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Xuejie Fang,1,&ast; Zhengtong Qiao,2,&ast; Xinjuan Yu,3,4,&ast; Rujin Tian,5 Kai Liu,5 Wei Han3 1School of Clinical Medicine, Weifang Medical University, Weifang, People’s Republic of China; 2School of Rehabilitation Medicine, Binzhou Medical University, Yantai, People’s Republic of China; 3Department of Respiratory and Critical Medicine, Respiratory Disease Key Laboratory of Qingdao, University of Health and Rehabilitation Sciences Qingdao Hospital (Qingdao Municipal Hospital), Qingdao, People’s Republic of China; 4Clinical Research Center, University of Health and Rehabilitation Sciences Qingdao Hospital (Qingdao Municipal Hospital), Qingdao, People’s Republic of China; 5Department of Rehabilitation Medicine, University of Health and Rehabilitation Sciences Qingdao Hospital (Qingdao Municipal Hospital), Qingdao, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Han, Department of Respiratory and Critical Medicine, Respiratory Disease Key Laboratory of Qingdao, University of Health and Rehabilitation Sciences Qingdao Hospital (Qingdao Municipal Hospital), No. 5 Donghaizhong Road, Qingdao, 266071, People’s Republic of China, Tel +86 532 85937579, Email hanw@qdu.edu.cn Kai Liu, Department of Rehabilitation Medicine, University of Health and Rehabilitation Sciences Qingdao Hospital (Qingdao Municipal Hospital), No. 5 Donghaizhong Road, Qingdao, 266071, People’s Republic of China, Tel +86 532 85937671, Email liukaidpt@126.comBackground: Chronic obstructive pulmonary disease (COPD) is a chronic lung disease which feature is progressive airflow obstruction. Singing is a popular and convenient activity that requires people to manage their lung volumes and airflow actively. Despite the well-known benefits of singing to healthy people, the specific effect still remains unclear.Objective: To investigate the mental and psychological benefits of singing in patients with stable COPD.Search Methods: We used Preferred Reporting Items for Systematic Reviews and Meta-Analyses Guidelines (PRISMA) on randomized controlled trials (RCTs) including singing exercise as the main intervention in stable COPD. We searched 8 electronic databases, including Web of Science, PubMed, Embase, Cochrane Library, Clinical Trials.gov, and the Physical Therapy Evidence Database (PEDro), CNKI, and Wanfang Database from inception until May 2022. The searching languages was English or Chinese. Data extraction using standardized templates was performed by two independent reviewers. The quality of the studies was assessed using the PEDro scale. Data synthesis was performed with Revman 5.4. The pooled effect sizes are reported by MD and 95% CI.Results: Five RCTs involving 333 patients with stable COPD were included in this meta-analysis. Singing was regarded as the main intervention in the experimental group. Meta-analysis revealed that singing improves quality of life on Short Form 36 physical component summary (SF-36 PCS) (MD = 12.63, 95% CI: 5.52 to 19.73, P < 0.01) and respiratory muscle in maximal expiratory pressure (PEmax) (MD = 14.30, 95% CI: 0.87 to 27.73, P = 0.04) in patients with COPD. However, it has limited effects on Short Form 36 mental component summary (SF-36 MCS), lung function, exercise capability, and adverse mental state.Conclusion: Based on results of the meta-analysis, singing could be used to improve quality of life (SF-36 PCS) and respiratory muscles (PEmax) in patients with COPD.Keywords: COPD, singing, pulmonary function, pulmonary rehabilitation

Yuan Shi,&ast; Zhidong Qiao,&ast; Xiaoduo Bi, Chenxin Zhang, Junxian Fu, Yuexin Jia, Guanglu Yang Department of Pediatric, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, 010000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guanglu YangDepartment of Pediatric, The Affiliated Hospital of Inner Mongolia Medical University, No. 1 Tongdao North Road, Hohhot, Inner Mongolia Autonomous Region, Hohhot, 010000, People’s Republic of ChinaTel +86 13451311622Email yamgguamglu471@163.comObjective: Gene mutation analysis was performed on a family with familial hemophagocytic lymphohistiocytosis (FHL) so as to provide an accurate etiological diagnosis, leading to genetic counseling for the family members.Methods: The clinical data of two probands (siblings) with FHL in one family were analyzed, and eight genes related to the onset of the primary hemophagocytic lymphohistiocytosis (pHLH) (PRF1, UNC13D, STX11, STXBP2, SH2D1A, BIRC4/XIAP, Rab27a, LYST) were detected and analyzed in the probands and their parents with whole exome sequencing.Results: Proband 1 was a two-year-old male with the clinical manifestations of fever, hepatosplenomegaly, and a decreased peripheral blood cell count, sCD25: 12504pg/mL. The results of genetic testing showed that there was a c.1349C>T heterozygous missense mutation and a c.853_855del heterozygous mutation in the PRF1 in proband 1. Proband 2 was an eight-year-old female with the clinical manifestations of convulsions and disturbance of consciousness with fever. The genetic test results were the same as those of proband 1. There was a single heterozygous mutation in the parents of the probands, and both probands had compound heterozygous mutations.Conclusion: According to the clinical manifestations, laboratory tests, and results of the family molecular genetic testing, the probands could be clinically diagnosed as FHL2. The results of gene sequencing revealed that this was an autosomal recessive family with familial hemophagocytic syndrome. A rare pathogenic mutation (c.853_855del) in the PRF1 was discovered in the two patients with HLH.Keywords: FHL, PRF1, novel mutation

