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Abstract Triple-negative breast cancer (TNBC), the most aggressive subtype, presents a critical challenge due to the absence of approved targeted therapies. Hence, there is an urgent need to identify effective therapeutic targets for this condition. While epidermal growth factor receptor (EGFR) is prominently expressed in TNBC and recognized as a therapeutic target, anti-EGFR therapies have yet to gain approval for breast cancer treatment due to their associated side effects and limited efficacy. Here, we discovered that intercellular adhesion molecule-1 (ICAM-1) exhibits elevated expression levels in metastatic breast cancer and serves as a pivotal binding adaptor for EGFR activation, playing a crucial role in malignant progression. The activation of EGFR by tumor-expressed ICAM-1 initiates biased signaling within the JAK1/STAT3 pathway, consequently driving epithelial-to-mesenchymal transition and facilitating heightened metastasis without influencing tumor growth. Remarkably, ICAM-1-neutralizing antibody treatment significantly suppressed cancer metastasis in a breast cancer orthotopic xenograft mouse model. In conclusion, our identification of ICAM-1 as a novel tumor intrinsic regulator of EGFR activation offers valuable insights for the development of TNBC-specific anti-EGFR therapies.

Abstract Migratory cells exist in the heart, such as immune cells, fibroblasts, endothelial cells, etc. During myocardium injury, such as ischemia–reperfusion (MIRI), cells migrate to the site of injury to perform repair functions. However, excessive aggregation of these cells may exacerbate damage to the structure and function of the heart, such as acute myocarditis and myocardial fibrosis. Myocardial injury releases exosomes, which are a type of vesicle with signal transduction function and the miRNA carried by exosomes can control cell migration function. Therefore, regulating this migratory cell population through cardiac-derived exosomal miRNA is crucial for protecting and maintaining cardiac function. Through whole transcriptome RNA sequencing, exosomal miRNA sequencing and single-cell dataset analysis, we (1) determined the potential molecular regulatory role of the lncRNA‒miRNA‒mRNA axis in MIRI, (2) screened four important exosomal miRNAs that could be released by cardiac tissue, and (3) screened seven genes related to cell locomotion that are regulated by four miRNAs, among which Tradd and Ephb6 may be specific for promoting migration of different cells of myocardial tissue in myocardial infarct. We generated a core miRNA‒mRNA network based on the functions of the target genes, which may be not only a target for cardiac repair but also a potential diagnostic marker for interactions between the heart and other tissues or organs. In conclusion, we elucidated the potential mechanism of MIRI in cardiac remodeling from the perspective of cell migration, and inhibition of cellular overmigration based on this network may provide new therapeutic targets for MIRI and to prevent MIRI from developing into other diseases.

Two new spider species of the genus Trachelas L. Koch, 1872 are described from China: Trachelas kavanaughi sp. nov. (♀) and Trachelas ventriosus sp. nov. (♀). The male of Trachelas gaoligongensis Jin, Yin & Zhang, 2017 is described for the first time. Illustrations of the body and copulatory organs and a distribution map are provided.

Background/purpose: External root resorption is a main side effect of orthodontic treatment and is more likely to occur on the pression side than the tension side. To explore the potential protective mechanisms on the tension side, this study investigated the influence of mechanical tension on cementoblast mineralization and elucidated the role of autophagy in mediating this process. Materials and methods: Mechanical tension was applied to cementoblasts using iStrain. The expression of mineralization-related and autophagy-related markers was detected by qRT-PCR, Western blot analysis, and immunofluorescence staining. RNA sequencing identified key regulators. Immunohistochemical staining assessed related markers expression in in vivo experiments. Results: Applying tension to cementoblasts increased mineralization-related gene expression in a force-dependent and time-dependent manner. The immunohistochemical staining result of in vivo experiments supported these findings, demonstrating elevated expression of mineralization markers under tension. Mechanical tension also enhanced autophagic activity in cementoblasts, which was demonstrated by the results of qRT-PCR, Western blot analysis, immunofluorescence staining, and in vivo experiments. Suppression of autophagy with chloroquine attenuated the mineralization of cementoblasts induced by tension stimulus. RNA-seq identified Postn as a key regulator, and the knockdown of Postn impaired the mechanical tension-promoted mineralization of cementoblasts. Conclusion: This study proposed the tension-induced promotion in mineralization of cementoblasts and emphasized the mediating role of autophagy in this process. Postn, a mediator connecting autophagy and mineralization, was identified as a key regulator. These discoveries helped elucidate orthodontic-related microprocesses on tooth roots and offer potential targets for therapeutic interventions to prevent and restore external root resorption clinically.

Abstract Unmanned aerial vehicle (UAV)-assisted communication based on automatic modulation classification (AMC) technology is considered an effective solution to improve the transmission efficiency of wireless communication systems, as it can adaptively select the most suitable modulation method according to the current communication environment. However, many existing deep learning (DL)-based AMC methods cannot be directly applied to UAV platform with limited computing power and storage space, because of the contradiction between accuracy and efficiency. This paper mainly studies the lightweight of DL-based AMC networks to improve adaptability in resource-constrained scenarios. To address this challenge, we propose an ultra-lightweight neural network (ULNN). This network incorporates a lightweight convolutional structure, attention mechanism, and cross-channel feature fusion technique. Additionally, we introduce data augmentation (DA) based on signal phase offsets during the model training process, aimed at improving the model’s generalization ability and preventing overfitting. Through experimental validation on the public dataset RML2016.10 A, the ULNN we proposed achieves an average precision of 62.83% with only 8815 parameters and reaches a peak classification accuracy of 92.11% at SNR = 10 dB. The experimental results show that ULNN can achieve high recognition accuracy while keeping the model lightweight, and is suitable for UAV platform with limited resources.

Abstract Progressive supranuclear palsy (PSP), a rare Parkinsonian disorder, is characterized by problems with movement, balance, and cognition. PSP differs from Alzheimer’s disease (AD) and other diseases, displaying abnormal microtubule-associated protein tau by both neuronal and glial cell pathologies. Genetic contributors may mediate these differences; however, the genetics of PSP remain underexplored. Here we conduct the largest genome-wide association study (GWAS) of PSP which includes 2779 cases (2595 neuropathologically-confirmed) and 5584 controls and identify six independent PSP susceptibility loci with genome-wide significant (P

Abstract Background This single-blind randomized controlled trial was aimed to evaluate the microbiological and clinical effects of Zeger therapy on gingival health. Methods Twenty-four adults with gingivitis were recruited and monitored micro-biologically and clinically at baseline (Day 0), 4 weeks (Day 29) after therapy. All volunteers received one-stage full-mouth supragingival scaling as basic oral health care for baseline, and then randomly divided into experimental (koumiss, n = 12) or control (none, n = 12) group. The koumiss was used once a day for 4 weeks. Results The microbial diversity of the experimental group increased significantly after drinking koumiss (p 0.05). However, there was no significant difference between the two groups in the clinical parameters (p > 0.05). Conclusions Zeger therapy promotes the diversity of supragingival microbiome in adults with gingivitis and increases the abundance of some beneficial flora while decreasing some harmful without clinical parameters marked changing, which holds promise for improving of gingivitis and may be a valuable oral health care approach in the future. Trial registration The clinical trial was approved by the Medical Ethics Committee of West China Hospital of Stomatology, Sichuan University, batch No. WCHSIRB-D-2021-428. Before patient registration began, the prospective clinical trial was registered in www.clinicaltrials.gov public repository in China under the registration number ChiCTR2200060555 on 04/06/2022.

