% (P = 0.001). Additionally, the MoiM assay correctly identified C. guilliermondii and C. lusitaniae, not covered by the BCID2 panel. Among the 10 discrepant results between the two assays, all 10 cases were incompletely identified by the BCID2 panel, but the results from the MoiM assay were identical to the culture results. The MoiM assay was designed as an automated sample-to-answer molecular assay for the detection of Candida species from positive blood cultures. Our study revealed that this assay shows good overall agreement with routine culture and is comparable to the BCID2 panel.

Abstract The aim of this study was to investigate lymphocyte subsets, especially natural killer (NK) cells, in patients with systemic sclerosis (SSc) and evaluate the diagnostic value of NK cells in secondary pulmonary arterial hypertension (PAH). A total of 115 SSc patients and 100 age- and sex-matched health controls (HCs) were enrolled in this study. Flow cytometry was employed to quantify NK cells, while the association between NK cells and disease activity as well as PAH was investigated to further elucidate its diagnostic potential. The absolute count of NK (CD3-CD56+) cells significantly decreased in SSc patients. There was a negative correlation between the mRSS score and the injury index. The levels of cytokine exhibited significant elevation among SSc patients. Conversely, SSc-PAH patients demonstrated significantly elevated levels of CRP, UA, and BNP. Additionally, there was a significant reduction in the absolute level of NK cells. ROC curve analysis revealed that the optimal cut-off point for NK cells was 185 cells/µL, while for BNP it was 70.50 pg/mL and for UA it was 323.00 µmol/L. Our study revealed a significant inverse correlation between peripheral blood NK cell levels and the incidence of complicated PAH in patients with SSc.

Abstract Residual Cancer Burden (RCB) after neoadjuvant chemotherapy (NAC) is validated to predict event-free survival (EFS) in breast cancer but has not been studied for invasive lobular carcinoma (ILC). We studied patient-level data from a pooled cohort across 12 institutions. Associations between RCB index, class, and EFS were assessed in ILC and non-ILC with mixed effect Cox models and multivariable analyses. Recursive partitioning was used in an exploratory model to stratify prognosis by RCB components. Of 5106 patients, the diagnosis was ILC in 216 and non-ILC in 4890. Increased RCB index was associated with worse EFS in both ILC and non-ILC (p = 0.002 and p

Abstract Background The impact of otolaryngological diseases on sleep quality, anxiety, and depression has garnered significant attention. However, research has primarily focused on unveiling the effects of only one or two specific diseases, without analyzing the impact of multiple concurrent diseases. Furthermore, investigation into the interaction mechanisms among these factors has been lacking. Objectives This study reveals the effects of different otolaryngological diseases on sleep quality, anxiety, and depression, and investigates their interaction mechanisms. Methods In total, 2,080 patients with otolaryngological diseases were recruited from six centers in mainland China. Data on sociodemographics, history of smoking and alcohol consumption, diagnosis, anxiety, depression, and sleep quality were collected through hospital information system queries and questionnaires. We uncovered the psychological status and sleep quality of otolaryngology outpatients with different diseases and revealed the interaction mechanisms between these diseases and anxiety, depression, and sleep quality. Multivariable polynomial linear regression models explored the impact of different otolaryngological diseases on anxiety, depression and sleep quality, and mediation analysis explored the interaction mechanisms. Results Chronic laryngitis, eustachian tube disorders, laryngeal swelling, laryngopharyngeal reflux, neck lymphatic inflammation, snoring, sudden deafness, tinnitus, nasopharyngeal lesions, and trauma had a significant impact on Pittsburgh Sleep Quality Index scores. Chronic tonsillitis, chronic laryngitis, and laryngopharyngeal reflux had a significant impact on Zung Self-Rating Depression Scale scores. Patients with giddiness (P = 0.006) and tinnitus (P = 0.006) tended to have higher Zung Self-Rating Anxiety Scale scores. Anxiety mediated the effect of tinnitus on sleep quality (70.41%; 95% confidence interval [CI]: 40.07, 76.00), and depression also had a mediation effect (13.24%; 95% CI: 4.46, 28.58). Other diseases also exhibited mediating effects and interactions with anxiety, depression, and sleep quality. Conclusions Sleep quality significantly mediates the relationships of specific otolaryngological diseases with anxiety and depression. Similarly, anxiety and depression play important mediating roles in the relationships of different diseases with sleep quality. By revealing the interactive effects of different otolaryngological diseases on anxiety, depression, and sleep quality, this study could aid early interventions aiming to reduce anxiety and depression and improve patients’ sleep quality and quality of life.

Abstract Background Prior research has established a correlation between childhood maltreatment (CM) and personality traits. The current understanding regarding the potential variability in the relationship between CM and its impact on personality dimensions among those with major depressive disorder (MDD) and healthy controls (HCs) remains elusive. Aims This study analyzes the association between CM and personality traits in the MDD and HC groups. Methods The study recruited 188 individuals with MDD and 132 HC. The Childhood Trauma Questionnaire (CTQ) was used to assess CM, and the Sixteen Personality Factor Questionnaire (16PF) was used to assess personality traits. We used a 2*2 analysis of covariance (ANCOVA) of the diagnosis and CM on 16PF, and hierarchical regression explored the association between specific types of CM and 16PF in both groups. Results The 2*2 ANCOVA results indicated significant interaction effects between CM and diagnosis on personality traits, with CM’s impact notably different between groups. In the MDD group, sexual abuse (SA) independently predicted the subscale Q1 (Openness to Change), related to the Big Five’s openness. In the HC group, emotional abuse (EA) predicted the subscales C (emotional stability), O (apprehension), and Q4(tension), linked to Big Five’s neuroticism. Conclusion The findings highlight the impact of early adversity on personality development, informing psychology and guiding tailored therapy development.