Zhifen Qiao,1,* Shiyi Huang,1,* Fang Leng,1,2 Yu Bei,2 Yingzhi Chen,2 Minjie Chen,2 Yunfeng Hu,3 Yadong Huang,1,2 Qi Xiang1,2 1Institute of Biomedicine and Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou, 510632, People’s Republic of China; 2Biopharmaceutical R&D Center of Jinan University, Guangzhou, 510632, People’s Republic of China; 3The First Affiliated Hospital of Jinan University, Department of Dermatology, Guangzhou, 510632, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qi XiangInstitute of Biomedicine and Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou, 510632, People’s Republic of ChinaTel +86-020-8556-3234Email txiangqi@jnu.edu.cnBackground: Sensitive skin (SS) is easily irritated by various environmental stimuli, and epidemiological surveys surprisingly find that self-perceived SS is widespread worldwide.Objective: To investigate whether SS is linked to changes in the skin bacterial population using 16S rRNA sequencing and bioinformatic analysis.Patients and Methods: According to both the Huaxi SS Questionnaire and Lactic Acid Stimulation Test, 60 female volunteers in Guangzhou were classified into normal skin (NS) and SS groups. Skin barrier parameters were assessed by the CK skin tester. The DNA of the bacterial flora on the facial skin surface was extracted and was subjected to 16S rRNA sequencing.Results: The skin hydration was significantly lower in the SS group compared to the NS group (P =0.032). Based on 16S rRNA sequencing and bioinformatic analysis, the number of operational taxonomic units (OTUs) significantly decreased in the SS group (P =0.0235, SS vs NS). The relative abundance of Neisseriaceae in SS group decreased significantly (P < 0.05, SS vs NS), while that of Neisseria (within the Neisseriaceae family) increased significantly (P < 0.05, SS vs NS).Conclusion: SS is accompanied by a decrease in species diversity and richness, which may be relevant to the weakening of the microbial barrier (due to the increase of Neisseria or the decrease of Neisseriaceae). Thus, corresponding treatment for Neisseriaceae may be a new idea in the treatment of SS.Keywords: sensitive skin, 16S rRNA sequencing, bacterial, skin microbiome, skin barrier

Zhongjie Qiao,1,* Hongshuang Dai,1,* Yunzhu Zhang,2 Qiang Li,1 Meng Zhao,3 Tongyun Yue4 1Urology Department, The Affiliated Cancer Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, People’s Republic of China; 2The 1st Nephrology Department, Heilongjiang Academy of Traditional Chinese Medicine, Harbin, Heilongjiang 150036, People’s Republic of China; 3Urology Department, The 1st Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang 150040, People’s Republic of China; 4Interventional Department, The Affiliated Cancer Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, People’s Republic of China*These authors contributed equally to this workCorrespondence: Tongyun YueIntervention Department, The Affiliated Cancer Hospital of Harbin Medical University, No. 150 Haping Road, Nangang District, Harbin, Heilongjiang 150081, People’s Republic of ChinaEmail kksjeobnggpf5@163.comBackground: Long noncoding RNAs (lncRNAs) play critical and complex roles in regulating various biological processes of cancers. Our study aimed to investigate the involvement of lncRNA NCK1-AS1 in urinary bladder cancer (UBC).Methods: qRT-PCR was used to detect the expression of lncRNA NCK1-AS1 and miR-143 in UBC tissues and cells. The dual-luciferase reporter system assays were used to confirm the interaction between NCK1-AS1 and miR-143, and flow cytometry assays were applied to examine the behavioral changes in HT-1376 and HT-1197 cell lines.Results: It was observed that NCK1-AS1 was up-regulated, while miR-143 was down-regulated in tumor tissues than in adjacent healthy tissues of urinary bladder cancer (UBC) patients. A 5-year survival analysis showed that the survival rate of patients with high NCK1-AS1 level or low miR-143 level in tumor tissues appears relatively low. Correlation analysis revealed a significant inverse correlation between NCK1-AS1 and miR-143 in tumor tissues. Over-expression NCK1-AS1 reduced the expression level of miR-143, while elevating the level of miR-143 failed to affect NCK1-AS1 expression. NCK1-AS1 over-expression led to promoted proliferation and increased percentage of CD133+ (stemness) cells.Conclusion: Therefore, NCK1-AS1 promotes cancer cell proliferation and increases cell stemness in UBC patients by down-regulating miR-143.Keywords: NCK1-AS1, miR-143, urinary bladder cancer, survival, proliferation, stemness