Abstract Background Associations of dietary sodium and potassium intake with fracture risk are inconsistent and the effects of salt substitute on fracture incidence are unknown. We assessed the effect of salt substitute compared to regular salt intake on fracture incidence using data from the Salt Substitute and Stroke Study (SSaSS). Methods SSaSS was a cluster-randomized controlled trial conducted in 600 villages in northern China. Villages were randomly allocated into intervention and control groups in a 1:1 ratio. Salt substitute was provided to intervention villages and control villages continued regular salt use for 5 years. The primary outcome for this secondary analysis was the incidence of all fractures. Secondary outcomes included incidence of vertebral fracture, non-vertebral fracture, and fracture of unknown or non-specific location. Results 20,995 participants were included in this study, and 821 fractures occurred during follow-up. Intention-to-treat analyses showed no differences between the salt substitute and regular salt groups in the incidence of all fractures (rate ratio (RR) 0.96; 95% CI 0.81 to 1.14), vertebral fracture (RR 0.82; 95% CI 0.53 to 1.26), non-vertebral fracture (RR 1.05; 95% CI 0.86 to 1.29), or fracture of unknown or non-specific location (RR 0.80; 95% CI 0.54 to 1.18). Conclusions Use of salt substitute compared to regular salt had no detectable effect on the incidence of fracture in a population at high risk of cardiovascular disease and fracture. Trial registration ClinicalTrials.gov, NCT02092090. Registered on March 12, 2014.

Abstract Background The incidence of autoimmune diseases and breast cancer is significantly higher in women compared to men. Previous observational studies have not conclusively determined the relationship between these two conditions. This study utilizes the Mendelian randomization approach to investigate the genetic association between autoimmune diseases and breast cancer. Method Two-sample Mendelian randomization was conducted on a European population using the GWAS database. The inverse variance-weighted method served as the primary analytical approach. The MR-PRESSO test was applied to detect horizontal pleiotropy. To ensure result robustness, the FDR correction method was used. Result The study revealed that Sjögren’s syndrome lowers the overall risk of breast cancer (OR 0.96, 95% CI [0.93–0.99], p = 0.011). Idiopathic inflammatory myopathy shows a protective effect against overall breast cancer (OR 0.98, 95% CI [0.97–0.99], p = 0.035). An association was identified between rheumatoid arthritis and overall breast cancer (OR 0.98, 95% CI [0.96–1.00], p = 0.050). No causal link was found between systemic lupus erythematosus, systemic sclerosis, and overall breast cancer. The study also suggests that Sjögren’s syndrome, rheumatoid arthritis, and idiopathic inflammatory myopathy might reduce the risk of developing HER + breast cancer. Specifically, Sjögren’s syndrome (OR = 0.90, 95% CI [0.83–0.98], p = 0.02), rheumatoid arthritis (OR = 0.94, 95% CI [0.91–0.98], p = 0.006), and idiopathic inflammatory myopathy (OR = 0.96, 95% CI [0.93–0.99], p = 0.036). Additionally, systemic lupus erythematosus was found to lower the risk of HER- breast cancer (OR = 0.95, 95% CI [0.91–0.99], p = 0.046). The study did not establish a causal relationship between these five autoimmune diseases and ER + or ER- breast cancer. Conclusion This study found that autoimmune diseases may act as protective factors against breast cancer risk.

Background: The homologous recombination deficiency (HRD) score serves as a promising biomarker to identify patients who are eligible for treatment with PARP inhibitors (PARPi). Previous studies have suggested a 3-biomarker Genomic Instability Score (GIS) threshold of ≥ 42 as a valid biomarker to predict response to PARPi in patients with ovarian cancer and breast cancer. However, the GIS threshold for prostate cancer (PCa) is still lacking. Here, we conducted an exploratory analysis to investigate an appropriate HRD score threshold and to evaluate its ability to predict response to PARPi in PCa patients. Methods: A total of 181 patients with metastatic castration-resistant PCa were included in this study. Tumor tissue specimens were collected for targeted next-generation sequencing for homologous recombination repair (HRR) genes and copy number variation (CNV) analysis. The HRD score was calculated based on over 50,000 single-nucleotide polymorphisms (SNP) distributed across the human genome, incorporating three SNP-based assays: loss of heterozygosity, telomeric allelic imbalance, and large-scale state transition. The HRD score threshold was set at the last 5th percentile of the HRD scores in our cohort of known HRR-deficient tumors. The relationship between the HRD score and the efficacy in 16 patients of our cohort who received PARPi treatment were retrospectively analyzed. Results: Genomic testing was succeeded in 162 patients. In our cohort, 61 patients (37.7%) had HRR mutations (HRRm). BRCA mutations occurred in 15 patients (9.3%). The median HRD score was 4 (ranged from 0 to 57) in the total cohort, which is much lower than that in breast and ovarian cancers. Patients who harbored HRRm and BRCA or TP53 mutations had higher HRD scores. CNV occured more frequently in patients with HRRm. The last 5th percentile of HRD scores was 43 in the HRR-mutant cohort and consequently HRD high was defined as HRD scores ≥43. In the 16 patients who received PARPi in our cohort, 4 patients with a high HRD score achieved an objective response rate (ORR) of 100% while 12 patients with a low HRD score achieved an ORR of 8.3%. Progression-free survival (PFS) in HRD high patients was longer compared to HRD low patients, regardless of HRRm. Conclusions: A HRD score threshold of 43 was established and preliminarily validated to predict the efficacy of PARPi in this study. Future studies are needed to further verify this threshold.

Abstract Background With a series of clinical trials confirming the sensitivity of small cell lung cancer (SCLC) to immunotherapy, research on personalized treatment for SCLC has gained increasing attention. Currently, the most widely accepted subtype of SCLC is based on the expression levels of Achaete-Scute Family BHLH Transcription Factor 1 (ASCL1), neurogenic differentiation factor 1 (NEUROD1), and POU class 2 homeobox 3 (POU2F3). However, real-world studies on this classification remain limited. Methods We retrospectively collected biopsy specimens from patients who received immunotherapy at Shandong Provincial Hospital between January 2019 and July 2021. After determining the patient subtypes using immunohistochemistry, we analyzed the relationships between each subtype and survival as well as some clinical characteristics. Results In our study, we found that the subtype I achieved a significant survival advantage compared to the other groups. Additionally, the subtype A demonstrated a significant survival disadvantage. Among patients in the subtype I, there was a higher proportion of early brain metastasis and patients with a family history of tumors, while the subtype A had a lower proportion. Furthermore, the subtype A exhibited relatively poor immune infiltration. Conclusion In a diverse cohort of SCLC patients receiving immunotherapy, the subtype-I showed significant survival advantages while the subtype-A experienced a worse survival.

Abstract Objective To investigate the impact of vitamin A (VA), vitamin D (VD), and homocysteine (Hcy) on cardiometabolic multimorbidity (CMM). Methods This study is a cross-sectional study conducted in Ningxia Province, China. A total of 5000 participants aged 25–74 were recruited and divided into two groups based on the definition of cardiometabolic multimorbidity: the CMM group and the Non CMM group. Demographic, lifestyle, and laboratory data were collected to investigate the correlation between vitamin A, D, Hcy levels and CMM risk. The association was analyzed using multiple logistic regression and restricted cubic spline method. Results CMM incidence increased with age, being higher in females (20.05%) compared to males, Hypertension was present in 96.20% of CMM cases. Reduced VD levels correlated with an elevated CMM risk (OR = 1.799, 95% CI: 1.466–2.238), showing an inverse dose-response relationship, even after adjusting for confounders (OR = 1.553, 95% CI: 1.233–1.956). However, VA and Hcy levels were not significantly associated with CMM risk. The inverse correlation between VD status and CMM risk was more pronounced in males, obese individuals, and those with normal blood lipid profiles (P

In the last 40 years, there has been a notable rise in the occurrence of diabetes within China, leading to the country now having the highest number of individuals affected by this condition globally. This prospective observational study examined the effect of different baseline relative leukocyte telomere length (RTL) and the combined effect of baseline RTL and plasma phospholipid fatty acid (PPFA) on the risk of developing diabetes. Adults from Ningxia Province who underwent baseline and follow-up surveys were included in the study. The correlation between the baseline RTL and PPFA was investigated using a multiple linear regression model. The combined effects of baseline RTL and PPFA levels on the risk of developing type 2 diabetes mellitus (T2DM) were investigated using a Cox regression model with time as the covariate. A total of 1461 study subjects were included in this study. According to the diagnostic criteria of the Chinese Diabetes Society, 141 subjects developed T2DM during the follow-up period. The baseline age was negatively correlated with RTL. After adjustment for age, C16:0, C18:1 n-9, C20:4 n-6, C20:3 n-3, and monounsaturated fatty acid (MUFA) concentrations were negatively correlated with RTL. Multiple linear regression analysis showed that C16:0 and MUFA concentrations influenced RTL. Subjects with shorter RTL at baseline had a higher risk of developing diabetes than those with longer RTL. Subjects with shorter RTL and higher C16:0 and MUFA concentrations at baseline had a higher risk of developing T2DM than those with longer RTL and lower C16:0 and MUFA concentrations. Our findings indicated that PPFA affects changes in RTL. In addition, RTL and PPFA are associated with the occurrence of T2DM.

