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The fibroblast growth factor receptor (FGFR) is a crucial receptor tyrosine kinase involved in essential biological processes, including growth, development, and tissue repair. However, FGFR gene mutations, including amplification, fusion, and mutation, can disrupt epigenetics, transcriptional regulation, and tumor microenvironment interactions, leading to cancer development. Targeting these kinase mutations with small molecule drugs or antibodies has shown clinical benefits. For example, erdafitinib is approved for treating locally advanced or metastatic urothelial cancer patients with FGFR2/FGFR3 mutations, and pemigatinib is approved for treating cholangiocarcinoma with FGFR2 fusion/rearrangement. Effective screening of FGFR variant patients is crucial for the clinical application of FGFR inhibitors. Various detection methods, such as polymerase chain reaction, next-generation sequencing, fluorescence in situ hybridization, and immunohistochemistry, are available, and their selection should be based on diagnostic and treatment decision-making needs. Our developed expert consensus aims to standardize the diagnosis and treatment process for FGFR gene mutations and facilitate the practical application of FGFR inhibitors in clinical practice.

Median palatal cyst is a rare nonodontogenic facial cleft cyst. A case of median palatal cyst was admitted to the Department of Otolaryngology, Renji Hospital. A 26-year-old female patient was admitted with ‘repeated bilateral nasal congestion for two years’ and was diagnosed as a median palatal cyst. Endoscopic resection of the cyst at the bottom of the nose plus free nasal septal cartilage transplantation were performed. The wound healed well and the cyst did not recur after one year of follow-up.

Abstract Background The long-term outcomes (≥ 2 years of follow-up) of volar locked plate (VLP) fixation versus closed reduction and casting (CRC) for the treatment of displaced distal radial fractures (DRFs) remain unclear. This study aimed to conduct a meta-analysis comparing the long-term clinical outcomes of VLP and CRC in elderly patients (aged ≥ 60 years). Methods A comprehensive search of PubMed, Web of Science, and Cochrane Library was performed to identify studies comparing the long-term outcomes of VLP and CRC for DRFs. Only randomized controlled trials (RCTs) with a mean follow-up duration of at least 2 years and participants aged 60 years or older were included. The risk of bias in the included studies was assessed. The primary outcome measure was the Patient-Rated Wrist Evaluation (PRWE). Secondary outcomes included the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire, EuroQol 5 Dimension 5-level score (EQ-5D-5 L), grip strength, and incidence of reoperation. Results Four RCTs, comprising 423 patients, were included. The meta-analysis revealed that VLP fixation was associated with significantly improved outcomes compared to CRC in terms of PRWE score (pooled mean difference: -6.21; 95% CI: -10.28 to -2.15; p = 0.003), DASH score (pooled mean difference: -8.18; 95% CI: -13.35 to -3.01; p = 0.002), and grip strength (pooled mean difference: -6.63; 95% CI: 0.25 to 13.01; p = 0.04). There were no significant differences in EQ-5D-5 L score (95% CI: -0.08 to 0.05; p = 0.74) or incidence of reoperation (RR = 0.56; 95% CI: 0.22 to 1.42; p = 0.22). Conclusions A two-year follow-up of displaced DRFs in elderly patients showed no significant long-term clinical advantage of VLP fixation over CRC.

Abstract Background Orthodontic treatment carries potential risks and complications, especially if the path of tooth movement extends beyond the alveolar bone or if the patient has a thin bone plate. This amplifies the patient’s risk of complications such as bone fenestration and bone dehiscence. Hence, orthodontists should consider the patient’s periodontal and dental condition during treatment and opt for a multidisciplinary approach when necessary to achieve optimal results. Case presentation This case report describes a successfully treated case of Class III malocclusion using an adjuvant therapy known as periodontally accelerated osteogenic orthodontics (PAOO). A 25-year-old man sought treatment primarily due to an evident anterior negative overjet. The patient was diagnosed with a skeletal Class III relationship and mandibular prognathism. A clinical examination revealed a severe Class III molar relationship and an anterior negative overjet. Moreover, cone-beam computed tomography revealed a thin labial bone plate in relation to the mandibular anterior teeth. The molar relation was corrected through molar distalization using miniscrews, and the mandibular incisors were retracted in conjunction with the PAOO procedure. Post-treatment outcomes demonstrated improved occlusal relationship, thickened labial bone plate of the mandibular anterior teeth, and absence of bone fenestration or dehiscence. Conclusions This clinical case shows that orthodontic treatment requires a multidisciplinary approach. The favorable results indicate that PAOO is effective in maintaining alveolar bone thickness and reducing the risk of periodontal complications.

Abstract The growth of timber assortment is related to site conditions and forest management measures. To our knowledge, however, the effects and relative importance of these factors on the growth of different timber assortments of Chinese fir have not yet been explored. Based on data from long-term fixed observation plots in the northwest of the Chinese fir distribution zone, we examined the effects of planting density and the site index on the timber assortment structure of Chinese fir. Furthermore, we quantified the relative importance of stand factors (age, planting density, stand density index, number of living trees, Gini coefficient, and site index) in determining the growth of various timber assortments. The results showed that the wood yield of all timber assortment types increased as the site quality improved. The outturn and outturn rate of large- and medium-diameter timber were negatively correlated with the planting density. Before the age of 22, planting density had a negative impact on total timber yield and small-diameter timber outturn. After 22 years, planting density had a positive impact on total timber yield and small-diameter timber outturn. SDI (stand density index), age, and SD (stand density) were the most important factors influencing total timber yield and small-diameter timber. The relative importance of age to large-diameter timber was the greatest, followed by SI (site index) and SD. The effects of age, SD, SI, and PD (planting density) on the medium-diameter timber were greater than those of SDI and Gini coefficient. The results indicate small- and medium-diameter timber as the primary target timber assortment types to be cultivated in the study area, while large-diameter timber cannot be effectively produced under the current site conditions. Our findings provide valuable insights for the management of Chinese fir plantations and the directed cultivation of target timber assortments in the northwest of the Chinese fir distribution zone.

Abstract Background Fatty acid binding protein 1 (FABP1), a low molecular weight intracellular protein, has been proposed as a potential useful serum biomarker for liver injury. However, limited investigations have been conducted in chronic hepatitis B virus (HBV)-related liver disease. Objective To investigate the diagnostic potential of FABP1 in disease progression among patients with chronic HBV-related liver disease. Methods A prospective study was conducted on 293 patients with chronic HBV-related liver diseases, including chronic asymptomatic carrier (ASC), chronic hepatitis B (CHB). FABP1 was measured in serum samples collected at admission and some selected liver biopsies. Results Immunohistochemical analysis revealed abundant cytoplasmic expression of FABP1 in hepatocytes. A significant negative correlation was observed between FABP1 expression and inflammation grades in liver tissue (Spearman's r = -0.355, P = 0.017). However, no statistically significant correlation was found with fibrosis (P > 0.05). Serum FABP1 levels in the case group were significantly higher than in the healthy control (HC) group [median: 804.2 (687.8, 939.2) vs. 709.1 (626.2, 807.8) ng/ml, Z = -5.505, P

Abstract Background Patients with programmed cell death‐ligand 1 (PD‐L1) ≥50% metastatic non‐small cell lung cancer (NSCLC) treated with first‐line immunotherapy showed heterogeneous tumor responses. In this study, we investigated the clinical and immune‐inflammatory markers distinguishing patients with metastatic NSCLC achieving high depth of tumor response (HDPR) from those with non‐high depth of response (NHDPR). The impact of clinical features on the prognosis of patients with PD‐L1 ≥50% were further clarified. Methods The clinical characteristics and immune‐inflammatory markers of 17 patients with PD‐L1 ≥50% metastatic NSCLC at Beijing Tiantan Hospital between July 2020 and December 2023 were retrospectively analyzed. Results Among the 17 patients, seven (41.2%) patients achieved HDPR (range: −50%, −72%) and 10 (58.8%) patients achieved NHDPR (range: −13%, −45%). Below normal CD4 + T lymphocytes/CD8 + T lymphocytes (CD4/CD8) ratio (p = 0.01) and oncogenes and/or tumor suppressor gene mutations (TP53/KRAS/EGFR) (p = 0.001) were found enriched for NHDPR compared with HDPR. With a median follow‐up of 26.0 months (range: 17.2–34.8 months), the median progression‐free survival (PFS) following first‐line immunotherapy and overall survival (OS) were 9.0 months (95% CI: 5.0–13.0) and not reached (NR), respectively. The neutrophil‐to‐lymphocyte ratio (NLR) was identified as an independent prognostic factor on first‐line PFS. Patients with an NLR ≥4 exhibited a shorter median PFS (7.0 months vs. NR; p = 0.033; 95% CI: 1.2–80.2) than those with an NLR