To optimize the enzymatic hydrolysis process of Morchella esculenta and expore the volatile flavor compounds in its enzymatic hydrolysate, the enzymatic hydrolysis was optimized by response surface design, and the key flavor compounds were identified by headspace-solid phase microextraction-gas chromatography-mass spectrometry (HS-SPME-GC-MS) combined with the odor activity value (OAV). Results indications were as follows: enzyme addition amount of 5000 U/g, pH6.7, enzymolysis temperature at 44 ℃ for 2 h, the hydrolysis degree was 34.11% under the above mentioned conditions and a total of 23 volatile flavor compounds were identified by GC-MS analysis, among which 17 werein blank group and 21 in enzymatic group. After enzymatic hydrolysis process, the content of flavor compounds increased by 203.71%. Aldehydes were the main volatile flavor compounds, accounting for 78.50% of the whole flavor compounds. Compounds with OAV≥1 were further analyzed, including 7 in the blank group and 9 in the enzymatic group. Isovaleraldehyde, phenylacetaldehyde, hexenal, benzaldehyde, nonanal, linalool, 2-amylfuran, limonene and naphthalene were identified as the key flavor compounds in the enzymatic hydrolysate of Morchella esculenta. Enzymatic hydrolysis can promote the release of flavor compounds, thus providing data basis for the flavor utilization, the deep processing and development of seasoning for Morchella esculenta.

Abstract Background Although nutrition-starvation therapy for malignancies such as HNSCC is highly desirable, the clinical outcomes remain disappointing. Understanding the spatial heterogeneity of glucose deficiency can reveal the molecular mechanisms regulating cancer metabolism and identify therapeutic targets to improve effective nutrient-starvation therapies. Methods Multiple omics data from RNA-seq, proteomics and spatial transcriptome analyses of HNSCC samples were integrated to analyze the spatial heterogeneity of glucose deficiency. In vivo and in vitro CXCL8 and CLU expression levels in tumor cells were determined using qPCR, immunohistochemistry and ELISA. The ability of CLU from TAMs to respond to tumor-derived CXCL8 was assessed using RNA sequencing, siRNA silencing, immunofluorescence and CCK-8 assays. A mouse subcutaneous xenograft model was used to assess the outcomes of nutrition-starvation therapy combined with blockade of CXCL8 signaling. Results A set of genes that was significantly upregulated in HNSCC under conditions of glucose deficiency was identified using integrating multiple omics data analyses. The upregulated gene set was used to determine the glucose-deficient area according to transcriptome data of HNSCC, and CXCL8 was one of the most highly upregulated genes. The levels of both CXCL8 mRNA and its protein IL-8 in cancer cells under conditions of glucose deficiency were increased in an NF-κB-dependent manner. Supplementary IL-8 stimulated TAMs to synthesize CLU, and CLU counteracted oxidative stress in HNSCC cells under conditions of glucose deficiency. Moreover, pharmacological blockade of CXCL8 signaling (reparixin) sensitized HNSCC cells to nutrient-starvation therapy (anlotinib) in two xenograft models. Conclusion Our results provide novel evidence of a feedback loop between cancer cells and TAMs in glucose-deficient regions. HNSCC-derived CXCL8 favors endogenous antioxidative processes and confers therapeutic resistance to nutrient-starvation therapies in HNSCC. Graphical Abstract

Abstract Aims Whether medication adherence to angiotensin receptor‐neprilysin inhibitor (ARNI) in real‐world practice is associated with the reduced risk of all‐cause mortality or hospitalization relative to that with traditional renin–angiotensin system (RAS) blockade remains unclear. This study investigated the influence of medication adherence of ARNI and traditional RAS blockade in heart failure with reduced ejection fraction (HFrEF). Method We conducted a nationwide longitudinal cohort study with patients with HFrEF using data from the Korean National Health Insurance Service data (2017–2021) covering the entire population. A total of 13 483 patients with HFrEF who received ARNI were matched 1:1 with 13 483 patients who received traditional RAS blockade using propensity score matching. The primary outcome was a composite of all‐cause mortality or any hospitalization within one year. Medication adherence was assessed by calculating the proportion of days covered (PDC) relative to total medication prescribed. ARNI and traditional RAS blockade adherence rates were directly compared to analyse their respective associations with the primary outcome. Results Patients in the ARNI group had a lower rate of the primary outcome than those in the traditional RAS blockade group [hazard ratio (HR) 0.78; 95% confidence interval (CI) 0.75–0.81; P

The eastern uplift of the Junggar Basin has great coalbed methane (CBM) exploration potential. CBM selection and evaluation will provide scientific guidance and direction for CBM exploration in the region. Utilizing well logging data, core analysis test results, and seismic data, well-seismic calibration and seismic profile interpretation were carried out. Connecting-well profiles and thickness distribution maps for coal seams in the Jurassic Xishanyao and Badaowan formations were compiled. The study analyzed main accumulation factors, including gas source, basic characteristics of coal rocks, reservoir physical properties, gas content, and preservation conditions. The results show that: ① Coal seams of the Xishanyao Formation are distributed continuously in the Wucaiwan-Wutongwozi sags to the north of the Shaqi Uplift, while to the south of the Shaqi Uplift, the seams are mainly distributed in the Jimusaer-Jinan sags. Coal seams of the Badaowan Formation are strongly segmented and mainly distributed in parts of the sags. ② This region contains self-sourced biogenic gas from coal seams, low-maturity thermogenic gas, and high-maturity deep-seated exogenous gas. ③ The organic components in coal rocks are mainly inertinite, followed by vitrinite with small amounts of exinite. The vitrinite reflectance (Ro) in coal rocks is low (0.39%-0.47%), indicating low-rank coal. CBM mainly consists of N2, CO2, and CH4, with N2 being the dominant component. The combustible gas (CH4) content is low relative to the total gas content in coal rocks. ④ CBM enrichment and accumulation models include piedmont fault depression, deep depression, and open slope gas escape models. ⑤ Evaluation parameters and classification standards were established. The Wucaiwan, Wutongwozi, Jimusaer, and Jinan sags are favorable areas for CBM exploration. The Shazhang fault-fold belt and the Shiqiantan Sag are moderately favorable areas. The Shishugou and Gucheng sags are unfavorable areas.