Abstract Background ST-elevation myocardial infarction (STEMI) is a common acute ischemia heart disease that causes serious damage to human health worldwide. Even though morbidity and mortality have significantly decreased by percutaneous coronary intervention (PCI), an additional cardiac protection strategy is still required. Acupuncture therapy has presented a dominant cardiac protection in many studies lately. Thus, we aim to evaluate the effect and safety of acupuncture as an adjunctive therapy in STEMI patients after PCI through a randomized controlled trial. Methods/Design This study describes a protocol of multicenter, double-blinded, parallel-controlled, randomized controlled trial. Ninety-six patients with STEMI aged 18–85 years who undergoing PCI will be recruited from the Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, The Affiliated Third Hospital of Chengdu Traditional Chinese Medicine University/Chengdu Pidu District Hospital of Traditional Chinese Medicine, and Zhaotong Municipal Hospital of Traditional Chinese Medicine. Participants will be randomly assigned (1:1 ratio) to the verum acupuncture plus basic therapy (i.e., treatment) group or the sham acupuncture plus basic therapy (i.e., control) group. These participants will be treated for 5 days and then will be followed up for 24 weeks. Any adverse events will be recorded throughout the study to evaluate safety. Discussion The present study aims to investigate the effect and safety of acupuncture for patients with STEMI after PCI and set up standardized treatment programs for acupuncture of these patients. Trial registration This study was registered in the Chinese Clinical Trial Registry (Registration ID: [ChiCTR2400081117]), on February 22, 2024.

Abstract Heterochromatin de-condensation in companion gametic cells is conserved in both plants and animals. In plants, microspore undergoes asymmetric pollen mitosis (PMI) to produce a vegetative cell (VC) and a generative cell (GC). Subsequently, the GC undergoes pollen mitosis (PMII) to produce two sperm cells (SC). Consistent with heterochromatin de-condensation in the VC, H3K9me2, a heterochromatin mark, is barely detected in VC. However, how H3K9me2 is differentially regulated during pollen mitosis remains unclear. Here, we show that H3K9me2 is gradually evicted from the VC since PMI but remain unchanged in the GC and SC. ARID1, a pollen-specific transcription factor that facilitates PMII, promotes H3K9me2 maintenance in the GC/SC but slows down its eviction in the VC. The genomic targets of ARID1 mostly overlaps with H3K9me2 loci, and ARID1 recruits H3K9 methyltransferase SUVH6. Our results uncover that differential pattern of H3K9me2 between two cell types is regulated by ARID1 during pollen mitosis.

Abstract Immune checkpoint inhibitor (ICI)-induced myocarditis involves intensive immune/inflammation activation; however, its molecular basis is unclear. Here, we show that gasdermin-E (GSDME), a gasdermin family member, drives ICI-induced myocarditis. Pyroptosis mediated by GSDME, but not the canonical GSDMD, is activated in myocardial tissue of mice and cancer patients with ICI-induced myocarditis. Deficiency of GSDME in male mice alleviates ICI-induced cardiac infiltration of T cells, macrophages, and monocytes, as well as mitochondrial damage and inflammation. Restoration of GSDME expression specifically in cardiomyocytes, rather than myeloid cells, in GSDME-deficient mice reproduces ICI-induced myocarditis. Mechanistically, quantitative proteomics reveal that GSDME-dependent pyroptosis promotes cell death and mitochondrial DNA release, which in turn activates cGAS-STING signaling, triggering a robust interferon response and myocardial immune/inflammation activation. Pharmacological blockade of GSDME attenuates ICI-induced myocarditis and improves long-term survival in mice. Our findings may advance the understanding of ICI-induced myocarditis and suggest that targeting the GSDME-cGAS-STING-interferon axis may help prevent and manage ICI-associated myocarditis.

RNA-binding proteins (RBPs) are key post-transcriptional regulators, and the malfunctions of RBP-RNA binding lead to diverse human diseases. However, prediction of RBP binding sites is largely based on RNA sequence features, whereas in vivo RNA structural features based on high-throughput sequencing are rarely incorporated. Here, we designed a deep bimodal information fusion network called DeepFusion for unraveling protein-RNA interactions by incorporating structural features derived from DMS-seq data. DeepFusion integrates two sub-models to extract local motif-like information and long-term context information. We show that DeepFusion performs best compared with other cutting-edge methods with only sequence inputs on two datasets. DeepFusion’s performance is further improved with bimodal input after adding in vivo DMS-seq structural features. Furthermore, DeepFusion can be used for analyzing RNA degradation, demonstrating significantly different RBP-binding scores in genes with slow degradation rates versus those with rapid degradation rates. DeepFusion thus provides enhanced abilities for further analysis of functional RNAs. DeepFusion’s code and data are available at http://bioinfo.org/deepfusion/.

Abstract Laryngeal carcinoma (LC) is a common cancer of the respiratory tract. This study aims to investigate the role of RNA-binding motif protein 15 (RBM15) in the cisplatin (DDP) resistance of LC cells. LC-DDP-resistant cells were constructed. RBM15, lysine-specific demethylase 5B (KDM5B), lncRNA Fer-1 like family member 4 (FER1L4), lncRNA KCNQ1 overlapping transcript 1 (KCNQ1OT1), glutathione peroxidase 4 (GPX4), and Acyl-CoA synthetase long-chain family (ACSL4) was examined. Cell viability, IC50, and proliferation were assessed after RBM15 downregulation. The enrichment of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) and N6-methyladenosine (m6A) on KDM5B was analyzed. KDM5B mRNA stability was measured after actinomycin D treatment. A tumor xenograft assay was conducted to verify the role of RBM15 in LC. Results showed that RBM15 was upregulated in LC and its knockdown decreased IC50, cell viability, proliferation, glutathione, and upregulated iron ion content, ROS, malondialdehyde, ACSL4, and ferroptosis. Mechanistically, RBM15 improved KDM5B stability in an IGF2BP3-dependent manner, resulting in FER1L4 downregulation and GPX4 upregulation. KDM5B increased KCNQ1OT1 and inhibited ACSL4. KDM5B/KCNQ1OT1 overexpression or FER1L4 knockdown promoted DDP resistance in LC by inhibiting ferroptosis. In conclusion, RBM15 promoted KDM5B expression, and KDM5B upregulation inhibited ferroptosis and promoted DDP resistance in LC by downregulating FER1L4 and upregulating GPX4, as well as by upregulating KCNQ1OT1 and inhibiting ACSL4. Silencing RBM15 inhibited tumor growth in vivo.