Shouliang Wang,1 Bin Xia,1 Zonglei Qiao,2 Lian Duan,3 Gongming Wang,1 Wenjun Meng,1 Zhifei Liu,1 Yu Wang,1 Mengyuan Zhang11Department of Anesthesiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, People’s Republic of China; 2Department of Anesthesiology, Qingyun County People’s Hospital, Dezhou 253700, Shandong Province, People’s Republic of China; 3Department of Ophthalmology, Qianfoshan Hospital Affiliated to Medical School of Shandong University, Jinan 250014, Shandong Province, People’s Republic of ChinaBackground: Bupivacaine (BUP) acts as a local anesthetic, which is extensively used for clinical patients but could generate neurotoxicity in neurons. Tetramethylpyrazine (TET) exhibits strong neuron protective effects against neurotoxicity. Hence, we investigate the effect of TET on BUP-induced neurotoxicity in SH-SY5Y cells.Methods: CCK-8 assay was used to detect cell proliferation in SH-SY5Y cells. In addition, Western blotting was used to examine Bax, Bcl-2, active caspase 3, LC3II, Beclin 1 and p-62 protein levels in cells. Moreover, ELISA assay was used to detect the levels of total glutathione (GS), superoxide dismutase (SOD) and malondialdehyde (MDA) in cells.Results: In this study, we found that TET attenuated the neurotoxicity of BUP on SH-SY5Y cells. Meanwhile, TET alleviated BUP-induced apoptosis in SH-SY5Y cell via decreasing the expressions of active caspase-3 and Bax and increasing the expression of Bcl-2. In addition, monodansylcadaverine staining assay and Western blotting results confirmed that TET induced autophagy in SH-SY5Y cells via increasing the LC3II/I and Beclin 1 levels. Furthermore, TET attenuated BUP-induced oxidative damage in SH-SY5Y cells via upregulation of the levels of total GS and SOD and downregulation of the level of MDA. Interesting, the protective effects of TET against BUP-induced neurotoxicity in SH-SY5Y cells were reversed by autophagy inhibitor 3-methyladenine (3MA).Conclusion: These data indicated that TET may play a neuroprotective role via inhibiting apoptosis and inducing autophagy in SH-SY5Y cells. Therefore, TET may be a potential agent for the treatment of human neurotoxicity induced by BUP.Keywords: tetramethylpyrazine, bupivacaine, neurotoxicity, human neuroblastoma cell

Jinghong Chen,1,2,4 Ze-hui Gong,4 Hao Yan,2 Zhijun Qiao,3 Bo-yi Qin41Department of Internal Medicine, Neuroscience Program, The University of Texas Medical Branch, Galveston, TX, USA; 2The Divisions of Pharmacy, Pharmacology core lab, MD Anderson Cancer Center, Houston, TX, USA; 3University of Texas-Pan American, Edinburg, TX, USA; 4Beijing Institute of Pharmacology and Toxicology, Beijing, China Abstract: The discovery of the tetrodotoxin-resistant (TTX-R) Na+ channel in nociceptive neurons has provided a special target for analgesic intervention. In a previous study we found that both morphine tolerance and persistent visceral inflammation resulted in visceral hyperalgesia. It has also been suggested that hyperexcitability of sensory neurons due to altered TTX-R Na+ channel properties and expression contributes to hyperalgesia; however, we do not know if some TTX-R Na+ channel property changes can be triggered by visceral hyperalgesia and morphine tolerance, or whether there are similar molecular or channel mechanisms in both situations. To evaluate the effects of morphine tolerance and visceral inflammation on the channel, we investigated the dorsal root ganglia (DRG) neuronal change following these chronic treatments. Using whole-cell patch clamp recording, we recorded TTX-R Na+ currents in isolated adult rat lumbar and sacral (L6-S2) DRG neurons from normal and pathologic rats with colon inflammatory pain or chronic morphine treatment. We found that the amplitudes of TTX-R Na+ currents were signiflcantly increased in small-diameter DRG neurons with either morphine tolerance or visceral inflammatory pain. Meanwhile, the result also showed that those treatments altered the kinetics properties of the electrical current (ie, the activating and inactivating speed of the channel was accelerated). Our current results suggested that in both models, visceral chronic inflammatory pain and morphine tolerance causes electrophysiological changes in voltage-gated Na channels due to the chronic administration of these medications. For the first time, the present investigation explored the adaptations of this channel, which may contribute to the hyperexcitability of primary afferent nerves and hyperalgesia during these pathologic conditions. The results also suggest that neurophysiologic mechanisms of morphine tolerance and visceral hyperalgesia are related at the TTX-R Na+ channel.Keywords: TTX-resistant Na+ channel, neuroplasticity, visceral hyperalgesia, morphine tolerance, DRG