Abstract Th17 cells are activated by STAT3 factors in the nucleus, and these factors are correlated with the pathologic progression of rheumatoid arthritis (RA). Recent studies have demonstrated the presence of STAT3 in mitochondria, but its function is unclear. We investigated the novel role of mitochondrial STAT3 (mitoSTAT3) in Th17 cells and fibroblast-like synoviocytes (FLSs) and analyzed the correlation of mitoSTAT3 with RA. We used a collagen-induced arthritis (CIA) mouse model to determine the effect of mitochondrial STAT3. We observed changes in the RA mouse model via the use of a mitochondrial STAT3-inducing vector and inhibitor. We observed the accumulation of abnormal autophagosomes, increased inflammatory cell death signaling, and decreased mitoSTAT3 activity in FLSs from both patients with RA and patients with IL-17-treated FLSs. We first discovered that IL-17 increased the accumulation of abnormal autophagosomes and the expression of inflammatory cell death factors in synovial fibroblasts and decreased mitoSTAT3 activation. In a mouse model of CIA, arthritis and joint inflammation were decreased by injection vectors that induced mitoSTAT3 overexpression. The abnormal accumulation of autophagosomes and the expression of inflammatory cell death factors were also decreased in these mice. In mouse and human immune cells, ZnSO4, an inducer of mitochondrial STAT3, decreases the production of reactive oxygen species, the IL-17 concentration, and differentiation into Th17 cells. However, mitoSTAT3 blockade accelerated the development of arthritis, inflammatory cell death, and abnormal autophagosome/autophagolysosome formation. Therefore, this study suggests a novel inhibitory mechanism of RA using mitoSTAT3 via the regulation of autophagy, Th17 differentiation, and inflammatory cell death.

Abstract Background Cadaveric dissection is an essential practice for medical students to understand human anatomy and internalize professional attitudes toward death, such as empathy and respect for the deceased. Previous studies have focused on emotional responses such as shock, anxiety, and fear at the start of dissection practice. However, limited research exists on students’ reflective thinking and perceptions before practice. This study aims is to understand premedical students’ perceptions and attitudes before dissection by analyzing their reflective writing. Methods Text network analysis of essays written in 2022 by 136 s-year premedical students before cadaveric dissection was performed. Keywords were preprocessed to extract significant themes. Centrality analysis and topic modeling were performed to analyze students’ perceptions and attitudes. Results Centrality analysis identified “cadaveric dissection,” “donation,” and “gratitude” as major keywords, indicating the students’ deep appreciation and respect for donors. Two main topics emerged from topic modeling. The first, “gratitude and respect for donors,” included keywords such as “gratitude” and “donation.” The second, “growth and responsibility of doctors through medical study and practice,” included keywords such as “study” and “medical school.” Conclusion The participants had profound gratitude and respect for donors before cadaveric dissection, which increased their motivation to learn. Analyzing reflective writing is an effective approach to understanding students’ initial perceptions and attitudes toward cadaveric dissection; further, it can inform educational strategies that aid students in forming their professional identity.

Abstract Background Osteoarthritis (OA) is prevalent, yet its management remains challenging. This meta-analysis aims to evaluate the efficacy of acupuncture combined with moxibustion versus other standard treatments in patients with knee osteoarthritis (KOA) based on randomized controlled trials (RCTs). Methods Searches were conducted in Ovid MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials to retrieve relevant RCTs. Data on baseline characteristics, treatment efficacy, and adverse events were extracted. The analysis utilized pooled weighted mean differences (WMD) and risk ratios (RR) with 95% confidence intervals (CIs) to assess the superior treatment modality. Results A total of 18 RCTs were included. Acupuncture combined with moxibustion demonstrated significant improvement in the visual analog scale (VAS) for pain and the long-term (> 60 weeks) Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores for pain, stiffness, and physical function compared to other treatments. In contrast, short- (

Abstract Background Clear cell renal cell carcinoma (ccRCC) represents the most prevalent subtype, accounting for nearly 80% of all RCC cases. Recent research has shown that high expression of circular non-coding RNA (circRNA) is associated with poor prognosis in patients with renal clear cell carcinoma (ccRCC), however, the underlying mechanism remains unclear. Methods After analysing self-sequenced renal cancer and paracancer circRNA sequencing data and comparing it with the GEO public database, we discovered that circASAP1 expression was significantly up-regulated in renal cancers. We also tested circASAP1 levels in 102 renal cancer patients and found that high expression of circASAP1 was associated with poor prognosis and metastasis. The interaction between circASAP1, HNRNPC and their downstream target genes was confirmed through experiments such as RNA pull-down, RIP and fluorescence in situ hybridisation. A series of in vitro and in vivo functional experiments were performed to verify the effects of circASAP1 on RCC proliferation and metastasis. Results Circular RNA sequencing analysis revealed that circASAP1 expression was markedly elevated in ccRCC, with a significant association observed between elevated circASAP1 expression and poor prognosis and metastasis. Actinomycin D, RNase R, as well as fluorescence in situ hybridization (FISH) analyses revealed the ring structure and cytoplasmic localization of circASAP1. High circASAP1 expression was associated with ccRCC cell proliferative viability, invasion, and metastasis in CCK-8, transwell, plate cloning, and EdU experiments. Interaction of circASAP1 with HNRNPC and their downstream target genes was confirmed by RNA pull-down, RNA immunoprecipitation, FISH, silver staining, and mass spectrometry. Experiments using truncated isoforms demonstrated that amino acids 16–87 of HNRNPC bound circASAP1. Proteins altered by circASAP1 were enriched in the ferroptosis pathway on the Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. Conclusions The relationship between circRNA and the ASAP1/HNRNPC/GPX4 axis was demonstrated by experimental data, which was further confirmed by rescue experiments. circASAP1 influenced tumor growth and ferroptosis in animal experiments and predicted the prognosis of patients with ccRCC. The circASAP1/HNRNPC/GPX4 axis provides novel directions and potential targets for RCC treatment.