Abstract Background The aberrant expression of phosphofructokinase-platelet (PFKP) plays a crucial role in the development of various human cancers by modifying diverse biological functions. However, the precise molecular mechanisms underlying the role of PFKP in head and neck squamous cell carcinoma (HNSCC) are not fully elucidated. Methods We assessed the expression levels of PFKP and c-Myc in tumor and adjacent normal tissues from 120 HNSCC patients. A series of in vitro and in vivo experiments were performed to explore the impact of the feedback loop between PFKP and c-Myc on HNSCC progression. Additionally, we explored the therapeutic effects of targeting PFKP and c-Myc in HNSCC using Patient-Derived Organoids (PDO), Cell Line-Derived Xenografts, and Patients-Derived Xenografts. Results Our findings indicated that PFKP is frequently upregulated in HNSCC tissues and cell lines, correlating with poor prognosis. Our in vitro and in vivo experiments demonstrate that elevated PFKP facilitates cell proliferation, angiogenesis, and metastasis in HNSCC. Mechanistically, PFKP increases the ERK-mediated stability of c-Myc, thereby driving progression of HNSCC. Moreover, c-Myc stimulates PFKP expression at the transcriptional level, thus forming a positive feedback loop between PFKP and c-Myc. Additionally, our multiple models demonstrate that co-targeting PFKP and c-Myc triggers synergistic anti-tumor effects in HNSCC. Conclusion Our study demonstrates the critical role of the PFKP/c-Myc positive feedback loop in driving HNSCC progression and suggests that simultaneously targeting PFKP and c-Myc may be a novel and effective therapeutic strategy for HNSCC.

Multifunctional therapeutics have emerged as a solution to the constraints imposed by drugs with singular or insufficient therapeutic effects. The primary challenge is to integrate diverse pharmacophores within a single-molecule framework. To address this, we introduced DeepSA, a novel edit-based generative framework that utilizes deep simulated annealing for the modification of articaine, a well-known local anesthetic. DeepSA integrates deep neural networks into metaheuristics, effectively constraining molecular space during compound generation. This framework employs a sophisticated objective function that accounts for scaffold preservation, anti-inflammatory properties, and covalent constraints. Through a sequence of local editing to navigate the molecular space, DeepSA successfully identified AT-17, a derivative exhibiting potent analgesic properties and significant anti-inflammatory activity in various animal models. Mechanistic insights into AT-17 revealed its dual mode of action: selective inhibition of NaV1.7 and 1.8 channels, contributing to its prolonged local anesthetic effects, and suppression of inflammatory mediators via modulation of the NLRP3 inflammasome pathway. These findings not only highlight the efficacy of AT-17 as a multifunctional drug candidate but also highlight the potential of DeepSA in facilitating AI-enhanced drug discovery, particularly within stringent chemical constraints.

High-performance dielectric tunable materials with both high dielectric tunability and low dielectric loss are urgently needed for new-generation electronic tunable devices. In the present study, a new system, (Ba0.675Sr0.325)1−xLaxTi1−xMnxO3 (x = 0.25%, 0.5%, 0.75%, and 1.0%), was designed. The acceptor dopant Mn was added to lower dielectric loss, while the donor dopant La was introduced to enhance dielectric tunability. The samples were prepared using the conventional solid-state (CS) reaction method and the semi-solution (SS) method. The experimental results showed that the morphology of the ceramics was optimized by further improving the processing procedure. Dense microstructures, homogeneous grains, and uniform dopant distributions could be achieved successfully by the semi-solution method. Moreover, a significant enhancement in the tunable properties was realized owing to the improved microstructure mentioned above. The optimum tunable properties occurred in the samples prepared by the semi-solution method at x = 0.75%, with a high dielectric tunability of 85.0%, a low dielectric loss of 0.0011, and an excellent figure of merit (FOM) of 773. The tunable properties of (Ba,Sr)TiO3 (BST) ceramics were even superior to those of lead-based materials, with an FOM of approximately 700. All the results suggested that the semi-solution method rendered BST ceramics more promising for applications in tunable devices.

Abstract Background Carney syndrome is an uncommon autosomal disorder closely linked to mutations in the PRKAR1A gene. Skin lesions are the most pronounced feature of Carney syndrome, affecting over 80% of individuals with this condition. This syndrome is characterized by a triad of myxomas, skin pigmentation, and endocrine hyperfunction, featuring multiple endocrine neoplasms with skin and cardiac involvement. Dilated cardiomyopathy, a primary cardiomyopathy, is defined as the dilation and impaired systolic function of the left or both ventricles. Its clinical presentation varies from being asymptomatic to heart failure or sudden cardiac death, making it a leading global cause of heart failure. Currently, Dilated cardiomyopathy has an estimated prevalence of 1/2500–1/250 individuals, predominantly affecting those aged 30–40 years, with a male-to-female ratio of 3:1. This case report describes a heart failure patient with cardiac myxoma caused by Carney syndrome combined with dilated cardiomyopathy. The patient was successfully treated for heart failure by heart transplantation. Case presentation Herein, we report a case of heart failure due to Carney syndrome that resulted in cardiac myxoma combined with dilated cardiomyopathy. A 35-year-old male was admitted to the hospital three years ago because of sudden chest tightness and shortness of breath. Echocardiography indicated myxoma, and a combination of genetic screening and physical examination confirmed Carney syndrome with cardiac myxoma. Following symptomatic management, he was discharged. Surgical interventions were not considered at the time. However, the patient’s chest tightness and shortness of breath symptoms worsened, and he returned to the hospital. A New York Heart Association grade IV heart function was confirmed, and echocardiography indicated the presence of dilated cardiomyopathy accompanied by cardiac myxoma. Ultimately, the patient’s heart failure was successfully treated with heart transplantation. Conclusions Cardiac myxoma caused by Carney syndrome combined with heart failure caused by dilated cardiomyopathy can be resolved by heart transplantation.

Abstract It is important to study the effect of hydrate production on the physical and mechanical properties of low‐permeability clayey–silty reservoirs for the large‐scale exploitation of hydrate reservoirs in the South China Sea. In this study, a multiphysical‐field coupling model, combined with actual exploration drilling data and the mechanical experimental data of hydrate cores in the laboratory, was established to investigate the physical and mechanical properties of low‐permeability reservoirs with different slope angles during 5‐year hydrate production by the depressurization method via a horizontal well. The result shows that the permeability of reservoirs severely affects gas production rate, and the maximum gas production amount of a 20‐m‐long horizontal well can reach 186.8 m3/day during the 5‐year hydrate production. Reservoirs with smaller slope angles show higher gas production rates. The depressurization propagation and hydrate dissociation mainly develop along the direction parallel to the slope. Besides, the mean effective stress of reservoirs is concentrated in the near‐wellbore area with the on‐going hydrate production, and gradually decreases with the increase of the slope angle. Different from the effective stress distribution law, the total reservoir settlement amount first decreases and then increases with the increase of the slope angle. The maximum settlement of reservoirs with a 0° slope angle is up to 3.4 m, and the displacement in the near‐wellbore area is as high as 2.2 m after 5 years of hydrate production. It is concluded that the pore pressure drop region of low‐permeability reservoirs in the South China Sea is limited, and various slope angles further lead to differences in effective stress and strain of reservoirs during hydrate production, resulting in severe uneven settlement of reservoirs.

Abstract Background Forests play a crucial role in absorbing CO2 from the atmosphere. 55% of the carbon in terrestrial ecosystems is stored in forests, with the majority of forest carbon stored in soil. To better understand soil organic carbon (SOC) of forests and to access interventions that affect their SOC concentration, we conducted a comparative analysis between natural and planted forests. Forest interventions refer to the actions taken by humans to manage, protect, or transform forests, and can be divided into two main categories: environmental intervention and anthropogenic intervention. This study focused on the effects of different interventions on SOC in natural and planted forests by reviewing a total of 75 randomized controlled trials in the global literature and extracting a total of 15 different interventions. Results Through network meta-analysis, we found that natural forests have 22.3% higher SOC than planted forests, indicating their stronger carbon storage function. In natural forests, environmental interventions have a stronger impact. SOC is significantly influenced by forest age, fertilization, and elevation. In planted forests, however, anthropogenic interventions have a stronger impact. Pruning branches and fertilization are effective interventions for planted forests. Furthermore, forest degradation has a significantly negative impact on SOC in planted forests. Conclusion Overall, interventions to enhance soil carbon storage function differ between natural and planted forests. To address global climate change, protect biodiversity, and achieve sustainable development, it is imperative to globally protect forests and employ scientifically sound forest management practices. Regarding natural forests, the emphasis should be on comprehending the effects of environmental interventions on SOC. Conversely, concerning planted forests, the emphasis should be on comprehending the effects of anthropogenic interventions.