Abstract Characterization of the vascular heterogeneity within the pancreas has previously been lacking. Here, we develop strategies to enrich islet-specific endothelial cells (ISECs) and acinar-specific endothelial cells (ASECs) from three human pancreases and corroborate these findings with three published pancreatic datasets. Single-cell RNA sequencing reveals the unique molecular signatures of ISECs, including structural genes COL13A1, ESM1, PLVAP, UNC5B, and LAMA4, angiocrine genes KDR, THBS1, BMPs and CXCR4, and metabolic genes ACE, PASK and F2RL3. ASECs display distinct signatures including GPIHBP1, CCL14, CD74, AQP1, KLF4, and KLF2, which may manage the inflammatory and metabolic needs of the exocrine pancreas. Ligand-receptor analysis suggests ISECs and ASECs interact with LUM+ fibroblasts and RGS5+ pericytes and smooth muscle cells via VEGF-A:VEGFR2, CXCL12:CXCR4, and LIF:LIFR pathways. Comparative expression and immunohistochemistry indicate disruption of endothelial-expressed CD74, ESM1, PLVAP, THBD, VWA1, and VEGF-A cross-talk among vascular and other cell types in diabetes. Thus, our data provide a single-cell vascular atlas of human pancreas, enabling deeper understanding of pancreatic pathophysiology in health and disease.

Abstract Background Diprosopus is one of the rarest anomalies. It typically manifests as bilateral alterations and often involves anomalies within the cranial structures. In this report, we present a case of a fetus with diprosopus diagnosed prenatally. Along with reviewing relevant literature on prenatal ultrasound diagnosis of diprosopus, we aim to raise awareness of its ultrasound characteristics. Case presentation We report a case of craniofacial and intracranial abnormalities detected during a 26-week ultrasound examination. Two-dimensional ultrasound (2D ultrasound) demonstrates significant increases in head circumference, widening of the interocular distance, and abnormal echo patterns in the facial structure. Three-dimensional ultrasound (3D ultrasound) revealed the presence of three eye sockets (the lateral eye sockets contained eyeballs, while the central region exhibited fusion without visible eyeballs), two noses, and two mouths, with no abnormalities observed in other areas. The ultrasound findings suggested diprosopus. Following risk counseling at the prenatal diagnosis center, the pregnant woman decided to induce labor. The newborn passed away thirty minutes after delivery. The facial features of the newborn were consistent with the 3D ultrasound imaging, and the appearance of the trunk and limbs was normal. Both CT and MRI scans confirmed the diagnosis of diprosopus. Conclusion The prenatal 2D ultrasound revealed intracranial and facial abnormalities in the fetus. 3D ultrasound imaging clearly displayed the facial duplication anomalies, highlighting the advantages of 3D ultrasound in diagnosing diprosopus. We hope to raise awareness of this rare condition and provide insights into prenatal ultrasound diagnosis through this case.

Abstract In recent years, large amounts of researches showed that pulmonary embolism (PE) has become a common disease, and PE remains a clinical challenge because of its high mortality, high disability, high missed and high misdiagnosed rates. To address this, we employed an artificial intelligence–based machine learning algorithm (MLA) to construct a robust predictive model for PE. We retrospectively analyzed 1480 suspected PE patients hospitalized in West China Hospital of Sichuan University between May 2015 and April 2020. 126 features were screened and diverse MLAs were utilized to craft predictive models for PE. Area under the receiver operating characteristic curves (AUC) were used to evaluate their performance and SHapley Additive exPlanation (SHAP) values were utilized to elucidate the prediction model. Regarding the efficacy of the single model that most accurately predicted the outcome, RF demonstrated the highest efficacy in predicting outcomes, with an AUC of 0.776 (95% CI 0.774–0.778). The SHAP summary plot delineated the positive and negative effects of features attributed to the RF prediction model, including D-dimer, activated partial thromboplastin time (APTT), fibrin and fibrinogen degradation products (FFDP), platelet count, albumin, cholesterol, and sodium. Furthermore, the SHAP dependence plot illustrated the impact of individual features on the RF prediction model. Finally, the MLA based PE predicting model was designed as a web page that can be applied to the platform of clinical management. In this study, PE prediction model was successfully established and designed as a web page, facilitating the optimization of early diagnosis and timely treatment strategies to enhance PE patient outcomes.

Abstract Ampullary adenocarcinoma (AMPAC) is a rare and heterogeneous malignancy. Here we performed a comprehensive proteogenomic analysis of 198 samples from Chinese AMPAC patients and duodenum patients. Genomic data illustrate that 4q loss causes fatty acid accumulation and cell proliferation. Proteomic analysis has revealed three distinct clusters (C-FAM, C-AD, C-CC), among which the most aggressive cluster, C-AD, is associated with the poorest prognosis and is characterized by focal adhesion. Immune clustering identifies three immune clusters and reveals that immune cluster M1 (macrophage infiltration cluster) and M3 (DC cell infiltration cluster), which exhibit a higher immune score compared to cluster M2 (CD4+ T-cell infiltration cluster), are associated with a poor prognosis due to the potential secretion of IL-6 by tumor cells and its consequential influence. This study provides a comprehensive proteogenomic analysis for seeking for better understanding and potential treatment of AMPAC.