Abstract The efficacy of neoadjuvant therapy varies significantly with hormone receptor (HR) status for patients with human epidermal growth factor receptor 2 (HER2) positive breast cancer (BC). Despite extensive research on HER2 + BC, the optimal neoadjuvant strategy for HR+/HER2 + BC remains inconclusive. This study aimed to identify the optimal neoadjuvant regimen for HR+/HER2 + BC treatment. We conducted a systematic search for trials comparing neoadjuvant regimens for HR+/HER2 + BC and a network meta-analysis. Odds ratios for pathological complete response (pCR) and hazard ratios for event-free survival (EFS) were calculated. Treatment regimens were ranked using the surface under the cumulative ranking curve. 20 trials with 2809 patients were included. In pCR analysis, three neoadjuvant regimens sequentially ranked at the top, namely those comprising T-DM1, pertuzumab with trastuzumab, and tyrosine kinase inhibitor with trastuzumab, demonstrating significantly higher pCR rates than monotherapies. In EFS analysis, pertuzumab with trastuzumab ranked the first while T-DM1 containing regimen ranked the last. Anthracycline-free regimens showed a marginally higher pCR rate than anthracycline-containing regimens, while carboplatin-containing regimens demonstrated a numerically higher pCR rate than carboplatin-free regimens. Significant heterogeneity was observed in endocrine therapy analysis, which may be caused by different strategies for incorporating endocrine therapy. In conclusion, trastuzumab plus pertuzumab stands out as the optimal neoadjuvant HER2-targeting regimen for HR+/HER2 + BC Furthermore, anthracycline-free carboplatin-containing chemotherapy emerges as a promising combination treatment. Further investigation is required to clarify the role of endocrine therapy in HR+/HER2 + BC to guide its clinical application.

Abstract Unsymmetric disulfides are prevalent in natural products and are essential in medicinal chemistry and materials science, but their robust synthesis poses significant challenges. In this paper, we report an expeditous transition-metal-free methodology for synthesizing unsymmetric disulfides through the addition of perthiyl radicals to alkenes. This study marks the use of generating perthiyl radicals by reacting SO2 with unactivated alkyl (pseudo)halides (Cl/Br/I/OTs). Various primary, secondary and tertiary alkyl (pseudo)halides substituted with different functional groups successfully function as suitable reactants. The formation of perthiyl radicals and their involvement in the reaction process are verified through mechanistic studies and DFT calculations. Overall, this method leverages readily available alkyl electrophiles and alkenes alongside SO2 in a single reaction setup to efficiently form both carbon-sulfur and sulfur-sulfur bonds simultaneously.

Abstract Employing electrochemistry for the selective functionalization of liquid alkanes allows for sustainable and efficient production of high-value chemicals. However, the large potentials required for C(sp 3)-H bond functionalization and low water solubility of such alkanes make it challenging. Here we discover that a Pt/IrO x electrocatalyst with optimized Cl binding energy enables selective generation of Cl free radicals for C-H chlorination of alkanes. For instance, we achieve monochlorination of cyclohexane with a current up to 5 A, Faradaic efficiency (FE) up to 95% and stable performance over 100 h in aqueous KCl electrolyte. We further demonstrate that our system can directly utilize concentrated seawater derived from a solar evaporation reverse osmosis process, achieving a FE of 93.8% towards chlorocyclohexane at a current of 1 A. By coupling to a photovoltaic module, we showcase solar-driven production of chlorocyclohexane using concentrated seawater in a membrane electrode assembly cell without any external bias. Our findings constitute a sustainable pathway towards renewable energy driven chemicals manufacture using abundant feedstock at industrially relevant rates.

The orb-weaver spider genus Yaginumia Archer, 1960 from China is revised, and three species, including two new species, are recognized: Y. medog Mi & Wang, sp. nov. (♂♀) from Xizang and Y. qiong Mi & Wang, sp. nov. (♂♀) from Hainan; the type species, Y. sia (Strand, 1906) (♂♀), is redescribed based on specimens from Guizhou and Hubei. A distributional map of the studied specimens is also provided.

Abstract Background The practical application of infectious disease emergency plans in mental health institutions during the ongoing pandemic has revealed significant shortcomings. These manifest as chaotic management of mental health care, a lack of hospital infection prevention and control (IPC) knowledge among medical staff, and unskilled practical operation. These factors result in suboptimal decision-making and emergency response execution. Consequently, we have developed a digital-based emergency prevention and control system to reinforce IPC management in psychiatric hospitals and enhance the hospital IPC capabilities of medical staff. Methods The system incorporates modern technologies such as cloud computing, big data, streaming media, and knowledge graphs. A cloud service platform was established at the PaaS layer using Docker container technology to manage infectious disease emergency-related services. The system provides application services to various users through a Browser/Server Architecture. The system was implemented in a class A tertiary mental health center from March 1st, 2022, to February 28th, 2023. Twelve months of emergency IPC training and education were conducted based on the system. The system’s functions and the users’ IPC capabilities were evaluated. Results A total of 116 employees participated in using the system. The system performance evaluation indicated that functionality (3.78 ± 0.68), practicality (4.02 ± 0.74), reliability (3.45 ± 0.50), efficiency (4.14 ± 0.69), accuracy (3.36 ± 0.58), and assessability (3.05 ± 0.47) met basic levels (> 3), with efficiency improvement and practicality achieving a good level (> 4). After 12 months of training and study based on the system, the participants demonstrated improved emergency knowledge (χ2 = 37.69, p