Abstract. Background:. There is a need for effective and safe therapies for psoriasis that provide sustained benefits. The aim of this study was to assess the efficacy and safety of tildrakizumab, an anti-interleukin-23p19 monoclonal antibody, for treating moderate-to-severe plaque psoriasis in Chinese patients. Methods:. In this multi-center, double-blind, phase III trial, patients with moderate-to-severe plaque psoriasis were enrolled and randomly assigned (1:1) to receive subcutaneous tildrakizumab 100 mg or placebo at weeks 0 and 4. Patients initially assigned to placebo were switched to receive tildrakizumab at weeks 12, 16, and every 12 weeks thereafter. Patients in the tildrakizumab group continued with tildrakizumab at week 16, and every 12 weeks until week 52. The primary endpoint was the Psoriasis Area and Severity Index (PASI 75) response rate at week 12. Results:. At week 12, tildrakizumab demonstrated significantly higher PASI 75 response rates (66.4% [73/110] vs. 12.7% [14/110]; difference, 51.4% [95% confidence interval (CI), 40.72, 62.13]; P

Abstract Purpose The purpose of this study was to compare the learning in the implant dentistry hands-on course to that of the flipped classroom (FC) and the traditional lecture cohorts (control). Materials and methods In this study,80 students were enrolled for the first time in an implant dentistry program. Subsequently, they were divided into two groups. The first, the FC group, which had free access to a video with a PowerPoint presentation on the Chaoxing-WHU-MOOC platform about the implant placement on first molar sites before class. The second, the control group, which attended a didactic lecture describing implant practice on the first molar site via a bidirectional multimedia interactive teaching demonstration and then operated on a simulation model. Cone beam computed tomography (CBCT) and the deviation gauge were utilized to analyze the accuracy of the implant placement in the students’ models. An online satisfaction questionnaire was distributed to both groups one week after the class. Results The linear deviation of the CBCT examination did not show any statistical difference between the two groups concerning cervical, apex, and angular. A significant buccal deviation was observed in the control group compared with the FC group (mean: 0.7436 mm vs. 0.2875 mm, p = 0.0035), according to the restoration-level deviation gauge. A total of 74.36% of students in the FC group placed implant within 0.5 mm buccal-to-lingual deviations, but only 41.03% of students in the control group reached within 0.5 mm buccal-to-lingual deviation ranges. Additionally, 91.67% of the students in the FC group and 97.5% of the students in the control group were satisfied with the practical implant class. Conclusion FC was more effective than a didactic lecture for implant dentistry practical skill acquisition.

Streptococcus pneumoniae is a pathogenic bacterium that causes infections such as pneumonia, meningitis, otitis media, and bacteremia. The prevention of pneumococcal disease by vaccination has become more urgent due to increased antibiotic resistance. Pneumococcal capsular polysaccharides (CPS) are effective vaccine antigens that stimulate the host to produce protective antibodies. S. pneumoniae serotype 14 is one of most prevalent types in Latin America and across the world. However, the yield of S. pneumoniae serotype 14 CPS from existing fermentation processes remains low and requires improvement. In this study, various aspects of the fermentation process were optimized to improve pneumococcal growth and polysaccharide productivity, including feed medium, cultivation gas environment, fermentation pH, and temperature. A simplified purification method was also developed to obtain pure CPS, including ultrafiltration, acid and ethanol precipitation, diafiltration, and lyophilization. These fermentation optimizations significantly enhanced the optical density of pneumococcal bacterial cultures and increased fermentation yields to 2.4–2.6 g/L—significantly higher than previously achieved. Furthermore, the test results of pure CPS could meet the requirements in the European Pharmacopoeia (11th edition). These optimizations provide valuable insights into the nutritional requirements and impact of varying fermentation process parameters on pneumococcal growth and CPS productivity, thus contributing to the development of a more efficient and cost-effective method for the production of pneumococcal CPS—essential for manufacturing vaccines against pneumococcal infections.

To improve the accuracy and efficiency of machine learning models in predicting and designing the mechanical properties and designing of lightweight high-entropy alloys, we have trained multi-classification machine learning models using stacking ensemble method. This ensembled model achieves high prediction accuracy of 0.9457 and good anti-overfitting performance. Two candidate high-entropy alloys with high hardness from the predicted results (Al0.38Ti0.36V0.05Zr0.16Nb0.05 and Al0.51Ti0.28V0.04Zr0.16Nb0.01) were selected to prepare bulk samples using arc melting method. The experimentally measured micro Vickers hardness of two samples were 723.7 HV and 691.0 HV respectively, and only slightly lower than the hardness values predicted by the model, with an error of less than 8 %. The phase structure of the samples, which is a mixture of HCP and FCC, also agrees well with the predicted results. This indicates that our machine learning approaches is highly effective in predicting the hardness of high-entropy alloys, with accuracy that has been experimentally verified, thereby significantly enhancing the efficiency of designing new lightweight high-hardness high-entropy alloys.

Endowing tactile feedback for prosthetic hands is profound for upper‐limb amputees. However, existing prosthetic hands are generally not in possession of the embedded sensory feedback. Herein, a flexible tactile sensor array which can be integrated into an untethered soft prosthetic hand to achieve static and dynamic discrimination tasks is presented. The flexible piezoresistive sensory arrays with 25 sensor units which can be arranged on five fingers of the soft prosthetic hand are fabricated. According to the collected large‐scale tactile dataset (including pressure distribution and pressure magnitude) during different grasping tasks, a learning‐based classification model that can reveal the correspondences between tactile information and object attributes while interacting with touched objects is developed. To transfer tactile information extracted from tactile sensor arrays, a wearable vibrotactile feedback band with a spatial coding feedback strategy is implemented by selectively activating vibrotactile motors located on the skin of the upper arm. In a set of tests performed by an individual with transradial amputation and eight able‐bodied subjects, the soft prosthetic hand integrated with tactile sensor arrays can help the users regain finger tactile sensation, discriminate grasped objects, and achieve real‐time dynamic rolling detection.

IntroductionThe crown clade is one of two major groups in the Russula subg. Russula.Methods/materialAn analysis of Chinese samples was performed based on the morphology, internal transcribed spacer (ITS) sequences, and multi-gene phylogenies of 28S nrLSU, 16S mtSSU, rpb1, rpb2, and tef1-α.ResultsThe results supported the independence of six new species: Russula alboflava (sect. Amethystinae), R. chrysantha (subsect. Chamaeleontinae), R. liyui (subsect. Laricinae), R. lutescens (subsect. Olivaceinae), R. paraxerampelina, and R. prunicolor (subsect. Xerampelinae) from Fagaceae forest habitats. Subsect. Alboflavinae was newly proposed in sect. Amethystinae. Members of the new subsection include R. alboflava, R. burlinghamiae, and possibly R. ballouii.DiscussionOur analyses also supported the claim that two species of R. fulvograminea (subsect. Laricinae) and R. subrubens (subsect. Xerampelinae) have a Eurasian distribution. The habitat and primary hosts of the main phylogenetic clades within related subsections were summarized and discussed.