Abstract Climate change poses direct and indirect threats to public health, including exacerbating air pollution. However, the influence of rising temperature on air quality remains highly uncertain in the United States, particularly under rapid reduction in anthropogenic emissions. Here, we examined the sensitivity of surface-level fine particulate matter (PM2.5) and ozone (O3) to summer temperature anomalies in the contiguous US as well as their decadal changes using high-resolution datasets generated by machine learning. Our findings demonstrate that in the eastern US, stringent emission control strategies have significantly reduced the positive responses of PM2.5 and O3 to summer temperature, thereby lowering the population exposure associated with warming-induced air quality deterioration. In contrast, PM2.5 in the western US became more sensitive to temperature, highlighting the urgent need to manage and mitigate the impact of worsening wildfires. Our results have important implications for air quality management and risk assessments of future climate change.

Abstract Direct carbonylation of CH4 to CH3COOH provides a promising pathway for upgrading of natural gas to transportable liquid chemicals, in which high-efficiency CH4 activation and controllable C–C coupling are both critical but challenging. Herein, we report that highly efficient photo-driven carbonylation of CH4 with CO and O2 to CH3COOH is achieved over MoS2-confined Rh-Zn atomic-pair in conjunction with TiO2. It delivers a high CH3COOH productivity of 152.0 μmol gcat. −1 h−1 and turnover frequency of 62.0 h−1 with a superior selectivity of 96.5%, outperforming previous photocatalytic CH4 carbonylation processes. Mechanistic investigations disclose the key effect of Rh-Zn synergy in combination with photo-excited electrons from TiO2 for CH3COOH formation. The active OH species produced from O2 photoreduction on the Zn site through proton-coupled electron transfer promotes CH4 dissociation to CH3 species, which then facilely couples with adsorbed CO on the adjacent Rh site forming the key CH3CO intermediate for CH3COOH formation.

Chronic heart failure is a common chronic disease that has a significant impact on patients' quality of life and health. The ability to self-care plays a vital role in the management of patients with chronic heart failure. This study reviewed the recent researches on network-based interventions on self-care ability of patients with chronic heart failure, focusing on the effects of different network-based interventions on improving patients' self-care ability, enhancing symptom management and promoting mental health. The aim of this study is to ensure that these interventions meet the needs of different individuals to optimize the self-care management of chronic heart failure. (慢性心力衰竭是一种常见的慢性疾病, 严重影响患者的健康和生活质量。自我护理能力在慢性心力衰竭患者的健康管理中发挥着至关重要的作用。本研究综述了近年来关于慢性心力衰竭患者自我护理能力网络干预的研究进展, 重点分析了不同网络干预形式在提高患者自我护理能力、改善症状管理及促进心理健康方面的效果, 为提高慢性心力衰竭患者的自我护理能力提供有效的途径和方法。)

Abstract The molecular mechanism underlying the role of hippocampal hilar interneuron degeneration in temporal lobe epilepsy (TLE) remains unclear. Especially, very few studies have focused on the role of neuronal nitric oxide synthase (nNOS, encoded by Nos1) containing hilar interneurons in TLE. In the present study, Nos1 conditional knockout mice were constructed, and we found that selective deletion of Nos1 in hilar interneurons rather than dentate granular cells (DGCs) triggered epileptogenesis. The level of nNOS was downregulated in patients and mice with TLE. Nos1 deletion led to excessive epilepsy-like excitatory input circuit formation and hyperexcitation of DGCs. Replenishment of hilar nNOS protein blocked epileptogenic development and memory impairment in pilocarpine-induced TLE mice. Moreover, chronic treatment with DETA/NONOate, a slowly released exogenous nitric oxide (NO) donor, prevented aberrant neural circuits of DGCs and the consequent epileptogenesis without acute antiseizure effects. Therefore, we concluded that NO donor therapy may be a novel anti-epileptogenesis strategy, different from existing antiseizure medications (ASMs), for curing TLE.