Abstract Background Rimegepant, a small molecule calcitonin gene-related peptide (CGRP) receptor antagonist, is indicated for acute and preventive migraine treatment in the United States and other countries. However, there is a lack of prospective real-world evidence for the use of rimegepant in Chinese migraine patients. Methods This was a single-arm, prospective, real-world study. While taking rimegepant to treat migraine attacks as needed, eligible participants were asked to record their pain intensity, functional ability, and accompanying symptoms for a single attack at predose and 0.5, 1, 2, 24, and 48 h postdose via a digital platform. Adverse events (AEs) during the rimegepant treatment period were recorded and analysed. The percentages of participants who experienced moderate to severe pain at predose and 0.5, 1, 2, 24, and 48 h postdose were assessed. Additionally, the percentages of participants who reported better/good outcomes in terms of pain intensity, functional ability, and accompanying symptoms at 0.5, 1, 2, 24, and 48 h postdose were analysed. In addition, the total cohort (full population, FP) was stratified into a prior nonresponder (PNR) group to observe the effectiveness and safety of rimegepant for relatively refractory migraine and a rimegepant and eptinezumab (RE) group to observe the effectiveness and safety of the combination of these drugs. Results By November 24th, 2023, 133 participants (FP, n = 133; PNR group, n = 40; RE group, n = 28) were enrolled, and 99 participants (FP, n = 99; PNR group, n = 30; RE group, n = 23) were included in the analysis. Rimegepant was effective in treating migraine in the FP and both subgroups, with a significant decreasing trend in the percentages of participants experiencing moderate to severe pain postdose (p

Abstract Background Defects in PPP1R12A can lead to genitourinary and/or brain malformation syndrome (GUBS). GUBS is primarily characterized by neurological or genitourinary system abnormalities, but a few reported cases are associated with neonatal seizures. Here, we report a case of a female newborn with neonatal seizures caused by a novel variant in PPP1R12A, aiming to enhance the clinical and variant data of genetic factors related to epilepsy in early life. Methods Whole-exome and Sanger sequencing were used for familial variant assessment, and bioinformatics was employed to annotate the variant. A structural model of the mutant protein was simulated using molecular dynamics (MD), and the free binding energy between PPP1R12A and PPP1CB was analyzed. A mutant plasmid was constructed, and mutant protein expression was analyzed using western blotting (WB), and the interaction between the mutant and PPP1CB proteins using co-immunoprecipitation (Co-IP) experiments. Results The patient experienced tonic-clonic seizures on the second day after birth. Genetic testing revealed a heterozygous variant in PPP1R12A, NM_002480.3:c.2533 C > T (p.Arg845Ter). Both parents had the wild-type gene. MD suggested that loss of the C-terminal structure in the mutant protein altered its structural stability and increased the binding energy with PPP1CB, indicating unstable protein–protein interactions. On WB, a low-molecular-weight band was observed, indicating that the protein was truncated. Co-IP indicated that the mutant protein no longer interacted with PPP1CB, indicating an effect on the structural stability of the myosin phase complex. Conclusion The PPP1R12A c.2533 C > T variant may explain the neonatal seizures in the present case. The findings of this study expand the spectrum of PPP1R12A variants and highlight the potential significance of truncated proteins in the pathogenesis of GUBS.

Abstract Background For patients with sepsis receiving non-invasive ventilation (NIV), early rehabilitation is crucial. The Sitting Baduanjin (SBE) is an efficient early rehabilitation exercise suitable for bed patients. There is no consensus about the effect of SBE on the early rehabilitation of septic patients with NIV. This study focused on how the SBE affected the early rehabilitation of sepsis patients with NIV. Methods 96 sepsis patients with NIV were randomly assigned to either an Baduanjin group that received the SBE based on the routine rehabilitation exercise (n = 48) or a control group (n = 48) that received routine rehabilitation exercise. The primary outcome was the Medical Research Council(MRC)score, and the Barthel Index score, the duration of NIV, length of ICU stay, length of total stay, hospitalization expense as secondary outcomes. Results A total of 245 sepsis patients were screened, with 96 randomly assigned. The study was completed by 90 patients out of the 96 participants.Results revealed that the MRC score increased in both groups, but the improvement of muscle strength in Baduanjin group was more obvious, with statistical significance (p

Abstract The immunosuppressive tumor microenvironment (TME) remains a major obstacle to tumor control and causes suboptimal responses to immune checkpoint blockade (ICB) therapy. Thus, developing feasible therapeutic strategies that trigger inflammatory responses in the TME could improve the ICB efficacy. Mitochondria play an essential role in inflammation regulation and tumor immunogenicity induction. Herein, we report the discovery and characterization of a class of small molecules that can recapitulate aqueous self-assembly behavior, specifically target cellular organelles (e.g., mitochondria), and invigorate tumor cell immunogenicity. Mechanistically, this nanoassembly platform dynamically rewires mitochondria, induces endoplasmic reticulum stress, and causes apoptosis/paraptosis-associated immunogenic cell death. After treatment, stressed and dying tumor cells can act as prophylactic or therapeutic cancer vaccines. In preclinical mouse models of cancers with intrinsic or acquired resistance to PD-1 blockade, the local administration of nanoassemblies inflames the immunologically silent TME and synergizes with ICB therapy, generating potent antitumor immunity. This chemically programmed small-molecule immune enhancer acts distinctly from regular cytotoxic therapeutics and offers a promising strategy for synchronous and dynamic tailoring of innate immunity to achieve traceless cancer therapy and overcome immunosuppression in cancers.

Abstract With the continuous accumulation of massive amounts of mobile data, point-of-interest (POI) recommendation has become a vital task for location-based social networks. Deep neural networks or matrix factorization (MF) alone are challenging to effectively learn user–POI interaction functions. Moreover, the user–POI interaction matrix is sparse, and the heterogeneous characteristics of auxiliary information are underused. Therefore, we propose an innovative POI recommendation method that integrates attention-aware meta-paths based on deep neural matrix factorization (DNMF-AM). First, we develop a multi-relational heterogeneous information network of “user–POI–geographic region–POI category.” Multiple-weighted isomorphic information networks based on meta-paths are employed to obtain node-embedding vectors across different relationships. Attention networks are employed to aggregate node vectors across various relationships and serve as auxiliary information to mitigate the challenges of data sparsity. Subsequently, the internal embedding vectors of the users and POIs are extracted using feature embedding based on the user–POI interaction matrix. Second, these vectors are integrated with the embedding vectors obtained by aggregating the attention networks. Third, deep neural matrix factorization is used to learn linear and nonlinear user–POI interactions to mitigate the implicit feedback problem. This outcome is achieved using generalized matrix factorization and convolution-constrained multi-head self-attention mechanism deep neural networks. Extensive experiments conducted on two real-world datasets demonstrate that the DNMF-AM outperforms the optimal baseline NeuMF-CAA by 4.24% and 5.04% in terms of HR@10 and NDCG@10, respectively.