Abstract Treatment strategies for hard tissue defects aim to establish a mineralized microenvironment that facilitates tissue remodeling. As a mineralized tissue, cementum shares a similar structure with bone and exhibits an excellent capacity to resist resorption under compression. Macrophages are crucial for mineralized remodeling; however, their functional alterations in the microenvironment of cementum remain poorly understood. Therefore, this study explores the mechanisms by which cementum resists resorption under compression and the regulatory roles of cementoblasts in macrophage functions. As a result, extracellular vesicles from compression‐loaded cementoblasts (Comp‐EVs) promote macrophage M2 polarization and enhance the clearance of apoptotic cells (efferocytosis) by 2‐ to 3‐fold. Local injection of Comp‐EVs relieves cementum destruction in mouse root resorption model by activating the tissue repair function of macrophages. Moreover, Comp‐EV‐loaded hydrogels achieve significant bone healing in calvarial bone defect. Unexpectedly, under compression, EV secretion in cementoblasts is reduced by half. RNA‐Seq analysis and verification reveal that Rab35 expression decreases by 60% under compression, thereby hampering the release of EVs. Rab35 overexpression is proposed as a modification of cementoblasts to boost the yield of Comp‐EVs. Collectively, Comp‐EVs activate the repair function of macrophages, which will be a potential therapeutic strategy for hard tissue repair and regeneration.

PurposeRapid diagnosis of acute ischemic stroke (AIS) is critical to achieve positive outcomes and prognosis. This study aimed to construct a model to automatically identify the infarct core based on non-contrast-enhanced CT images, especially for small infarcts.MethodsThe baseline CT scans of AIS patients, who had DWI scans obtained within less than 2 h apart, were included in this retrospective study. A modified Target-based deep learning model of YOLOv5 was developed to detect infarctions on CT. Randomly selected CT images were used for testing and evaluated by neuroradiologists and the model, using the DWI as a reference standard. Intraclass correlation coefficient (ICC) and weighted kappa were calculated to assess the agreement. The paired chi-square test was used to compare the diagnostic efficacy of physician groups and automated models in subregions. p

Background: Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by multi-organ involvement and the presence of autoantibodies, pathogenic factors that can serve as diagnostic biomarkers. The current research has been focusing on exploring specific autoantigens with clinical relevance for SLE subtypes. In line with this objective, this study investigated potential antigenic targets associated with specific phenotypes in SLE by leveraging an omics-based approach combined with immunoassay techniques. Methods: A transcriptomic analysis was conducted in a cohort of 70 SLE patients to identify genes significantly correlated to the relevant phenotype. Epitope mapping and sequence analysis techniques were used to predict autoantigens, and the corresponding antibodies were subsequently quantified by enzyme-linked immunosorbent assay (ELISA) and validated by Western blot. Results: Transcriptomic data analysis revealed a group of hub genes exhibiting a significant correlation with the neuropsychiatric phenotype and a positive relationship with platelets. Subsequent epitope prediction for the corresponding proteins highlighted vasodilator-stimulated phosphoprotein (VASP) as a potential autoantigen. Moreover, ELISA and immunoblotting confirmed that the anti-VASP antibody present in the serum was significantly elevated in SLE patients with neuropsychiatric involvement and positively associated with demyelination. Conclusion: VASP harbors autoantigenic epitopes associated with neuropsychiatric phenotype, especially the demyelination symptom in SLE, and its antibodies may serve as promising biomarkers in this disease.

Summary: Mesenchymal stem cells (MSCs) are heterogeneous in morphology and transcriptome, resulting in varying therapeutic outcomes. In this study, we found that 3D spheroid culture of heterogeneous MSCs, which have undergone conventional 2D monolayer culture for 5–6 passages, synchronized the cells into a uniform cell population with dramatically reduced cell size, and considerably increased levels of immunosuppressive genes and growth factors. Single-cell RNA sequencing (scRNA-seq) analysis of the cells revealed that 3D MSCs consisted of 2 major cell subpopulations and both expressed high levels of immunosuppressive factors, compared to 6 subpopulations in 2D MSCs. In addition, 3D MSCs showed a greater suppressive effect on T cells. Moreover, intravenous infusion of a large dose of 3D MSCs prior to imiquimod (IMQ) treatment significantly improved psoriatic lesion. Thus, our results indicate that 3D spheroid culture reprograms heterogeneous MSCs into a uniform immunosuppressive phenotype and promises a novel therapeutic potential for inflammatory diseases.

Reversible data hiding (RDH) algorithms have been extensively employed in the field of copyright protection and information dissemination. Among various RDH algorithms, the multiple histogram modification (MHM) algorithm has attracted significant attention because of its capability to generate high-quality marked images. In previous MHM methods, the prediction error histograms were mostly generated in a fixed way. Recently, clustering algorithms automatically classify prediction errors into multiple classes, which enhances the similarity among prediction errors within the same class. However, the design of features and the determination of clustering numbers are crucial in clustering algorithms. Traditional algorithms utilize the same features and fix the number of clusters (e.g., empirically generate 16 classes), which may limit the performance due to the lack of adaptivity. To address these limitations, an adaptive initial feature selection scheme and a clustering number optimization scheme based on the Fuzzy C-Means (FCM) clustering algorithm are proposed in this paper. The superiority of the proposed scheme over other state-of-the-art schemes is verified by experimental results.

ABSTRACT: The freezability of chicken spermatozoa is low, therefore, effective cryoprotectants is desiderated. Antifreeze proteins (AFPs) are widely found in cold-tolerant species and help them to survive in freezing environments. This study was the first to evaluate the effects of different concentrations of plant-originated antifreeze glycoprotein (AFGP) (0, 0.1, 1, and 5 μg/mL) on post-thawed sperm motion characteristics, morphology, mitochondrial function, antioxidant activity, and fertilizing potential in chickens. Results showed that the total motility of 0.1 to 1 μg/mL AFGP groups were significantly higher than those of the 5 μg/mL AFGP group (P < 0.05). The post-thawed sperm viability of 0.1 μg/mL AFGP group was significantly higher than any of test groups (P < 0.05). Higher abnormal morphology rate of post-thawed sperm was observed in the control group (0 μg/mL AFGP) than in the 0.1, 1, and 5 μg/mL AFGP groups (P < 0.05). The concentrations of malondialdehyde (MDA) decreased gradually with the increase of AFGP concentration. ATP was significantly higher in the 0.1 and 1 μg/mL AFGP groups than those of control and any of test groups (P < 0.05). The 0.1 to 1 μg/mL AFGP groups had increased mitochondrial membrane potential (MMP) level (P > 0.05). The 0.1 μg/mL AFGP group had the highest average fertility (61.36%) compared with control group (57.02%) and any of test groups of chickens at 31 wk of age, and the 1 μg/mL AFGP group had the highest average fertility (37.72%) compared with control group (21.73%) and any of test groups of chickens at 65 wk of age. In conclusion, the results from this study suggest lower concentration of AFGP (0.1–1 μg/mL) showed positive effect for sperm function. This study inspires the continuous evaluation and seeking right way of adopting different kinds of AFPs in rooster semen cryopreservation.

Programmed cell death 2 (PDCD2) is related to cancer progression and chemotherapy sensitivity. The role of PDCD2 in solid cancers (excluding hematopoietic malignancies) and their diagnosis and prognosis remains unclear. The TCGA, CGGA, GEPIA, cBioPortal, and GTEx databases were analyzed for expression, prognostic value, and genetic modifications of PDCD2 in cancer patients. Functional enrichment analysis, CCK8, colony formation assay, transwell assay, and xenograft tumor model were undertaken to study the PDCD2's biological function in glioma (GBMLGG). The PDCD2 gene was associated with solid cancer progression. In the functional enrichment analysis results, PDCD2 was shown to participate in several important GBMLGG biological processes. GBMLGG cells may be inhibited in their proliferation, migration, invasion, and xenograft tumor growth by knocking down PDCD2. Our research can provide new insights into solid cancer prognostic biomarkers of PDCD2.