This study proposes to address the stability of roadway surrounding rock under three-dimensional stress field based on the Drucker-Prager criterion and the theory of elastic-plastic mechanics. Specifically, we deduced the boundary equation of plastic zone of roadway surrounding rock under three-dimensional stress field by introducing the axial stress solution, and analyzed the shape and size of plastic zone of surrounding rock under different stress field conditions. We compared the effect of five Drucker-Prager yield criteria on the shape and size of plastic zone under variations of cohesion, internal friction angle, Poisson's ratio and roadway radius in roadway surrounding rock. We then analyzed its implications for engineering practice based on the evolution characteristics. Results show that ① Variations in horizontal stress exerts significant impact on the plastic zone morphology of roadway surrounding rock: too high or too low horizontal stress will lead to a butterfly-shaped expansion in the roadway surrounding rock. ② Variations in axial pressure has little effect on the plastic zone shape of roadway surrounding rock, yet exerts major influence on the plastic zone size of surrounding rock: under the same horizontal stress, different axial stress will lead to a bowl-shaped development in the plastic zone size of surrounding rock. With variations in the cohesion, internal friction angle and roadway radius, we observed consistency in the size variation of plastic zone in roadway surrounding rock under different Drucker-Prager criteria. Therefore, the choice of different Drucker-Prager criteria will affect the calculation results of plastic zone in surrounding rock of roadway.

Abstract Background Previous studies have established a correlation between elevated levels of remnant cholesterol (RC) and the occurrence of type 2 diabetes mellitus (T2D) as well as insulin resistance (IR); however, the precise nature of these associations remains incompletely elucidated. This study aimed to evaluate the relationships between RC and IR, as well as RC and T2D, and to determine the extent to which IR mediated the relationship between RC and T2D. Methods This was an observational study that utilized cross-sectional methods to examine the general population in the National Health and Nutrition Examination Survey (NHANES) 1999–2020. The participants were divided into 4 groups according to the RC quartiles. The outcome was the prevalence of IR and T2D. Survey-weighted binary logistic regression analysis was used to analyze the associations, and the restricted cubic spline (RCS) curve was used to further analyze the nonlinear relationship. Receiver operating characteristic (ROC) curves were generated to evaluate the diagnostic performance, and the areas under the curves (AUC) of RC, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) were compared using the DeLong test. The mediating effect of IR on the relationship between RC and T2D was evaluated through mediation analysis. Results A total of 23,755 participants (46.02 ± 18.48 years, 48.8% male) were included in our study. Higher RC levels were significantly associated with increased prevalence of both IR and T2D. After adjusting for potential confounders, logistic regression analysis showed that higher RC quartiles were associated with the increased prevalence of IR [Quartile 4 vs. Quartile 1: odds ratio (OR) (95% confidence interval, CI): 1.65 (1.41–1.94), p

Selenium (Se)-enriched microalgae are emerging as new food or agricultural resources. Thus far, the microalgae tested for Se accumulation or biofortification are still very limited. Here, we investigated the effects of selenite on the growth of three terrestrial microalgae (Vischeria sp. WL1, Chlorella sp. WL1, and Nostoc flagelliforme) and their total Se accumulation levels. The three microalgae were previously collected at the same location and show great application potential but differ in classification and growth speed. Three concentrations (10, 20, and 40 mg/L) of selenite were used for treatment. The former two species could resist 40 mg/L selenite but the last one could not. At the relatively optimal concentration (20 mg/L selenite), their specific growth rates were 0.09, 0.10, and 0.05 μ day−1, respectively. Vischeria sp. WL1 could accumulate 3.3 mg/g dry weight (DW) Se after 16 days of cultivation; N. flagelliforme could accumulate 5.6 mg/g DW Se after 24 days of cultivation. Chlorella sp. WL1 accumulated a relatively lower amount of Se, being 0.74 mg/L DW after 18 days of cultivation, but its more rapid growth would be beneficial to saving production costs. These results indicate that three microalgae are capable of functioning as excellent carriers for Se nutrients. This study will contribute to enriching the microalgal resource pool for Se biofortification in food and agricultural areas.

Abstract Introduction Although the Tumor-Node-Metastasis (TNM) staging system is widely used for staging lung squamous cell carcinoma (LSCC), the TNM system primarily emphasizes tumor size and metastasis, without adequately considering lymph node involvement. Consequently, incorporating lymph node metastasis as an additional prognostic factor is essential for predicting outcomes in LSCC patients. Methods This retrospective study included patients diagnosed with LSCC between 2004 and 2018 and was based on data from the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute. The primary endpoint of the study was cancer-specific survival (CSS), and demographic characteristics, tumor characteristics, and treatment regimens were incorporated into the predictive model. The study focused on the value of indicators related to pathological lymph node testing, including the lymph node ratio (LNR), regional node positivity (RNP), and lymph node examination count (RNE), in the prediction of cancer-specific survival in LSCC. A prognostic model was established using a multivariate Cox regression model, and the model was evaluated using the C index, Kaplan–Meier, the Akaike information criterion (AIC), decision curve analysis (DCA), continuous net reclassification improvement (NRI), and integrated discrimination improvement (IDI), and the predictive efficacy of different models was compared. Results A total of 14,200 LSCC patients (2004–2018) were divided into training and validation cohorts. The 10-year CSS rate was approximately 50%, with no significant survival differences between cohorts (p = 0.8). The prognostic analysis revealed that models incorporating LNR, RNP, and RNE demonstrated superior performance over the TNM model. The LNR and RNP models demonstrated better model fit, discrimination, and reclassification, with AUC values of 0.695 (training) and 0.665 (validation). The RNP and LNR models showed similar predictive performance, significantly outperforming the TNM and RNE models. Calibration curves and decision curve analysis confirmed the clinical utility and net benefit of the LNR and RNP models in predicting long-term CSS for LSCC patients, highlighting their value in clinical decision-making. Conclusion This study confirms that RNP status is an independent prognostic factor for CSS in LSCC, with predictive efficacy comparable to LNR, with both models enhancing survival prediction beyond TNM staging.