Abstract Objective The current study aimed to investigate the baseline immune and inflammatory features and in-hospital outcomes of patients infected with the Omicron variant (PIWO) who presented with different disease severities during the first wave of mass Omicron infections in the Chinese population has occurred. Method A cross‐sectional study was conducted on 140 hospitalized PIWO between December 11, 2022, and February 16, 2023. The clinical features, antibodies against SARS-CoV-2, immune cells, and inflammatory cytokines among mildly, severely, and critically ill PIWO at baseline and during follow-up period were compared. Result Patients with severe (n = 49) and critical (n = 35) disease were primarily male, needed invasive mechanical ventilation treatment, and exhibited higher mortality than those with mild disease (n = 56). During acute infection, SARS-CoV-2-specific antibody levels fluctuated with disease severity, serum antibodies increased and the incidence of severe cases decreased in critically ill PIWO over time. Antibody titers in severe or critical PIWO with no antibody responses at baseline did not increase significantly over time. Meanwhile, CD4+T cell, CD8+T cell, and natural killer cell counts were negatively correlated with disease severity, whereas interleukin (IL)-6 and IL-10 levels were positively correlated. In addition, combined diabetes, immunosuppressive therapy before infection, serum amyloid A, IL-10 and neutrophil counts were independently associated with severe and critical illness in PIWO. Among the 11 nonsurvivors, 8, 2, 1 died of respiratory failure, sudden cardiac death, and renal failure, respectively. Compared with survivors, nonsurvivors exhibited lower seropositivity of SARS-CoV-2-specific antibody, reduced CD3+T and CD4+T cell counts, and higher IL-2R, IL-6, IL-8, and IL-10 levels. Of note, lactate dehydrogenase was a significant risk factor of death in severe or critically ill PIWO. Conclusion This present study assessed the dynamic changes of SARS-CoV-2-specific antibodies, immune cells and inflammatory indexes between severely and critically ill PIWO. Critical and dead PIWO featured compromised humoral immune response and excessive inflammation, which broadened the understanding of the pathophysiology of Omicron infection and provides warning markers for severe disease and poor prognosis.

Abstract We evaluate the value of oral contrast-enhanced gastric ultrasonography (OCUS) by comparing it with conventional gastroscopy in diagnosing and staging benign peptic ulcer. From July 2018 to December 2020, 44 patients with gastroscopy-confirmed benign peptic ulcers (a total of 45 ulcers were detected), who also received OCUS, were retrospectively reviewed. Each patient’s ultrasound images were compared with gastroscopy and pathology findings. The characteristics of ultrasonic images of different stages of ulcer were analysed. A total of 43 ulcers were detected by OCUS in 44 patients with benign peptic ulcers. There were no false positive results among the OCUS exams, but two ulcers were misdiagnosed. OCUS for benign peptic ulcer staging also shows acceptable clinical practice results. OCUS is useful for detecting and staging benign peptic ulcer, and may be considered an alternative method for conventional gastroscopy. OCUS is especially useful in the follow-up of BPU treatment, but futher study is needed to improve the diagnostic accuracy of benign and malignant ulcers.

The actively heated fiber-optic (AHFO) technology has become emerged as a research focus due to its advantages of distributed, real-time measurement and good durability. These attributes have led to the gradual application of AHFO technology to the water content measurement of in situ soil. However, all existing in situ applications of AHFO technology fail to consider the effect of soil–sensor contact quality on water content measurements, limiting potential for the wider application of AHFO technology. To address this issue, the authors propose a method for determining the soil–sensor thermal contact resistance based on the principle of an infinite cylindrical heat source. This is then used to establish an AHFO water content measurement technology that considers the thermal contact resistance. The reliability and validity of the new measurement technology are explored through a laboratory test and a field case study, and the spatial-temporal evolution of the soil water content in the case is revealed. The results demonstrate that method for determining the soil–sensor thermal contact resistance is highly effective and applicable to all types of soils. This method requires only the moisture content, dry density, and thermal response of the in situ soil to be obtained. In the field case, the measurement error of soil water content between the AHFO method, which takes into account the thermal contact resistance, and the neutron scattering method is only 0.011. The water content of in situ soil exhibits a seasonal variation, with an increase in spring and autumn and a decrease in summer and winter. Furthermore, the response of shallow soils to precipitation and evaporation is significant. These findings contribute to the enhancement of the accuracy of the AHFO technology in the measurement of the water content of in situ soils, thereby facilitating the dissemination and utilization of this technology.

In this study, choline chloride/lactic acid/guaiacol ternary deep eutectic solvent (DES) was used to extract Ganoderma lucidum polysaccharides (GLPs). The operational parameters of GLPs extraction by DES were optimized, and the obtained GLPs structure was characterized by Fourier transform infrared spectrophotometer (FT-IR) and gel chromatography (GPC). Furthermore, the in vitro antioxidant activities of GLPs were investigated. In the end, density functional theory (DFT) was leveraged to gain preliminary insights into the molecular mechanism underpinning polysaccharide extraction facilitated by DES. Results unveiled that when the moisture content within DES was maintained at 50%, extraction was carried out at a temperature of 80 ℃ for 1 h, and the liquid-to-solid mass-volume ratio stood at 1:30 g/mL, the extraction yield of GLPs reached 9.20%±0.27%. FT-IR and GPC results showed that GLPs had typical polysaccharide structures in the 4000~500 cm−1 regions, and the number average mass weight (Mn) of GLPs was 8057 Da with the polydispersity index (PDI) of 1.6. In the context of in vitro antioxidant activity experiments, when GLPs content was 5 mg/mL, the total reducing power was measured at 0.67±0.04. Notably, the IC50 values for GLPs' scavenging capabilities against DPPH, OH, and ABTS+ free radicals were determined to be 2.366, 6.179, and 2.440 mg/mL, respectively. DES simulation analyses revealed a binding energy of 65.29 kcal/mol between DES and glucose, a substantially higher value compared to the binding energy observed between water and glucose (20.38 kcal/mol). The GLPs extraction by DES was facilitated through the pivotal role of triple hydrogen bond interactions. The findings in this study elucidated the intrinsic mechanism at molecular level that underscores the superior effectiveness of DES in comparison to traditional hot water extraction methods.

Abstract Background In triple-negative breast cancer (TNBC) therapy, insufficient tumor infiltration by lymphocytes significantly hinders the efficacy of immune checkpoint inhibitors. We have previously demonstrated that Hainanenin-1 (HN-1), a host defense peptide (HDP) identified from Hainan frog skin, induces breast cancer apoptosis and boots anti-tumor immunity via unknown mechanism. Methods We used in vitro experiments to observe immunogenic cell death (ICD) indicators in HN-1-treated TNBC cell lines, a mouse tumor model to verify HN-1 promotion of mice anti-tumor immune response, and an in vitro drug sensitivity test of patient-derived breast cancer cells to verify the inhibitory effect of HN-1. Results HN-1 induced ICD in TNBC in a process during which damage-associated molecular patterns (DAMPs) were released that could further increase the anti-tumor immune response. The secretion level of interleukin 2 (IL-2), IL-12, and interferon γ in the co-culture supernatant was increased, and dendritic cells (DCs) were activated via a co-culture with HN-1-pretreated TNBC cells. As a result, HN-1 increased the infiltration of anti-tumor immune cells (DCs and T lymphocytes) in the mouse model bearing both 4T1 and EMT6 tumors. Meanwhile, regulatory T cells and myeloid-derived suppressor cells were suppressed. In addition, HN-1 induced DNA damage, and double-strand DNA release in the cytosol was significantly enhanced, indicating that HN-1 might stimulate ICD via activation of STING pathway. The knockdown of STING inhibited HN-1-induced ICD. Of note, HN-1 exhibited inhibitory effects on patient-derived breast cancer cells under three-dimensional culture conditions. Conclusions Collectively, our study demonstrated that HN-1 could be utilized as a potential compound that might augment immunotherapy effects in patients with TNBC.

Highlights A novel method is developed for precise control over the structure of 3D anodic aluminum oxide templates, enabling fine-tuning of both the vertical pore diameter and interspace within the templates. 3D carbon tube nanoarrays featuring significantly thinner and denser tubes are constructed as high-quality electrodes for miniaturized filter capacitors. The 3D compactly arranged carbon tube-based capacitor achieves a remarkable specific areal capacitance of 3.23 mF cm−2 with a phase angle of − 80.2° at 120 Hz.

Introduction: The calcineurin inhibitor cyclosporine A (CsA) has been shown to effectively reduce proteinuria. However, its precise mechanism is still not fully understood. Our previous study showed that CsA reduced proteinuria by directly stabilizing the foot process (FP) cytoskeletal structure via cofilin-1, suggesting that synaptopodin, a podocyte-specific actin protein, is not the sole target of CsA in podocytes. Methods: In this study, we established an adriamycin (ADR)-induced nephropathy rat model and a cultured podocyte injury model. We employed Western blotting and immunofluorescence techniques to assess the expression and distribution of transgelin, Krüppel-like factor-4 (KLF-4), nephrin, and synaptopodin. Results: We observed a significant increase in proteinuria levels accompanied by loss of normal FP structure in the ADR-induced nephropathy rat model. The levels of the actin cross-linking protein transgelin were increased significantly, while those of the podocyte-specific molecules nephrin and synaptopodin were decreased in vivo. Treatment with CsA effectively reduced proteinuria while restoring FP effacement stability in ADR-induced nephropathy models and restoring the expression of transgelin, nephrin, and synaptopodin both in vivo and in vitro. Furthermore, CsA treatment dose-dependently decreased transgelin levels while significantly increasing KLF-4 expression in injured podocytes. In addition, CsA failed to downregulate transgelin when KLF-4 was specifically knocked down. Conclusion: Our findings suggest that CsA protects against podocyte injury by downregulating abnormally high levels of transgelin via upregulation of KLF-4 expression.