Antibiotic resistance is an escalating global health concern, exacerbated by the pervasive presence of antibiotic resistance genes (ARGs) in natural environments. The Yangtze River, the world's third-longest river, traversing areas with intense human activities, presents a unique ecosystem for studying the impact of these genes on human health. Here, we explored ARGs in the Yangtze River, examining 204 samples from six distinct habitats of approximately 6000 km of the river, including free-living and particle-associated settings, surface and bottom sediments, and surface and bottom bank soils. Employing shotgun sequencing, we generated an average of 13.69 Gb reads per sample. Our findings revealed a significantly higher abundance and diversity of ARGs in water-borne bacteria compared to other habitats. A notable pattern of resistome coalescence was observed within similar habitat types. In addition, we developed a framework for ranking the risk of ARG and a corresponding method for calculating the risk index. Applying them, we identified water-borne bacteria as the highest contributors to health risks, and noted an increase in ARG risks in particle-associated bacteria correlating with heightened anthropogenic activities. Further analysis using a weighted ARG risk index pinpointed the Chengdu–Chongqing and Yangtze River Delta urban agglomerations as regions of elevated health risk. These insights provide a critical new perspective on ARG health risk assessment, highlighting the urgent need for strategies to mitigate the impact of ARGs on human health and to preserve the ecological and economic sustainability of the Yangtze River for future human use.

Background and aimsRheumatoid arthritis (RA) is a prevalent chronic autoimmune disease characterized by chronic inflammation. The Inflammatory Burden Index (IBI) is a newly proposed comprehensive inflammation index used to assess systemic inflammation. The relationship between IBI and RA, as well as its all-cause mortality, remains unclear. The objective of this study was to examine the correlation between IBI and RA and to analyze the association between IBI and all-cause mortality in RA.MethodsThe study comprehensively analyzes adult data from the National Health and Nutrition Examination Survey (NHANES) spanning 1999 to 2018. The participants’ IBI was calculated using the formula IBI = CRP * neutrophils/lymphocytes. Three models were constructed to investigate the relationship between IBI and the prevalence of RA. Nonlinear relationships were determined using restricted cubic spline curves. Stratified analyses and interaction tests were used to explore the relationship between RA and IBI in different subgroups. The same data analyses were applied to investigate the association between IBI and RA all-cause mortality.ResultsThe data analyses revealed a stable positive and nonlinear correlation between IBI and the risk of RA, as well as a positive, nonlinear, J-shaped association between IBI and RA all-cause mortality. The correlation and association were consistent across most subgroups, and multiple covariates had no effect on the results. No significant effect of multiple covariates on the association was found through interaction tests.ConclusionOur study has demonstrated a positive correlation between the prevalence of RA and all-cause mortality with the IBI index. This suggests that lower levels of inflammation in the body are associated with a reduced risk of RA prevalence and all-cause mortality. Further prospective studies are required to explore the mechanisms involved.

Abstract Background Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL‐S) is a rare autosomal dominant systemic microvascular disorder attributed to TREX1 (three‐prime repair exonuclease‐1) gene mutations, often proned to misdiagnosed. Methods We reported a case of RVCL‐S coexisting with systemic lupus erythematosus due to a mutation in the TREX1 gene. This study provided a summary and discussion of previously documented cases related to TREX1 mutations or RVCL‐S. Results A 39‐year‐old female patient visited the clinic due to progressive memory loss and speech difficulties. Magnetic resonance imaging results showed corpus callosum atrophy and multiple subcortical calcifications in both brain hemispheres. Genetic testing revealed a TREX1 gene mutation (c.294dupA). Treatment with immunosuppressive therapy for 2 months led to improvements in communication and mobility. We also summarized previously reported cases providing an overview of TREX1 gene mutation or RCVL‐S. Conclusion Our case establishes a compelling foundation for future RVCL‐S diagnosis and treatment paradigms. Notably, conducting systemic immunity screening in patients with RVCL‐S emerges as a strategic approach to prevent potential diagnostic oversights.

Abstract All‐solid‐state batteries equipped with solid‐state electrolytes (SSEs) have gained significant interest due to their enhanced safety, energy density, and longevity in comparison to traditional liquid organic electrolyte‐based batteries. However, many SSEs, such as sulfides and hydrides, are highly sensitive to water, limiting their practical use. As one class of important perovskites, the Ruddlesden–Popper perovskite oxides (RPPOs), show great promise as SSEs due to their exceptional stability, particularly in terms of water resistance. In this review, the crystal structure and synthesis methods of RPPOs SSEs are first introduced in brief. Subsequently, the mechanisms of ion transportation, including oxygen anions and lithium‐ions, and the relevant strategies for enhancing their ionic conductivity are described in detail. Additionally, the progress made in developing flexible RPPOs SSEs, which are critical for flexible and wearable electronic devices, has also been summarized. Furthermore, the key challenges and prospects for exploring and developing RPPOs SSEs in all‐solid‐state batteries are suggested. This review presents in detail the synthesis methods, the ion transportation mechanism, and strategies to enhance the room temperature ionic conductivity of RPPOs SSEs, providing valuable insights on enhancing their ionic conductivity and thus for their practical application in solid‐state batteries.

Introduction: Obesity, a global epidemic, is caused by an imbalance between energy intake and expenditure. The induction of white adipose browning to increase heat production has emerged as a potential effective strategy to address obesity. Ling-gui-zhu-gan (LGZG), a traditional Chinese medicine formula, has been proved to achieve promising results to combat obesity and related metabolic diseases, yet the mechanisms remain largely unexplored. This study aimed to elucidate the anti-obesity properties and the mechanisms of LGZG by investigating its browning effect on 3T3-L1 adipocytes.Methods: LGZG-containing serum obtained by oral administration of LGZG to animals was added to 3T3-L1 adipocytes to simulate in vivo conditions.Results: The results showed that 49 compounds were identified in LGZG-containing serum by UHPLC-Q-Orbitrap HRMS, including compounds such as atractylenolides and polyporenic acid C, etc. LGZG-containing serum alleviated the lipid accumulation and decreased both intracellular and extracellular triglyceride contents in a dose-dependent manner. This reduction is accompanied by enhanced mitochondrial respiratory and heat production function. Mechanistically, LGZG-containing serum led to a decrease in miR-27b expression and an increase in the mRNA and protein levels of browning-related markers, including UCP1, PRDM16, PGC-1α, PPARγ, CTBP1, and CTBP2. Further investigation using miR-27b mimic transfection confirmed that miR-27b/PRDM16 pathway might be a potential mechanism by which LGZG-containing serum promotes browning of 3T3-L1 adipocytes.Discussion: These results underscore the therapeutic potential of LGZG in addressing obesity and its associated metabolic disorders through the promotion of adipose browning.

IntroductionHepatocellular carcinoma (HCC) is a major cause of cancer-related mortality worldwide. Traditional Chinese Medicine (TCM) is widely utilized as an adjunct therapy, improving patient survival and quality of life. TCM categorizes HCC into five distinct syndromes, each treated with specific herbal formulae. However, the molecular mechanisms underlying these treatments remain unclear.MethodsWe employed a network medicine approach to explore the therapeutic mechanisms of TCM in HCC. By constructing a protein-protein interaction (PPI) network, we integrated genes associated with TCM syndromes and their corresponding herbal formulae. This allowed for a quantitative analysis of the topological and functional relationships between TCM syndromes, HCC, and the specific formulae used for treatment.ResultsOur findings revealed that genes related to the five TCM syndromes were closely associated with HCC-related genes within the PPI network. The gene sets corresponding to the five TCM formulae exhibited significant proximity to HCC and its related syndromes, suggesting the efficacy of TCM syndrome differentiation and treatment. Additionally, through a random walk algorithm applied to a heterogeneous network, we prioritized active herbal ingredients, with results confirmed by literature.DiscussionThe identification of these key compounds underscores the potential of network medicine to unravel the complex pharmacological actions of TCM. This study provides a molecular basis for TCM’s therapeutic strategies in HCC and highlights specific herbal ingredients as potential leads for drug development and precision medicine.