Abstract Background Little is known about the characteristics of patients with psoriatic arthritis (PsA) during the coronavirus disease 2019 (COVID‐19) pandemic. This study aimed to evaluate the impact of COVID‐19 on PsA progression and comprehend the role of COVID‐19 vaccination in the infection course. Methods A total of 163 adult patients with PsA from 15 province‐level regions in China were enrolled in this multiregional observational study from January 14, 2023, to March 22, 2023. Data on patient demographics, COVID‐19 status, and disease characteristics were collected through a structured questionnaire survey. Results Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infections could worsen PsA, with 29.0% (36/124) of patients experiencing deteriorating symptoms. Psoriasis was the symptom that was most exacerbated (22, 61.1%), followed by peripheral arthritis (19, 52.8%) and dactylitis (9, 25.0%). Compared with the patients whose arthritic condition was stable before contracting COVID‐19, those with active PsA experienced more severe COVID‐19 symptoms, reporting higher self‐assessed symptom severity scores and a greater prevalence of dyspnea (42.9% [6/14] vs. 7.3% [9/123]). Moreover, although full vaccination (≥2 doses) could not prevent COVID‐19, it could alleviate the infection symptoms, including diarrhea, fatigue, appetite changes, and axial joint pain. Additionally, fully vaccinated individuals had a higher probability of avoiding deterioration of their PsA condition after infection. Conclusions Active PsA and lack of COVID‐19 vaccination are risk factors for worsening COVID‐19 symptoms and PsA condition after infection. The evidence from this real‐world study suggests that COVID‐19 may exacerbate PsA.

Although the gut microbial metabolites exhibit potential effects on coronary heart disease (CHD), the underlying mechanism remains unclear. In this study, the active gut microbial metabolites acting on CHD and their potential mechanisms of action were explored through a network pharmacological approach. We collected a total of 208 metabolites from the gutMgene database and 726 overlapping targets from the similarity ensemble approach (SEA) and SwissTargetPrediction (STP) database, and ultimately identified 610 targets relevant to CHD. In conjunction with the gutMGene database, we identified 12 key targets. The targets of exogenous substances were removed, and 10 core targets involved in CHD were eventually retained. The microbiota–metabolites–targets–signalling pathways network analysis revealed that C-type lectin receptor signalling pathway, Lachnospiraceae, Escherichia, mitogen-activated protein kinase 1, prostaglandin-endoperoxidase synthase 2, phenylacetylglutamine and alcoholic acid are notable components of CHD and play important roles in the development of CHD. The results of molecular docking experiments demonstrated that AKT1-glycocholic acid and PTGS2-phenylacetylglutamine complexes may act on C-type lectin receptor signalling pathways. In this study, the key substances and potential mechanisms of gut microbial metabolites were analysed via network pharmacological methods, and a scientific basis and comprehensive idea were provided for the effects of gut microbial metabolites on CHD.

In order to investigate the effect of microstructural changes on the hardness and wear resistance of coatings，low-cost high-velocity oxygen-fuel spraying (HVOF) technology was used to pre-deposit WC-Ni coatings，and the coatings were treated by laser remelting at a power of 50～150 W.The influence of laser remelting power on the microstructure，phase composition，microhardness and wear resistance of WC-Ni coatings was studied.Results showed that after remelted by 150 W laser，the WC in the coating formed a honeycomb like skeleton structure，enhancing the toughness of the material and significantly suppressing the generation and propagation of cracks.When the laser power was low(50 W and 100 W)，no honeycomb like skeleton structure was observed in the coating.However，due to the thermal effect of the laser，the cohesion between the flat particles in the original coating was enhanced，and the hardness and wear resistance were improved to some extent.The average hardness of the original WC-Ni coating was 327 HV0.2，while the hardness of the coatings after 50 W and 100 W treatment increased to 335 HV0.2 and 346 HV0.2，respectively.Moreover，after 150 W treatment，a uniform honeycomb like WC skeleton structure was formed in the coating，and some WC and Ni formed Ni4W，thereby reducing slightly the hardness of the coating after 150 W treatment (288 HV0.2).The WC in the coating treated with 150 W evolved into a mesh like skeleton structure，which could effectively suppress the formation and propagation of cracks，and the wear rate was the lowest，only 3.544×10－5 mm3/(N·m)，This represented a reduction of 83.9%，75.1%，and 68.7%compared to the wear rates of the original WC-Ni coating [2.025×10－4 mm3/(N·m)] and coatings subjected to 50 W[1.424×10－4 mm3/(N·m)] and 100 W[1.132×10－4 mm3/(N·m)] laser remelting，respectively.Overall，the WC-Ni coatings with honeycomb structure could provide a new approach for the development of wear-resistant materials.