Long-term climate change significantly affects the spatiotemporal dynamics of soil erosion. To explore this, remote sensing technology, future climate scenarios, and deep learning are combined to model the historical and future variations in soil erosion, investigating its spatiotemporal dynamics influenced by climate change. This paper uses the Revised Universal Soil Loss Equation (RUSLE) to assess the historical changes in erosion in northeast China from 1980 to 2020. A soil erosion simulation (SES) model was developed, incorporating deep learning models, to forecast future trends in soil erosion under various climate scenarios. The SES model achieves an R-squared (R2) value of 0.7513. The SES model can simulate the Spatiotemporal dynamics of soil erosion influenced by long-term climate change. Soil erosion from 2001 to 2020 is lower than that from 1980 to 2000, indicating a decrease in soil erosion under natural variability conditions. Unlike historical trends, future soil erosion demonstrates significant variation across three scenarios: SSP1-RCP1.9 (SSP119), SSP2-RCP4.5 (SSP245), and SSP5-RCP8.5 (SSP585). The simulation results show that the SSP119 climate scenario has a minor impact on soil erosion, whereas the SSP245 scenario leads to a gradual increase in soil erosion. The SSP585 scenario, characterized by high social vulnerability and substantial radiative forcing, exacerbates the risk of soil erosion. The study provides valuable references for maintaining soil stability and managing surface runoff.

Renal tubule cells act as a primary site of injury in diabetic kidney disease (DKD), with dysfunctional mitochondrial quality control (MQC) closely associated with progressive kidney dysfunction in this context. Our investigation delves into the observed inactivation of yes-associated protein 1 (YAP1) and consequential dysregulation of MQC within renal tubule cells among DKD subjects through bioinformatic analysis of transcriptomics data from the Gene Expression Omnibus (GEO) dataset. Receiver operating characteristic curve analysis unequivocally underscores the robust diagnostic accuracy of YAP1 and MQC-related genes for DKD. Furthermore, we observed YAP1 inactivation, accompanied by perturbed MQC, within cultured tubule cells exposed to high glucose (HG) and palmitic acid (PA). This pattern was also evident in the tubulointerstitial compartment of kidney sections from biopsy-approved DKD patients. Additionally, renal tubule cell-specific Yap1 deletion exacerbated kidney injury in diabetic mice. Mechanistically, Yap1 deletion disrupted MQC, leading to mitochondrial aberrations in mitobiogenesis and mitophagy within tubule cells, ultimately culminating in histologic tubular injury. Notably, Yap1 deletion-induced renal tubule injury promoted the secretion of C-X-C motif chemokine ligand 1 (CXCL1), potentially augmenting M1 macrophage infiltration within the renal microenvironment. These multifaceted events were significantly ameliorated by administrating the YAP1 activator XMU-MP-1 in DKD mice. Consistently, bioinformatic analysis of transcriptomics data from the GEO dataset revealed a noteworthy upregulation of tubule cells-derived chemokine CXCL1 associated with macrophage infiltration among DKD patients. Crucially, overexpression of YAP1 via adenovirus transfection sustained mitochondrial membrane potential, mtDNA copy number, oxygen consumption rate, and activity of mitochondrial respiratory chain complex, but attenuated mitochondrial ROS production, thereby maintaining MQC and subsequently suppressing CXCL1 generation within cultured tubule cells exposed to HG and PA. Collectively, our study establishes a pivotal role of tubule YAP1 inactivation-mediated MQC dysfunction in driving DKD progression, at least in part, facilitated by promoting M1 macrophage polarization through a paracrine-dependent mechanism.

Purpose: We aimed to examine the clinical characteristics of patients with ovarian endometriosis (OMA) who were diagnosed with recurrent pain after laparoscopic surgery in an 8- to 12- year postoperative follow-up. Methods: We retrospectively analyzed data of 45 OMA patients with recurrent pain, including a minimum 8 years of post-laparoscopic follow-up reports. All laparoscopic cystectomy procedures were performed by the same surgeon at Peking Union Medical College Hospital between January 2009 and April 2013. Clinical data were retrieved to analyze patients' preoperative characteristics, relevant surgical findings, and postoperative outcomes at follow-up. Results: A total of 45 patients with OMA were included, with a mean age of 31.8 ± 4.92 years. The mean recurrence period was 45.78 ± 24.89 months. Before surgery, 60 % (27/45) of patients had severe dysmenorrhea. During surgery, 93.3 % (42/45) of patients were in stage III/IV, 51.1 % (23/45) had coexisting adenomyosis, and 66.7 % (30/45) had deep infiltrating endometriosis (DIE). For the whole study group, mean follow-up time was 121.96 ± 15.55 months. All patients underwent postoperative medical treatment. The mean recurrence period was 45.78 ± 24.89 months. Cyst recurrence was presented in 24.4 % (11/45) of patients, while 75.6 % (34/45) only complained of pain recurrence. At the end of follow-up, spontaneous pregnancy was seen in 24.4 % (11/45) of patients and 6.7 % (3/45) received in vitro fertilization and embryo transfer (IVF-ET). Conclusions: Patients with symptomatic recurrence after surgery had more severe dysmenorrhea, larger proportion of coexisting adenomyosis and DIE, and a higher revised American Fertility Society (rAFS) stage. Recurrence of endometrial cysts was not related to pain recurrence. Long-term postoperative pharmacological therapy is recommended to reduce recurrence.

Objective Angelica keiskei is a medicinal and edible plant that has been reported to possess potent antioxidant properties in several in vitro models, but its effectiveness on naturally aging organisms is still lacking. This study explores the antioxidant and health-promoting effects of Angelica keiskei in naturally aging mice.Methods We treated 48-week-old mice with Angelica keiskei water extract (AKWE) 30 days, and measured indicators related to aging and antioxidants. In addition, we conducted network pharmacology analysis, component-target molecular docking, real-time PCR, and MTS assays to investigate relevant factors.Results The results indicated that administration of AKWE to mice led to decrease blood glucose levels, improve muscle fiber structure, muscle strength, gait stability, and increase levels of glutathione and superoxide dismutase in serum. Additionally, it decreased pigmentation of the heart tissues. Angelica keiskei combats oxidative stress by regulating multiple redox signaling pathways, and its ingredients Coumarin and Flavonoids have the potential to bind to SIRT3 and SIRT5.Conclusions Our findings indicated the potential of Angelica keiskei as a safe and effective dietary supplement to combat aging and revealed the broad prospects of medicinal and edible plants for addressing aging and age-related chronic diseases.

The long half-life and the high decay energy of beta sources play a critical role in improving the performance of betavoltaic micro-nuclear batteries. In this study, the pure beta source 14C in the form of powder, which can be transformed into an ultra-thin film by using (14C6H5NH)2CO, was selected to design planar 4H-SiC p–n junction betavoltaic batteries. A comprehensive model was developed utilizing the Monte Carlo code and the COMSOL Multiphysics code to predict the output performance. As a result, based on a 100 μm-thick (14C6H5NH)2CO source with a maximum power density of 1.86 μW/cm2 and the current fabrication technology of 4H-SiC p–n junction, we optimized the thicknesses of the p−-type region (4.2 µm) with a doping concentration of Na = 3 × 1016 cm−3 and the n−-type region (5.8 µm) with a doping concentration of Nd = 2 × 1014 cm−3. The corresponding predicted performance values included the short-circuit current density of 0.1 μA/cm2, the open-circuit voltage of 2.15 V, and the maximum power density of 0.2 μW/cm2. Moreover, the energy conversion efficiency of the semiconductor converter can reach 10.6%, while the overall battery efficiency was determined to be 2.9%. Therefore, this research provides a feasible structure for a planar 4H-SiC p–n junction energy converter utilizing the (14C6H5NH)2CO source and presents a powerful model for predicting the performance of planar betavoltaic batteries.