Abstract Inter-individual variability in symptoms and the dynamic nature of brain pathophysiology present significant challenges in constructing a robust diagnostic model for migraine. In this study, we aimed to integrate different types of magnetic resonance imaging (MRI), providing structural and functional information, and develop a robust machine learning model that classifies migraine patients from healthy controls by testing multiple combinations of hyperparameters to ensure stability across different migraine phases and longitudinally repeated data. Specifically, we constructed a diagnostic model to classify patients with episodic migraine from healthy controls, and validated its performance across ictal and interictal phases, as well as in a longitudinal setting. We obtained T1-weighted and resting-state functional MRI data from 50 patients with episodic migraine and 50 age- and sex-matched healthy controls, with follow-up data collected after one year. Morphological features, including cortical thickness, curvature, and sulcal depth, and functional connectivity features, such as low-dimensional representation of functional connectivity (gradient), degree centrality, and betweenness centrality, were utilized. We employed a regularization-based feature selection method combined with a random forest classifier to construct a diagnostic model. By testing the models with varying feature combinations, penalty terms, and spatial granularities within a strict cross-validation framework, we found that the combination of curvature, sulcal depth, cortical thickness, and functional gradient achieved a robust classification performance. The model performance was assessed using the test dataset and achieved 87% accuracy and 0.94 area under the curve (AUC) at distinguishing migraine patients from healthy controls, with 85%, 0.97 and 84%, 0.93 during the interictal and ictal/peri-ictal phases, respectively. When validated using follow-up data, which was not included during model training, the model achieved 91%, 94%, 89% accuracies and 0.96, 0.94, 0.98 AUC for the total, interictal, and ictal/peri-ictal phases, respectively, confirming its robustness. Feature importance and clinical association analyses exhibited that the somatomotor, limbic, and default mode regions could be reliable markers of migraine. Our findings, which demonstrate a robust diagnostic performance using multimodal MRI features and a machine-learning framework, may offer a valuable approach for clinical diagnosis across diverse cohorts and help alleviate the decision-making burden for clinicians.

Abstract Background Older people living with HIV-1 (PLWH) experience a dual burden from the combined effects of aging and HIV-1 infection, resulting in significant immune dysfunction. Despite receiving HAART, immune reconstitution is not fully optimized. The objective of this study was to investigate the impact of aging and HAART on T cell subsets and function in PLWH across different age groups, thereby providing novel insights into the prognosis of older PLWH. Method This study was conducted at Yunnan AIDS Care Center, China, to explore the immunological responses of old PLWH to HAART and compared with the middle-age and the younger. Blood samples were collected from 146 PLWH to analyze T cell subsets and their functions, with a particular emphasis on markers related to T cell differentiation, activation, exhaustion, inflammation, and cellular function, using multicolor flow cytometry analysis. Results Older age may have a greater effect on long-term CD4+T cell recovery. Compared with young and middle-aged PLWH, older PLWH presented distinct alterations in their immune profile, including a decline in the Naïve CD4+T and CD8+T cell subsets, an expansion of effector memory cells, and other potential immune risk phenotypes, such as activation, exhaustion, and up-regulation of aging markers. In addition, we observed a significant association between the CD4 + EM3 subset and the CD8 + EM2 subset with HIV-1 progression, independent of age, suggesting their potential as reliable markers for assessing immune reconstitution in all PLWH. Conclusion Our study extends previous findings showing that older participants exhibit a wide range of late differentiation, senescence, or exhaustion phenotypes in cells, including all the CD4+T and CD8+T subsets, consistent with an immunosenescent phenotype. This may accelerate poor immune recovery in older PLWH. Identifying new strategies to improve the immune risk phenotypes of older PLWH may help improve their immune reconstitution outcomes. The CD4 + EM3 subset and the CD8 + EM2 subset should be studied as additional markers of late presentation.

Abstract Aims Assessing the risk for HF rehospitalization is important for managing and treating patients with HF. To address this need, various risk prediction models have been developed. However, none of them used deep learning methods with real‐world data. This study aimed to develop a deep learning‐based prediction model for HF rehospitalization within 30, 90, and 365 days after acute HF (AHF) discharge. Methods and results We analysed the data of patients admitted due to AHF between January 2014 and January 2019 in a tertiary hospital. In performing deep learning‐based predictive algorithms for HF rehospitalization, we use hyperbolic tangent activation layers followed by recurrent layers with gated recurrent units. To assess the readmission prediction, we used the AUC, precision, recall, specificity, and F1 measure. We applied the Shapley value to identify which features contributed to HF readmission. Twenty‐two prognostic features exhibiting statistically significant associations with HF rehospitalization were identified, consisting of 6 time‐independent and 16 time‐dependent features. The AUC value shows moderate discrimination for predicting readmission within 30, 90, and 365 days of follow‐up (FU) (AUC:0.63, 0.74, and 0.76, respectively). The features during the FU have a relatively higher contribution to HF rehospitalization than features from other time points. Conclusions Our deep learning‐based model using real‐world data could provide valid predictions of HF rehospitalization in 1 year follow‐up. It can be easily utilized to guide appropriate interventions or care strategies for patients with HF. The closed monitoring and blood test in daily clinics are important for assessing the risk of HF rehospitalization.