An optimized Affinity Selection-Mass Spectrometry (AS-MS) workflow has been developed for the efficient identification of potent USP1 inhibitors. USP1 was immobilized on agarose beads, ensuring low small molecule retention, efficient protein capture, and protein stability. The binding affinity of 49 compounds to USP1 was evaluated using the optimized AS-MS method, calculating binding index (BI) values for each compound. Biochemical inhibition assays validated the AS-MS results, revealing a potential correlation between higher BI values and lower IC50 values. This optimized workflow enables rapid identification of high-quality USP1 inhibitor hits, facilitating structure-activity relationship studies and accelerating the discovery of potential cancer therapeutics.

BackgroundLing-gui-zhu-gan (LGZG) formula has been demonstrated to effectively ameliorate the clinical symptoms of patients with obesity or metabolic syndrome. This study aimed to explore both the effect and the underlying mechanisms of LGZG against obesity.MethodsMale C57BL/6N mice were randomized into four groups (n = 8): normal control (NC), obese (OB), metformin (Met), and LGZG. After 8 weeks of gavage administration, the pharmacological effects of LGZG on obesity and metabolism were investigated using biochemical parameters, histomorphological examination, and lipidomics techniques. Pivotal factors associated with white adipose tissue browning were evaluated using quantitative real-time polymerase chain reaction and western blotting.ResultsThe results revealed that LGZG reduced the levels of obesity markers, including body weights, body fat mass and food intake in obese mice. Further evaluations highlighted that LGZG restored glucose homeostasis and significantly improved insulin sensitivity in obese mice. Importantly, LGZG could adjust serum lipid profiles and regulate the lipidomic spectrum of intestinal contents, with noticeable shifts in the levels of certain lipids, particularly diacylglycerols and monoacylglycerols. Histopathological examinations of LGZG-treated mice also revealed more favorable adipose tissue structures than their obese counterparts. Furthermore, we found that LGZG upregulated the expression of several key thermogenesis-related factors, such as UCP1, PRDM16, PGC-1α, PPARα, PPARγ, CTBP1, and CTBP2 in white adipose tissues.ConclusionOur findings position LGZG as a novel strategy for preventing obesity and improving metabolic health.

Brain development is a highly complex process regulated by numerous genes at the molecular and cellular levels. Brain tissue exhibits serial microstructural changes during the development process. High-resolution diffusion magnetic resonance imaging (dMRI) affords a unique opportunity to probe these changes in the developing brain non-destructively. In this study, we acquired multi-shell dMRI datasets at 32 µm isotropic resolution to investigate the tissue microstructure alterations, which we believe to be the highest spatial resolution dMRI datasets obtained for postnatal mouse brains. We adapted the Allen Developing Mouse Brain Atlas (ADMBA) to integrate quantitative MRI metrics and spatial transcriptomics. Diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI), and neurite orientation dispersion and density imaging (NODDI) metrics were used to quantify brain development at different postnatal days. We demonstrated that the differential evolutions of fiber orientation distributions contribute to the distinct development patterns in white matter (WM) and gray matter (GM). Furthermore, the genes enriched in the nervous system that regulate brain structure and function were expressed in spatial correlation with age-matched dMRI. This study is the first one providing high-resolution dMRI, including DTI, DKI, and NODDI models, to trace mouse brain microstructural changes in WM and GM during postnatal development. This study also highlighted the genotype-phenotype correlation of spatial transcriptomics and dMRI, which may improve our understanding of brain microstructure changes at the molecular level.

Natural environments play a crucial role in transmission of antimicrobial resistance (AMR). Development of methods to manage antibiotic resistance genes (ARGs) in natural environments are usually limited to the laboratory or field scale, partially due to the complex dynamics of transmission between different environmental compartments. Here, we conducted a nine-year longitudinal profiling of ARGs at a watershed scale, and provide evidence that restrictions on livestock farms near water bodies significantly reduced riverine ARG abundance. Substantial reductions were revealed in the relative abundance of genes conferring resistance to aminoglycosides (42%), MLSB (36%), multidrug (55%), tetracyclines (53%), and other gene categories (59%). Additionally, improvements in water quality were observed, with distinct changes in concentrations of dissolved reactive phosphorus, ammonium, nitrite, pH, and dissolved oxygen. Antibiotic residues and other pharmaceuticals and personal care products (PPCPs) maintain at a similarly low level. Microbial source tracking demonstrates a significant decrease in swine fecal indicators, while human fecal pollution remains unchanged. These results suggest that the reduction in ARGs was due to a substantial reduction in input of antibiotic resistant bacteria and genes from animal excreta. Our findings highlight the watershed as a living laboratory for understanding the dynamics of AMR, and for evaluating the efficacy of environmental regulations, with implications for reducing environmental risks associated with AMR on a global scale.

Abstract Rheumatoid arthritis (RA) is a progressive autoimmune disease accompanied by joint swelling, cartilage erosion and bone damage. Drug therapy for RA has been restricted due to poor therapeutic effect, recurrence and adverse effects. Macrophages and synovial fibroblasts both play important roles in the pathology of RA. Macrophages secrete large amount of pro-inflammatory cytokines, while synovial fibroblasts are tightly correlated with hypoxia synovium microenvironment, cytokine release, recruitment of pro-inflammatory cells, bone and cartilage erosion. Therefore, in this timely research, an injectable and pH-sensitive peptide hydrogel loading methotrexate (MTX) and bismuthene nanosheet/polyethyleneimine (BiNS/PEI) has been developed to reduce the activity of macrophages and eliminate over-proliferated synovial fibroblasts simultaneously. MTX can reduce the cytokine secretion of macrophages/anti-apoptosis property of synovial fibroblasts and BiNS/PEI can eliminate synovial fibroblasts via photodynamic therapy (PDT) and photothermal therapy (PTT) routes. The hydrogel was injected into the acidic inflammatory synovium for precise targeting and served as a drug reservoir for pH responsive and sustained drug release, while improving the bioavailability and reducing the toxicity of MTX. Excellent therapeutic efficacy has been achieved in both in vivo and in vitro studies, and this unique drug delivery system provides a new and robust strategy to eliminate synovial fibroblasts and modulate immune system for RA treatment in clinical. Graphic Abstract

Abstract Background Triple-negative breast cancer (TNBC) is a life-threatening subtype of breast cancer with limited treatment options. Therefore, this network meta-analysis (NMA) aimed to evaluate and compare the effect of various neoadjuvant chemotherapy (NCT) options on the long-term survival of patients with TNBC. Methods PubMed, Embase, Medline, Cochrane Library, Web of Science, and major international conference databases were systematically searched for randomized controlled trials (RCTs) on the efficacy of various NCT options in patients with TNBC. Searches were performed from January 2000 to June 2023. Study heterogeneity was assessed using the I2 statistic. Hazard ratios (HRs) and 95% confidence intervals (CIs) were used to evaluate disease-free survival (DFS) and overall survival (OS). Odds ratios (ORs) and 95% CIs were used to evaluate the pathologic complete response (pCR). The primary outcome was DFS. Results We conducted an NMA of 21 RCTs involving 8873 patients with TNBC. Our study defined the combination of anthracyclines and taxanes as the preferred treatment option. On this basis, the addition of any of the following new drugs is considered a new treatment option: bevacizumab (B), platinum (P), poly-ADP-ribose polymerase inhibitors (PARPi), and immune checkpoint inhibitor (ICI). Based on the surface under the cumulative ranking curve (SUCRA) values, the top three SUCRA area values of DFS were taxanes, anthracycline, and cyclophosphamide (TAC; 89.23%); CT (84.53%); and B (81.06%). The top three SUCRA area values of OS were CT (83.70%), TAC (62.02%), and B-containing regimens (60.06%). The top three SUCRA area values of pCR were B + P-containing regimens (82.7%), ICI + P-containing regimens (80.2%), and ICI-containing regimens (61.8%). Conclusions This NMA showed that standard chemotherapy is a good choice with respect to long-term survival. Moreover, B associated with P-containing regimens is likely to be the optimal treatment option for neoadjuvant TNBC in terms of pCR.