Respiratory infections caused by Pseudomonas aeruginosa are a major health problem globally. Current treatment for P. aeruginosa infections relies solely on antibiotics, but the rise of antibiotic-resistant strains necessitates an urgent need for a protective vaccine. Traditional parenteral vaccines, despite employing potent adjuvants aimed at serotype-dependent immunity, often fail to elicit the desired mucosal immune response. Thus, developing vaccines that target both localized mucosal and systemic immune responses represents a promising direction for future research on P. aeruginosa vaccination. In this study, we explored EPS301, the exopolysaccharide derived from the lung microbiota strain Lactobacillus plantarum WXD301, which exhibits excellent self-assembly properties, enabling the formation of homogeneous nanoparticles when encapsulating recombinant PcrV of P. aeruginosa, designated as EPS301@rPcrV. Notably, the EPS301 vector effectively enhanced antigen adhesion to the nasal and pulmonary mucosal tissues and prolonged antigen retention. Moreover, EPS301@rPcrV provided effective and sustained protection against P. aeruginosa pneumonia, surpassing the durability achieved with the "gold standard" cholera toxin adjuvant. The EPS301-adjuvanted vaccine formulation elicited robust mucosal IgA and Th17/γδ17 T cell responses, which exceeded those induced by the CTB-adjuvanted vaccination and were sustained for over 112 days. Additionally, Th 17 and γδ 17 resident memory T cells induced by EPS301@rPcrV were crucial for protection against P. aeruginosa challenge. Intriguingly, IL-17A knockout mice exhibited lower survival rates, impaired bacterial clearance ability, and exacerbated lung tissue damage upon EPS301 adjuvanted vaccination against P. aeruginosa-induced pneumonia, indicating an IL-17A-dependent protective mechanism. In conclusion, our findings provided direct evidence that EPS301@rPcrV mucosal vaccine is a promising candidate for future clinical application against P. aeruginosa-induced pulmonary infection.

BackgroundDue to its complex pathogenesis, the assessment of cancer-associated disseminated intravascular coagulation (DIC) is challenging. We aimed to develop a machine learning (ML) model to predict overt DIC in critically ill colorectal cancer (CRC) patients using clinical features and laboratory indicators.MethodsThis retrospective study enrolled consecutive CRC patients admitted to the intensive care unit from January 2018 to December 2023. Four ML algorithms were used to construct predictive models using 5-fold cross-validation. The models’ performance in predicting overt DIC and 30-day mortality was evaluated using the area under the receiver operating characteristic curve (ROC-AUC) and Cox regression analysis. The performance of three established scoring systems, ISTH DIC-2001, ISTH DIC-2018, and JAAM DIC, was also assessed for survival prediction and served as benchmarks for model comparison.ResultsA total of 2,766 patients were enrolled, with 699 (25.3%) diagnosed with overt DIC according to ISTH DIC-2001, 1,023 (36.9%) according to ISTH DIC-2018, and 662 (23.9%) according to JAAM DIC. The extreme gradient boosting (XGB) model outperformed others in DIC prediction (ROC-AUC: 0.848; 95% CI: 0.818–0.878; p < 0.01) and mortality prediction (ROC-AUC: 0.708; 95% CI: 0.646–0.768; p < 0.01). The three DIC scores predicted 30-day mortality with ROC-AUCs of 0.658 for ISTH DIC-2001, 0.692 for ISTH DIC-2018, and 0.673 for JAAM DIC.ConclusionThe results indicate that ML models, particularly the XGB model, can serve as effective tools for predicting overt DIC in critically ill CRC patients. This offers a promising approach to improving clinical decision-making in this high-risk group.

IntroductionBevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, is widely used as a first-line treatment for metastatic colorectal cancer (mCRC), with hypertension being a common adverse effect. However, there is limited data on the predisposing factors contributing to bevacizumab-induced blood pressure (BP) elevation. This study aims to identify clinical risk factors associated with bevacizumab-related hypertension in patients with mCRC.MethodsThis retrospective study included 178 patients treated between January and June 2020. Demographic data and medical histories were extracted from hospital electronic medical records.ResultsAmong the 178 patients, 54 (30.3%) developed bevacizumab-related hypertension, with a median onset time of 48 days. Univariate and multivariate analyses identified pre-existing hypertension [odds ratio (OR), 3.30; 95% confidence interval (CI), 1.56–6.99] and age ≥60 years (OR, 2.04; 95% CI, 1.00–4.17) as independent risk factors for bevacizumab-related hypertension. The area under the receiver operating characteristic (ROC) curve was 0.66 (95% CI, 0.57–0.75, P < 0.001). The median overall survival (OS) for the cohort was 30.53 months (95% CI, 22.23–38.84). No significant differences in OS were observed between patients with and without bevacizumab-related hypertension (31.13 vs. 27.87 months, P = 0.86).ConclusionPre-existing hypertension and age ≥60 years are significant clinical risk factors for bevacizumab-related hypertension in mCRC patients. Bevacizumab-related hypertension did not affect overall survival. Clinicians should closely monitor BP within the first 2 months of bevacizumab treatment in high-risk patients.

Objective: Previous studies evaluating the differences in COVID-19 mortality rates between immunocompromised patients and other patient groups have shown conflicting findings. This research aimed to compare the mortality rates of immunocompromised and immunocompetent patients during the Omicron-dominant period of the SARS-CoV-2 pandemic, and to identify factors associated with prognosis. Methods: We conducted a retrospective analysis of 1085 adult patients (aged ≥18 years) admitted with COVID-19 pneumonia to the China-Japan Friendship Hospital between December 1, 2022, and January 31, 2023. We assessed the prevalence of comorbidities, incidence of co-infections and nosocomial infections, and 30-day mortality. Results: Among the 1085 patients, 254 were immunocompromised, and 831 were immunocompetent. Immunocompromised patients had higher rates of non-invasive ventilation use (30.3 % vs. 21.1 %), invasive ventilation (12.2 % vs. 5.3 %), and 30-day mortality (19.7 % vs. 13.7 %) compared to immunocompetent patients. However, overall mortality rates did not significantly differ based on immunocompromised status. Cox regression analysis identified that elevated troponin T (≥0.15 ng/mL), respiratory failure, high lactate dehydrogenase (≥272.5 U/L), elevated D-dimer (≥1.295 mg/L), increased C-reactive protein (≥90 mg/L), elevated interleukin-6 (>11.67 ng/L), high peripheral blood neutrophil count (>9.84 × 10⁹/L), and immunocompromised status were independent predictors of poor COVID-19 prognosis. In the immunocompetent group, current smoking and a history of interstitial lung disease were related to a worse prognosis. Conclusions: COVID-19 pneumonia due to the Omicron variant may lead to worse outcomes in immunocompromised patients. In immunocompetent patients, careful monitoring is essential for those with respiratory failure, smoking history, or interstitial lung disease to prevent adverse outcomes.

LZ91 Mg-Li alloy plates with three types of initial texture were rolled by 70% reduction at both room temperature and 200 °C to explore the rolling texture formation of α-Mg phase. The results showed that the rolling texture is largely affected by the initial texture. All the samples exhibited two main texture components as RD-split double peaks texture and TD-split double peaks texture after large strain rolling. The intensity of the two texture components was strongly influenced by the initial orientation and rolling temperature. Extension twinning altered the large-split non-basal orientation to a near basal one at low rolling strain. The basal orientation induced by twinning is unstable, which finally transmitted to the RD-split texture. The strong TD-split texture formed due to slip-induced orientation transition from its initial orientation. The competition between prismatic 〈a〉 and basal slip determined the intensity and tilt angle of the TD-split texture. By increasing the rolling temperature, the TD-split texture component was enhanced in all three samples. Limitation of extension twinning behavior and the promotion of prismatic slip at elevated temperature are the main reasons for the difference in hot and cold rolling texture.