In the seismic mountainous regions such as western China, it is usuallly inevitable to construct tunnels near active fault zones. Those fault-crossing tunnel structures can be extremely vulnerable during earthquakes. Extensive experimental studies have been conducted on the response of continuous mountain tunnels under reverse and normal fault movements, limited experimental investigations are available in the literatures on mountain tunnels with special structural measures crossing strike-slip faults. In this study, a new experimental facility for simulating the movement of strike-slip fault was developed, accounting for the spatial deformation characteristics of large active fault zones. Two groups of sandbox experiment were performed on the scaled tunnel models to investigate the evolution of ground deformation and surface rupture subjected to strike-slip fault motion and its impact on a water conveyance tunnel. The nonlinear response and damage mechanism of continuous tunnels and tunnels incorporated with specially designed articulated system were examined. The test results show that most of slip between stationary block and moving block occurred within the fault core, and significant surface ruptures are observed along the fault strike direction at the fault damage zone. The continuous tunnel undergoes significant shrinkage deformation and diagonal-shear failure near the slip surface and resulted in localized collapse of tunnel lining. The segments of articulated system tunnel suffer a significant horizontal deflection of about 5°, which results in opening and misalignment at the flexible joint. The width of the damaged zone of the articulated system tunnel is about 0.44 to 0.57 times that of the continuous tunnel. Compared to continuous tunnels, the articulated design significantly reduces the axial strain response of the tunnel lining, but increases the circumferential tensile strain at the tunnel crown and invert. It is concluded that articulated design provides an effective measure to reduce the extent of damage in mountain tunnel.

Betaone is a variety of barley developed by the Korea Rural Development Administration. This study investigated the anti-osteoporosis effects of Betaone barley water extract (B1W) on ovariectomy (OVX)-induced bone loss in mice. To elucidate its mechanism, the effect of B1W on osteoclasts was assessed by measuring the protein expression of nuclear factor-activated T cells c1 (NFATc1), the expression of genes involved in osteoclast differentiation, and bone pit assays. B1W (300 mg/kg/day) significantly increased bone mineral density and bone volume fraction, but decreased trabecular separation compared to the OVX group. B1W also showed a trend towards decreasing serum C-telopeptide of collagen type 1 levels in OVX mice. Additionally, B1W reduced the expression of NFATc1 and downregulated the mRNA expression levels of various marker genes such as c-Fos, tartrate-resistant acid phosphatase (TRAP), cathepsin K (CTSK), dendritic cell-specific transmembrane protein (DC-STAMP), and osteoclast-associated Ig-like receptor (OSCAR). B1W reduced the osteoclast activity in the receptor activator of nuclear factor-κB ligand (RANKL)-treated osteoclasts by inhibiting the mitogen-activated protein kinase (MAPK) pathway. Based on the results, B1W can be considered a useful candidate for a therapeutic agent for treating conditions of bone loss and could also be used as an ingredient in health supplements.

Abstract Background The absence of other structural heart disease is a prerequisite for the diagnosis of non-compaction of the ventricular myocardium (NVM). We also observed that the phenomenon of non-compaction in ventricular muscle in some large patent ductus arteriosus (PDA) patients in children. This study was aimed to explore the prognosis of NVM associated with large PDA in children and provide a better understanding of the interplay between genetic and hemodynamic factors that lead to the phenotype of NVM. Methods We retrospectively analyzed the clinical data of the patients with the diagnosis of NVM with large PDA from January 2015 to January 2022 who underwent the interventional occlusion. We collected the data of the non-compacted myocardium/compacted myocardium (N/C) ratio, the size of the heart, cardiac function measured on color Doppler echocardiography and electrocardiograph (ECG) before and after interventional occlusion. Results From a total of 504 patients with large PDA underwent occlusion, 20 patients (3.94%; mean age 1.72 ± 1.44 years, 6males and 14 females) were also diagnosed with NVM. The mean diameter of the pulmonary artery end of the PDA was 7.15 ± 1.19 mm. The N/C ratio of all children significantly improved after PDA interventional occlusion with the decreased trend of LVDd and LVDs. The phenomenon of NVM regressed during the follow-up period: 9 cases(45%) after 1 M, 2 cases(10%) after 3 Ms, 4 cases(20%) after 6Ms, 1 case(5%) after 9Ms, 3 cases(15%) after 12Ms, and 1 case(5%) after 24Ms. However, there was no significant difference in the ejection fraction(EF) at all time points (P > 0.05). During the follow-up, the typical complications of NVM, include congestive heart failure, ventricular arrhythmias and thromboembolic events weren’t observed in these patients. Conclusion The phenomenon of NVM in this group maybe secondary to a large PDA. After the primary factors have been removed, hemodynamic changes and a decrease in the left heart’s preload favor the complete regression of the NVM.