Recently, a Schwarz crystal structure with curved grain boundaries (GBs) constrained by twin-boundary (TB) networks was discovered in nanocrystalline Cu through experiments and atomistic simulations. Nanocrystalline Cu with nanosized Schwarz crystals exhibited high strength and excellent thermal stability. However, the grain-size effect and associated deformation mechanisms of Schwarz nanocrystals remain unknown. Here, we performed large-scale atomistic simulations to investigate the deformation behaviors and grain-size effect of nanocrystalline Cu with Schwarz crystals. Our simulations showed that similar to regular nanocrystals, Schwarz nanocrystals exhibit a strengthening-softening transition with decreasing grain size. The critical grain size in Schwarz nanocrystals is smaller than that in regular nanocrystals, leading to a maximum strength higher than that of regular nanocrystals. Our simulations revealed that the softening in Schwarz nanocrystals mainly originates from TB migration (or detwinning) and annihilation of GBs, rather than GB-mediated processes (including GB migration, sliding and diffusion) dominating the softening in regular nanocrystals. Quantitative analyses of simulation data further showed that compared with those in regular nanocrystals, the GB-mediated processes in Schwarz nanocrystals are suppressed, which is related to the low volume fraction of amorphous-like GBs and constraints of TB networks. The smaller critical grain size arises from the suppression of GB-mediated processes.

Abstract Objective Incontinence seriously affects the lives of middle‐aged and older people. Pelvic floor muscle assessment is very important for incontinence, and handgrip strength can be used as an auxiliary diagnostic tool. Our study aims to find new cutoff points of handgrip strength as early indicators of incontinence and analyze the association between low handgrip strength and incontinence among Chinese middle‐aged and older people. Methods Participants were recruited from the 2015 China Health and Retirement Longevity Study. Receiver operating characteristic (ROC) curves were used to find the handgrip strength cutoff point. Logistic regression analysis was performed to explore other incontinence‐related risk factors. Results The study included 10,229 middle‐aged and older people. Compared with normal handgrip strength participants, medium strength participants had 1.510 [men, 95% confidence interval (CI) = 1.017–2.243] and 1.792 (women, 95% CI = 1.294–2.480) times greater risk of incontinence, and low strength participants had 2.420 (men, 95% CI = 1.787–3.277) and 1.516 (women, 95% CI = 1.130–2.032) times greater risk of incontinence. Trend test results showed that the risk of incontinence increased with decreasing handgrip strength in middle‐aged and older people. Conclusions Our study suggests that handgrip strength

Abstract Gasdermin D (GSDMD) is emerging as an important player in autoimmune diseases, but its exact role in lupus nephritis (LN) remains controversial. Here, we identified markedly elevated GSDMD in human and mouse LN kidneys, predominantly in CD11b+ myeloid cells. Global or myeloid-conditional deletion of GSDMD was shown to exacerbate systemic autoimmunity and renal injury in lupus mice with both chronic graft-versus-host (cGVH) disease and nephrotoxic serum (NTS) nephritis. Interestingly, RNA sequencing and flow cytometry revealed that myeloid GSDMD deficiency enhanced granulopoiesis at the hematopoietic sites in LN mice, exhibiting remarkable enrichment of neutrophil-related genes, significant increases in total and immature neutrophils as well as granulocyte/macrophage progenitors (GMPs). GSDMD-deficient GMPs and all-trans-retinoic acid (ATRA)-stimulated human promyelocytes NB4 were further demonstrated to possess enhanced clonogenic and differentiation abilities compared with controls. Mechanistically, GSDMD knockdown promoted self-renewal and granulocyte differentiation by restricting calcium influx, contributing to granulopoiesis. Functionally, GSDMD deficiency led to increased pathogenic neutrophil extracellular traps (NETs) in lupus peripheral blood and bone marrow-derived neutrophils. Taken together, our data establish that GSDMD deletion accelerates LN development by promoting granulopoiesis in a calcium influx-regulated manner, unraveling its unrecognized critical role in LN pathogenesis.

Abstract Introduction The efficacy of root canal treatment is greatly impacted by a thorough understanding of root canal anatomy. This systematic review and meta-analysis aim to thoroughly investigate the root morphology and canal configuration (RMCC) of permanent premolars (PMs). Methodology A comprehensive analysis was conducted following the PRISMA guidelines. Literature exploration was carried out across four electronic databases (PubMed, Embase, Cochrane, and Web of Science). The risk of bias assessment was conducted for the included studies utilizing the Anatomical Quality Assessment (AQUA) tool. Data analysis was performed utilizing SPSS and RevMAN5.3.3. The meta-analysis was applied with a 95% confidence interval to calculate odds ratios (OR). Results Among the 82 selected studies, 59 studies exhibited potential bias in domain one (objective(s) and subject characteristics), followed by domain three (methodology characterization). The majority of maxillary PM1s had either single root (46.7%) or double roots (51.9%), while three-rooted variants were uncommon (1.4%). Conversely, most other PMs exhibited a single root. In terms of canal configuration, maxillary PM1s predominantly featured double distinct canals (87.2%), with the majority of maxillary PM2s displaying either a single canal (51.4%) or double canals (48.3%). Mandibular PMs were primarily characterized by single canals, accounting for 78.3% of mandibular PM1s and 90.3% of mandibular PM2s. Subgroup analyses revealed higher incidences of single-rooted and single-canalled PMs among Asians compared to Caucasians. Additionally, women exhibited a higher incidence of single-rooted PMs, while men showed a greater frequency of double-rooted PMs. Conclusions The comprehensive analysis indicated that maxillary PM1s predominantly possess double roots and double canals, whereas maxillary PM2s and mandibular PMs were primarily characterized by single-rooted with a single canal. Notably, single root and single canal were more prevalent among women and Asian samples.

Leptomeningeal metastasis (LM) is a lethal complication of malignant tumors, with an incidence rate of 3%-5% among patients with non-small cell lung cancer (NSCLC). LM poses significant challenges in diagnosis, has poor prognosis, limited treatment options, and lacks standardized criteria for evaluating therapeutic efficacy, making it a difficult aspect of NSCLC management. Circulating tumor DNA (ctDNA), shed from tumor cells and carrying cancer-related information, holds significant value in precision oncology. Cerebrospinal fluid (CSF), present in the subarachnoid space of the brain, the spinal cord, and the central canal, and in direct contact with meningeal tissues, serves as the fluid medium that best reflects the genetic characteristics of LM. In recent years, CSF ctDNA has become a focal point due to its multi-omics features, playing a crucial role in the management of central nervous system (CNS) metastatic tumors. Its applications span the entire continuum of care, including aiding in diagnosis, assessing treatment response, predicting prognosis, and analyzing resistance mechanisms. This article provides a concise overview of CSF ctDNA detection techniques and their clinical applications in patients with NSCLC-LM.

Abstract Enhancing immune response activation through the synergy of effective antigen delivery and immune enhancement using natural, biodegradable materials with immune-adjuvant capabilities is challenging. Here, we present NAPS L.p that can activate the Toll-like receptor 4 (TLR4) pathway, an amphiphilic exopolysaccharide, as a potential self-assembly adjuvant delivery platform. Its molecular structure and unique properties exhibited remarkable self-assembly, forming a homogeneous nanovaccine with ovalbumin (OVA) as the model antigen. When used as an adjuvant, NAPS L.p significantly increased OVA uptake by dendritic cells. In vivo imaging revealed prolonged pharmacokinetics of NAPS L. p -delivered OVA compared to OVA alone. Notably, NAPS L.p induced elevated levels of specific serum IgG and isotype titers, enhancing rejection of B16-OVA melanoma xenografts in vaccinated mice. Additionally, NAPS L.p formulation improved therapeutic effects, inhibiting tumor growth, and increasing animal survival rates. The nanovaccine elicited CD4+ and CD8+ T cell-based immune responses, demonstrating the potential for melanoma prevention. Furthermore, NAPS L.p -based vaccination showed stronger protective effects against influenza compared to Al (OH)3 adjuvant. Our findings suggest NAPS L.p as a promising, natural self-adjuvanting delivery platform to enhance vaccine design across applications.

Abstract Colorectal cancer (CRC) is a highly malignant carcinoma associated with poor prognosis, and metastasis is one of the most common causes of death in CRC. Serpin Family A Member 1 (SERPINA1) is a serine protease inhibitor from the Serpin family. Till now, the function and mechanism of SERPINA1 in CRC progression have not been fully illustrated. We established highly metastatic colorectal cancer cells named as RKO-H and Caco2-H by mice liver metastasis model. By integrative bioinformatic approaches, we analyzed the prognostic value and clinical significance of SERPINA1 in CRC, and predicted potential transcription factors. Colony formation, EDU, MTS, Transwell and wound healing assay were performed to evaluate the biological functions of SERPINA1 in CRC in vitro. Experiments in vivo were conducted to explore the effects of SERPINA1 on liver metastasis of CRC. ChIP and luciferase reporter gene assays were performed to identify the transcriptional regulatory mechanism of SERPINA1 by CEBPB. Our results show that SERPINA1 is highly expressed in CRC and correlated with poor clinical outcomes. SERPINA1 promotes the proliferation, migration by activating STAT3 pathway. Mechanistically, CEBPB binds SERPINA1 gene promoter sequence and promotes the transcription of SERPINA1. SERPINA1 drives CEBPB-induced tumor cell growth and migration via augmenting STAT3 signaling. Our results suggest that SERPINA1 is a potential prognostic marker and may serve as a novel treatment target for CRC.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has severely impacted public health. In 2022, the Omicron variant of SARS-CoV-2 rapidly became the dominant circulating variant in the local COVID-19 outbreaks in Tianjin Municipality, China. To gain a deeper understanding of the genetic variations of the Omicron variant in Tianjin, specimens from individuals who tested positive for SARS-CoV-2 between December 2021 and November 2022 were used for virus whole genome sequencing and phylogenetic analysis. A total of 1,674 high-quality Omicron sequences were obtained, consisting of 1,339 sequences from local cases belonging to 20 Phylogenetic Assignment of Named Global Outbreak (PANGO) lineages and 335 sequences from imported cases belonging to 70 lineages. Tianjin experienced five waves of local outbreaks, accompanied by multiple substitutions among subvariants, ranging from the initial BA.1.1 lineage to the subsequent BA.2, BF.7, and BA.5.2 lineages. The evolutionary rate of local strains, estimated to be 28.999 substitutions per year, and the evolutionary rate of imported strains, estimated to be 24.946 substitutions per year, were lower than that of the strains circulating globally. The additional substitutions and deletions of local strains have been used to identify and disrupt the virus transmission chains. The subvariants such as BA.5.2.48, BA.5.2.49, BF.7.14, and XBB.1 circulating in the fifth epidemic wave presented criterial immune escape mutations including S: R346T, S: L452R and S: F486V. It is essential to implement genomic surveillance strategies to investigate further the development of genomic mutation characteristics in the SARS-CoV-2 variant. This ongoing monitoring will contribute to a better understanding of the virus's genetic changes and aid in effective control measures.

Abstract Background Diabetic foot ulcer (DFU) is one of the main chronic complications caused by diabetes, leading to amputation in severe cases. Bacterial infection affects the wound healing in DFU. Methods DFU patients who met the criteria were selected, and the clinical data were recorded in detail. The pus exudate from the patient’s foot wound and venous blood were collected for biochemical analysis. The distribution of bacterial flora in pus exudates of patients was analyzed by 16S rRNA sequencing, and the correlation between DFU and pathogenic variables, pyroptosis and immunity was analyzed by statistical analysis. Then, the effects of key bacteria on the inflammation, proliferation, apoptosis, and pyroptosis of polymorphonuclear leukocytes were investigated by ELISA, CCK-8, flow cytometry, RT-qPCR and western blot. Results Clinical data analysis showed that Wagner score was positively correlated with the level of inflammatory factors, and there was high CD3+, CD4+, and low CD8+ levels in DFU patients with high Wagner score. Through alpha, beta diversity analysis and species composition analysis, Corynebacterium accounted for a large proportion in DFU. Logistics regression model and Person correlation analysis demonstrated that mixed bacterial infections could aggravate foot ulcer, and the number of bacteria was closely related to inflammatory factors PCT, PRT, immune cells CD8+, and pyroptosis-related proteins GSDMD and NLRP3. Through in vitro experiments, Corynebacterium inhibited cell proliferation, promoted inflammation (TNF-α, PCT, CRP), apoptosis and pyroptosis (IL-1β, LDH, IL-18, GSDMD, NLRP3, and caspase-3). Conclusion Mixed bacterial infections exacerbate DFU progression with a high predominance of Corynebacterium, and Corynebacterium promotes inflammation, apoptosis and pyroptosis to inhibit DFU healing.

Abstract Background It is challenging to identify residual or recurrent fistulas from the surgical region, while MR imaging is feasible. The aim was to use dynamic contrast-enhanced MR imaging (DCE-MRI) technology to distinguish between active anal fistula and postoperative healing (granulation) tissue. Methods Thirty-six patients following idiopathic anal fistula underwent DCE-MRI. Subjects were divided into Group I (active fistula) and Group IV (postoperative healing tissue), with the latter divided into Group II (≤ 75 days) and Group III (> 75 days) according to the 75-day interval from surgery to postoperative MRI reexamination. MRI classification and quantitative analysis were performed. Correlation between postoperative time intervals and parameters was analyzed. The difference of parameters between the four groups was analyzed, and diagnostic efficiency was tested by receiver operating characteristic curve. Results Wash-in rate (WI) and peak enhancement intensity (PEI) were significantly higher in Group I than in Group II (p = 0.003, p = 0.040), while wash-out rate (WO), time to peak (TTP), and normalized signal intensity (NSI) were opposite (p = 0.031, p = 0.007, p = 0.010). Area under curves for discriminating active fistula from healing tissue within 75 days were 0.810 in WI, 0.708 in PEI, 0.719 in WO, 0.783 in TTP, 0.779 in NSI. All MRI parameters were significantly different between Group I and Group IV, but not between Group II and Group III, and not related to time intervals. Conclusion In early postoperative period, DCE-MRI can be used to identify active anal fistula in the surgical area. Trial registration Chinese Clinical Trial Registry: ChiCTR2000033072.

Background: Taxane-based chemotherapy is the primary treatment for triple-negative breast cancer (TNBC), yet clinical outcomes remain unsatisfactory due to the persistence of chemoresistance. Identifying key factors that contribute to chemoresistance and understanding the associated molecular mechanisms is therefore essential. Method: The GEO databases were utilized to pinpoint factors related to chemoresistance, which were subsequently validated using clinical tissue samples. The role of UGCG in the malignant progression and chemoresistance of TNBC was assessed through various functional assays. Western blotting, qRT-PCR, and immunohistochemistry were employed to investigate the signaling pathways associated with UGCG in TNBC. Results: UGCG expression was notably elevated in chemoresistant breast cancer tissues and cells, as identified in GEO databases and confirmed through immunohistochemistry. Additionally, findings from our cohorts indicated that higher levels of UGCG expression correlated with a lower rate of pathological complete response (pCR), suggesting it could serve as an independent predictor of chemotherapy effectiveness. Gain- and loss-of-function experiments demonstrated that UGCG enhanced the proliferation, metastasis, and stemness of breast cancer cells. Furthermore, treatment with paclitaxel or docetaxel resulted in increased UGCG expression, which in turn reduced chemotherapy-induced cell apoptosis and improved drug resistance and metastatic capabilities. Mechanistically, UGCG was found to amplify the activation of NF-κB and Wnt/β-catenin pathways, and the use of inhibitors targeting these pathways diminished the UGCG-induced malignant effects. Conclusion: Our findings underscore the significant role of UGCG in the chemoresistance and progression of breast cancer, suggesting it as a predictive biomarker and potential therapeutic target to combat chemoresistance in this disease.

ABSTRACT Background McLeod syndrome (MLS) and chorea‐acanthocytosis (ChAc) are exceedingly rare diseases characterized by a variety of movement disorders including chorea, dystonia, and Parkinsonism. Genetic analysis plays a key role in early and accurate diagnosis, but relevant variants are still under investigation. This study aims to explore new pathogenic variants in Chinese patients with MLS and ChAc and to conduct a comprehensive analysis of the clinical heterogeneity among these patients. Methods Eighteen Chinese patients who presented with choreatic movements with negative HTT genetic testing were identified and underwent targeted next‐generation sequencing, verified by Sanger sequencing. Results Two novel XK variants (c.970A>T, c.422_423del) were identified in three index MLS patients and six novel VPS13A variants (c.9219C>A, c.3467T>A, c.4208dup, c.9243_9246del, c.5364del, c.556‐290_697‐483del) in five index ChAc patients. One copy number variant of VPS13A (g.79827595_79828762del/c.556‐290_697‐483del) was firstly described in Chinese population. Conclusion As the currently largest descriptive study of MLS and ChAc patients in China, this study expands on the clinical and genetic spectrum of XK and VPS13A, contributing to the clinical diagnosis of MLS and ChAc.