Abstract. Background:. Renal ischemia–reperfusion (R-I/R) injury is the most prevalent cause of acute kidney injury, with high mortality and poor prognosis. However, the underlying pathological mechanisms are not yet fully understood. Therefore, this study aimed to investigate the role of N‐myc downstream‐regulated gene 2 (Ndrg2) in R-I/R injury. Methods:. We examined the expression of Ndrg2 in the kidney under normal physiological conditions and after R-I/R injury by immunofluorescence staining, real-time polymerase chain reaction, and western blotting. We then detected R-I/R injury in Ndrg2-deficient (Ndrg2–/–) mice and wild type (Ndrg2+/+) littermates in vivo, and detected oxygen and glucose deprivation and reperfusion (OGD-R) injury in HK-2 cells. We further conducted transcriptomic sequencing to investigate the role of Ndrg2 in R-I/R injury and detected levels of oxidative stress and mitochondrial damage by dihydroethidium staining, biochemical assays, and western blot. Finally, we measured the levels of mitophagy in Ndrg2+/+ and Ndrg2–/– mice after R-I/R injury or HK-2 cells in OGD-R injury. Results:. Ndrg2 was primarily expressed in renal proximal tubules and its expression was significantly decreased 24 h after R-I/R injury. Ndrg2–/– mice exhibited significantly attenuated R-I/R injury compared to Ndrg2+/+ mice. Transcriptomics profiling showed that Ndrg2 deficiency induced perturbations of multiple signaling pathways, downregulated inflammatory responses and oxidative stress, and increased autophagy following R-I/R injury. Further studies revealed that Ndrg2 deficiency reduced oxidative stress and mitochondrial damage. Notably, Ndrg2 deficiency significantly activated phosphatase and tensin homologue on chromosome ten-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy. The downregulation of NDRG2 expression significantly increased cell viability after OGD-R injury, increased the expression of heme oxygenase-1, decreased the expression of nicotinamide adenine dinucleotide phosphate oxidase 4, and increased the expression of the PINK1/Parkin pathway. Conclusion:. Ndrg2 deficiency might become a therapy target for R-I/R injury by decreasing oxidative stress, maintaining mitochondrial homeostasis, and activating PINK1/Parkin-mediated mitophagy.

Solid organ transplantation has significantly improved the survival rate of patients with terminal organ failure. However, its success is often compromised by allograft rejection, a process in which T helper 17 (Th17) cells play a crucial role. These cells facilitate rejection by enhancing neutrophil infiltration into the graft and by activating endothelial cells and fibroblasts. Additionally, Th17 cells can trigger the activation of other T cell types, including Th1, Th2, and CD8+ T cells, further contributing to rejection. An imbalance between Th17 and regulatory T cells (Tregs) is known to promote rejection. To counteract this, immunosuppressive drugs have been developed to inhibit T cell activity and foster transplant tolerance. Another approach involves the adoptive transfer of regulatory cells, such as Tregs and myeloid-derived suppressor cells, to dampen T cell functions. This review primarily focuses on the roles of Th17 cells in rejection and their interactions with other T cell subsets. We also explore various strategies aimed at suppressing T cells to induce tolerance.

Abstract The emerging role of ubiquitin-specific peptidase 21 (USP21) in stabilizing Fra-1 (FOSL1) highlights its involvement in promoting colorectal cancer (CRC) metastasis. Additionally, a reciprocal link between EGFR signaling and Fra-1 activation has been identified, mediated through matrix metalloproteinases (MMPs). However, the functional implications of the USP21-EGFR signaling axis in metastatic CRC (mCRC) are not fully understood. To investigate the clinical correlation between USP21 and EGFR expression, RNA-Seq data from tumor tissues (n = 27) and matched normal tissues (n = 27) of 27 mCRC patients were analyzed. Functional studies were performed, including the use of CRISPR/Cas9 to generate USP21-knockout (USP21-KO) CRC cells, in vitro assays for cancer progression and tumor formation, in vivo xenograft assays in NSG mice. Additionally, the therapeutic effect of the USP21 inhibitor, BAY-805, was evaluated. We found that elevated levels of USP21 and EGFR expression in mCRC patients were associated with poorer survival outcomes. Mechanistically, USP21 was found to enhance EGFR stability by deubiquitinating EGFR, leading to reduced EGFR degradation. USP21-KO colon cancer cells exhibited significantly reduced proliferation, migration, colony formation, and 3D tumor spheroid formation in response to EGF. Furthermore, the tumorigenic activity in vivo was markedly diminished in NSG mice xenografted with USP21-KO colon cancer cells. Importantly, BAY-805 demonstrated a notable inhibitory effect on the formation of 3D tumor spheroids in colorectal cancer cells stimulated with EGF. These findings suggest that USP21 could be a valuable therapeutic target and predictive biomarker for managing mCRC driven by EGF.

Abstract Background Group B Streptococcus (GBS) bacteremia in nonpregnant adults is of increasing concern, particularly among the elderly in underlying conditions. This study analyzed the serotype distribution, antimicrobial resistance patterns, and clinical characteristics of GBS bacteremia in nonpregnant adults over a 15-year period in two tertiary hospitals in Korea. Methods From 2007 to 2021, patients aged ≥ 19 years with GBS bacteremia were identified via retrospective electronic medical record review. GBS isolates were collected through a hospital-wide surveillance system and confirmed via MALDI-TOF-MS. Multilocus sequence typing (MLST) was conducted for serotype VIII and undetermined serotype isolates. Clinical and laboratory data were analyzed to assess trends and mortality risk factors. Results A total of 264 episodes of GBS bacteremia were identified, with 147 isolates successfully re-cultured and 125 isolates and patients included in the clinical characteristic analysis. Serotype VIII emerged as the most common serotype (42.1% in 2019–2021) with a significant increase in prevalence over time (P = 0.02). MLST of serotype VIII revealed ST2 as the dominant sequence type (87.8%). Antimicrobial resistance rates for erythromycin, clindamycin, and levofloxacin were 27.2%, 30.4%, and 23.2%, respectively, with notable variability among serotypes. The 30-day mortality rate was 12.8%. Male sex (aOR: 2.18; 95% CI: 1.15–4.13, P = 0.02) and SOFA score (aOR per unit increase: 1.25; 95% CI: 1.12–1.38, P