Abstract In recent years, negative pressure wound dressings have garnered widespread attentions. However, it is challenging to drain the accumulated fluid under negative pressures for hydrogel dressings. To address this issue, this study prepared a chemical/physical duel‐network PEG‐CMCS/AG/MXene hydrogel composed by chemical disulfide crosslinked network of four‐arm polyethylene glycol/carboxymethyl chitosan (4‐Arm‐PEG‐SH/CMCS), and the physical network of hydrogen bond of agar (AG). Under near‐infrared light (NIR) irradiation, the PEG‐CMCS/AG/MXene hydrogel undergoes photothermal heating due to integrate of MXene, which destructs the hydrogen bond network and allows the removal of exudate through a mechanism mimicking the sweat gland‐like effect of skin pores. The photothermal heating effect also enables the antimicrobial activity to prevent wound infections. The excellent electrical conductivity of PEG‐CMCS/AG/MXene can promote cell proliferation under the external electrical stimulation (ES) in vitro. The animal experiments of full‐thickness skin defect model further demonstrate its ability to accelerate wound healing. The conversion between thioester and thiol achieved with L‐cysteine methyl ester hydrochloride (L‐CME) can provides the on‐demand dissolution of the dressing in situ. This study holds promises to provide a novel solution to the issue of fluid accumulations under hydrogel dressings and offers new approaches to alleviating or avoiding the significant secondary injuries caused by frequent dressing changes.

Most computational methods for predicting driver mutations have been trained using positive samples, while negative samples are typically derived from statistical methods or putative samples. The representativeness of these negative samples in capturing the diversity of passenger mutations remains to be determined. To tackle these issues, we curated a balanced dataset comprising driver mutations sourced from the COSMIC database and high-quality passenger mutations obtained from the Cancer Passenger Mutation database. Subsequently, we encoded the distinctive features of these mutations. Utilizing feature correlation analysis, we developed a cancer driver missense mutation predictor called CDMPred employing feature selection through the ensemble learning technique XGBoost. The proposed CDMPred method, utilizing the top 10 features and XGBoost, achieved an area under the receiver operating characteristic curve (AUC) value of 0.83 and 0.80 on the training and independent test sets, respectively. Furthermore, CDMPred demonstrated superior performance compared to existing state-of-the-art methods for cancer-specific and general diseases, as measured by AUC and area under the precision-recall curve. Including high-quality passenger mutations in the training data proves advantageous for CDMPred’s prediction performance. We anticipate that CDMPred will be a valuable tool for predicting cancer driver mutations, furthering our understanding of personalized therapy.

Malic enzymes (MEs) are metabolic enzymes that catalyze the oxidation of malate to pyruvate and NAD(P)H. While researchers have well established the physiological metabolic roles of MEs in organisms, recent research has revealed a link between MEs and carcinogenesis. This review collates evidence of the molecular mechanisms by which MEs promote cancer occurrence, including transcriptional regulation, post-transcriptional regulation, post-translational protein modifications, and protein-protein interactions. Additionally, we highlight the roles of MEs in reprogramming energy metabolism, suppressing senescence, and modulating the tumor immune microenvironment. We also discuss the involvement of these enzymes in mediating tumor resistance and how the development of novel small-molecule inhibitors targeting MEs might be a good therapeutic approach. Insights through this review are expected to provide a comprehensive understanding of the intricate relationship between MEs and cancer, while facilitating future research on the potential therapeutic applications of targeting MEs in cancer management.

Previous studies reported that hemoprotein CYP450 catalyzed triclosan coupling is an “uncommon” metabolic pathway that may enhance toxicity, raising concerns about its environmental and health impacts. Hemoglobin, a notable hemoprotein, can catalyze endogenous phenolic amino acid tyrosine coupling reactions. Our study explored the feasibility of these coupling reactions for exogenous phenolic pollutants in plasma. Both hemoglobin and hemin were found to catalyze triclosan coupling in the presence of H₂O₂. This resulted in the formation of five diTCS-2 H, two diTCS-Cl-3 H, and twelve triTCS-4 H in phosphate buffer, with a total of nineteen triclosan coupling products monitored using LC-QTOF. In plasma, five diTCS-2 H, two diTCS-Cl-3 H, and two triTCS-4 H were detected in hemoglobin-catalyzed reactions. Hemin showed a weaker catalytic effect on triclosan transformation compared to hemoglobin, likely due to hemin dimerization and oxidative degradation by H₂O₂, which limits its catalytic efficiency. Triclosan transformation in the human plasma-like medium still occurs with high H₂O₂, despite the presence of antioxidant proteins that typically inhibit such transformations. In plasma, free H₂O₂ was depleted within 40 minutes when 800 µM H₂O₂ was added, suggesting a rapid consumption of H₂O₂ in these reactions. Antioxidative species, or hemoglobin/hemin scavengers such as bovine serum albumin, may inhibit but not completely terminate the triclosan coupling reactions. Previous studies reported that diTCS-2 H showed higher hydrophobicity and greater endocrine-disrupting effects compared to triclosan, which further underscores the potential health risks. This study indicates that hemoglobin and heme in human plasma might significantly contribute to phenolic coupling reactions, potentially increasing health risks.

Abstract Minimal hepatic encephalopathy (MHE) has a substantial impact on the clinical outcomes and quality of life (QOL) of patients with cirrhosis. However, timely diagnosis and intervention are challenging due to sophisticated diagnostic methods. In this study, 673 healthy controls and 905 patients with cirrhosis were screened, and 660 healthy controls and 757 patients with cirrhosis, divided into the test (292 patients) and validation (465 patients) cohort, were analyzed after screening. A diagnostic model of the Stroop test (Stroop‐CN) was constructed by multivariate linear regression based on the results of healthy controls. The prevalence of MHE and the comparison results with psychometric hepatic encephalopathy score through the Stroop‐CN model were stable in the test and validation cohorts. Moreover, the prevalence of MHE remained significantly higher in patients with worse disease conditions marked as high Child–Pugh grades and the Model for End‐stage Liver Disease and Sodium (MELD‐Na) scores in the test and validation cohort. The EuroQol 5‐D questionnaire revealed that patients with MHE had a worse QOL than those without MHE both in the test and validation cohort. In conclusion, an easy and practical Stroop‐CN model for MHE diagnosis based on the EncephalApp is established. It is found that a considerable number of Chinese patients with cirrhosis experience MHE, which significantly impacts their QOL.

ALKBH5 is one of the demethylases involved in the regulation of RNA m6A modification. In addition to its role in the dynamic regulation of RNA m6A modification, ALKBH5 has been found to play important roles in various tissues fibrosis processes in recent years. However, the mechanisms and effects of ALKBH5 in fibrosis have been reported inconsistently. Multiple cell types, including parenchymal cells, immune cells (neutrophils and T cells), macrophages, endothelial cells, and fibroblasts, play roles in various stages of fibrosis. Therefore, this review analyzes the mechanisms by which ALKBH5 regulates these cells, its impact on their functions, and the outcomes of fibrosis. Furthermore, this review summarizes the role of ALKBH5 in fibrotic diseases such as pulmonary fibrosis, liver fibrosis, cardiac fibrosis, and renal fibrosis, and discusses various ALKBH5 inhibitors that have been discovered to date, exploring the potential of ALKBH5 as a clinical target for fibrosis.

ObjectiveTo observe the effect of light walking combined with arthroscopic surgery on the efficacy and Bone Mineral Density (BMD) of patients with ankle arthritis. Methods 180 patients with ankle arthritis were retrospectively selected, who were divided into a control group (Group A) and an experimental group (Group B) according to treatment methods, with 90 patients in each group. Group A was treated with conventional open surgery and Group B was treated with light walking combined with arthroscopic surgery. The two groups were compared before and after treatment on scales such as the AOFAS ankle hindfoot score. Meanwhile, the patients' BMD and levels of inflammatory factors such as tumor cell necrosis factor-α (TNF-α) were compared before and after treatment. Results The Kofoed and AOFAS scale scores were higher for mild walking combined with arthroscopic surgery than for conventional treatment (P