Abstract Background Spinal cord injury (SCI) inflicts a severe burden on patients and lacks effective treatments. Owing to the poor regenerative capabilities of endogenous oligodendrocyte precursor cells (OPCs) following SCI, there is a growing interest in alternative sources, such as human umbilical cord mesenchymal stem cells (HUCMSCs). TET3 is a key DNA demethylase that plays an important role in neural differentiation, but its role in OPC formation is not well understood. This study aimed to explore the TET3-mediated one-step induction of HUCMSCs into OPCs. Methods In vitro, HUCMSCs were induced into OPCs following TET3 overexpression. Changes of methylation and hydroxymethylation during differentiation were monitored, mechanisms involved in the TET3-driven HUCMSC differentiation into OPCs were identified by RNA sequencing. Methylation levels in NG2 and PDGFRA promoter region were detected using Bisulfite Polymerase Chain Reaction (BSP).In vivo, therapeutic effects of iOPCs were evaluated through a rat Allen’s SCI model. Results The in vitro analysis confirmed that TET3 enhances HUCMSC differentiation into OPCs, validitied by specific marker expression. The induced OPCs (iOPCs) exhibited methylation and hydroxymethylation patterns similar to native OPCs. BSP analysis demonstrated that TET3 overexpression significantly reduced CpG island methylation in the NG2 and PDGFRA promoter regions. RNA sequencing revealed that TET3 induces iOPCs to express a series of genes essential for OPC formation while inhibiting the signaling pathways that hinder OPC development. In a rat model of SCI, TET3-overexpressing HUCMSCs appear to have the potential to differentiate into iOPCs in vivo, suppressed secondary injury, and promoted functional recovery. The therapeutic effects of iOPCs on SCI were superior to those of standard mesenchymal stem cell treatments. Conclusions Our study demonstrated that TET3-mediated demethylation reshapes the methylation patterns of HUCMSCs, enabling their efficient one-step conversion into OPCs and significantly reducing the time required for cell preparation. This approach offers a potential strategy for early intervention in SCI. In an SCI model, TET3-induced OPCs contributed to spinal cord repair, providing novel insights into cell therapy strategies for SCI through the lens of methylation regulation.

Abstract In the summer of 2018–2019, rocket‐triggered lightning experiments were conducted in Guangzhou, China. There were two types of lightning targets: ground and overhead line. By comparing the current and the electric field data in the two cases, it was found that when the continuous current level (ICC) and current amplitude (IM) of M‐components (current pulses generated during the continuous current stage) are large, the time difference between the electric field peak and the current peak (TD) will always be small. The rise time (RT) and half peak width (THPW) of M‐components with high ICC and IM are low in both the cases. The threshold upper limit of TD in the case of lightning striking the ground is higher, approximately 2.6 times than that in the case of lightning striking the overhead line. We use an optimised guided wave model to simulate the electric field waveforms of M‐components. It was found that the shorter RT and THPW of the M‐component, the smaller TD. The changes in wave speed and IM cannot affect the size of TD, and the impact of distance changes is very weak. The difference in the threshold upper limit of TD may be related to the significant difference in ground impedance in two cases.

Abstract Purpose This study aimed to investigate that AKT1-Mediated NOTCH1 phosphorylation promotes gastric cancer (GC) progression via targeted regulation of IRS-1 transcription. Methods The study utilized databases such as PhosphositePlus, TRANSFAC, CHEA, GPS 5.0, and TCGA, along with experimental techniques including Western Blot, co-IP, in vitro kinase assay, construction of lentiviral overexpression and silencing vectors, immunoprecipitation, modified proteomics, immunofluorescence, ChIP-PCR, EdU assay, Transwell assay, and scratch assay to investigate the effects of AKT1-induced Notch1 phosphorylation on cell proliferation, invasion and migration in vitro, as well as growth and epithelial-mesenchymal transition (EMT) in vivo. Results AKT1 was found to induce phosphorylation of Notch1 at the S2183 site in GC, subsequently altering the subcellular localization of Notch1-IC and promoting its nuclear translocation. The transcription factor RBPJ that binds to Notch1 transcriptionally regulated IRS-1, CDH5, TNL1, ASCL2, and LRP6. Experimental validation revealed that Notch1-IC can regulate the expression of IRS-1. Overexpression of Notch1-IC was shown to promote the proliferation, invasion, and metastasis of GC cells, while knockdown of IRS-1 partially inhibited the aforementioned effects induced by Notch1-IC overexpression. Further experiments in vitro and vivo confirmed that AKT1-induced Notch1 phosphorylation can regulate the expression of IRS-1 and promote the malignant behavior of GC, including proliferation, invasion, metastasis, and EMT, with knockdown of IRS-1 partially reversing these effects. Conclusion AKT1 induces the Notch1 phosphorylation and promotes the activation and nuclear translocation of Notch1-IC by targeting the regulation of IRS-1, thereby advancing the progression of GC.

Abstract The gene associated with the retinoid–IFN-induced mortality-19 (GRIM-19) protein is a regulator of a cell death regulatory protein that inhibits STAT3, which is a critical transcription factor for interleukin (IL)-17-producing T (Th17) cells and a key integrator of extracellular matrix accumulation in systemic sclerosis (SSc). This protein is also a component of mitochondrial complex I, where it directly binds to STAT3 and recruits STAT3 to the mitochondria via the mitochondrial importer Tom20. In this study, the role of GRIM19 and its relationship with STAT3 in SSc development was investigated using a murine model of SSc. We observed a decrease in the level of GRIM-19 in the lesional skin of mice with bleomycin-induced SSc, which was negatively correlated with the level of STAT3. Overexpression of GRIM-19 reduced dermal thickness and fibrosis and the frequency of Th2 and Th17 cells in SSc mice. Mitophagic dysfunction promoted fibrosis in mice lacking PINK1, which is a mitophagy inducer. In an in vitro system, the overexpression of GRIM-19 increased the level of mitochondrial STAT3 (mitoSTAT3), induced mitophagy, and alleviated fibrosis progression. MitoSTAT3 overexpression hindered the development of bleomycin-induced SSc by reducing fibrosis. These results suggest that GRIM-19 is an effective therapeutic target for alleviating the development of SSc by increasing mitophagy.