Abstract Myc-associated Zinc-finger Protein (MAZ) has been implicated in the malignant progression of various tumors. However, its expression and functional relationship of MAZ in melanoma have not been previously investigated. This study confirms elevated expression of MAZ in melanoma, correlating with poor patient prognosis. Furthermore, our findings demonstrate that MAZ enhances melanoma progression by promoting proliferation, migration and invasion. It is worth noting that we found that MAZ can target and regulate the transcription of NADH dehydrogenase [ubiquinone] iron-sulfur protein 3 (NDUFS3), a core subunit of mitochondrial complex I, to enhance mitochondrial metabolism and thus promote malignant progression of melanoma. Predictive modeling indicates that the co-expression of MAZ and NDUFS3 could serve as a potential prognostic marker for melanoma patients.

Abstract Astroblastoma, MN1-altered, is a rare circumscribed glial neoplasm that is composed of round, cuboidal, orcolumnar cells with astroblastic perivascular pseudorosettes, often associated with MN1::BEND2 and MN1::CXXC5 fusions. Atroblastoma-like gliomas harbouring EWSR1::BEND2 have been reported that they defined an epigenetically distinct subtype of astroblastoma. We report a case of a 19-year-old female with an intracranial neuroepithelial tumor featuring a novel TCF3::BEND2 fusion. This tumor, while classified as EWSR1::BEND2 gliomas based on DNA methylation, did not exhibit the MN1 alteration or typical astroblastoma morphology. The patient, initially diagnosed as ependymoma WHO grade 2 following surgery for an intracranial tumor four years prior, presented with a suspected recurrence. Magnetic resonance imaging identified a mixed solid-cystic lesion in the temporal area of the left lateral ventricle. For the recurrent tumor, the histological examination revealed the tumor cells predominantly exhibited a solid arrangement, with the solid areas primarily consisting of oval and short-spindle cells. In certain regions, loosely arranged short-spindle cells was observed. The tumor exhibited high cellular density, nuclear atypia, and frequent mitoses, but lacked the hallmark features typically associated with astroblastoma. Immunohistochemistry revealed patchy positivity for GFAP and OLIG2, diffuse positivity for EMA, and a high MIB-1 labeling index. Genome-wide DNA methylation profiling confirmed the tumor’s classification as EWSR1::BEND2 gliomas with a high-confidence match and revealed focal deletion of chromosome 9q. Targeted next-generation sequencing identified a TCF3::BEND2 fusion, validated by reverse transcription polymerase chain reaction and Sanger sequencing. This case broadens the genetic spectrum of high-grade neuroepithelial tumor and suggests that BEND2 alterations may serve as critical determinants for this EWSR1::BEND2 glioma subgroup within the methylation classifier.

Laser powder bed fusion (LPBF) is the most widely used metal additive manufacturing technology, but it still faces challenges in manufacturing efficiency. To address the issue, high-power LPBF (HP-LPBF) which employs kilowatt-level lasers emerges in recent years. In this study, a 4 kW Flat-top laser was used for the HP-LPBF of Ti6Al4V alloy. The samples in as-built state and annealed states (750 °C/2h, 850 °C/2h, 950 °C/2h, 1050 °C/2h) were investigated in terms of defects, microstructure, and mechanical properties. Results show that keyhole mode melting is avoided by adopting the Flat-top laser, so the relative density of as-built Ti6Al4V is generally positively correlated with the employed laser energy density. The minimum laser energy density to obtain the high-density (≥99.9%) sample is 50.0 J/mm3, and the highest build rate is 288 cm3/h. The microstructure in as-built state exhibits a unique alternating pattern of ''bright bands/dark bands''. The dark bands consist of needle-shaped α′ martensite, while the bright bands consist of needle-shaped α+β, which results from the decomposition of α′ under the in-situ annealing effect of the 4 kW Flat-top laser. After annealing at 750 °C, most of the residual α′ decomposes into needle-shaped α+β. As the annealing temperature increases from 750 °C to 1050 °C, the microstructure undergoes an evolution from needle-shaped α+β to lamellar α+β then to lamellar α+β with some globular α and finally to duplex α+β. An optimum strength-ductility balance is achieved after annealing at 850 °C, both the tensile strength and the elongation exceed the standard values of Ti6Al4V forgings.

Abstract Bladder cancer (BCa) exhibits the escalating incidence and mortality due to the untimely and inaccurate early diagnosis. Urinary exosome metabolites, carrying critical tumor cell information and directly related to bladder, emerge as promising non-invasive diagnostic biomarkers of BCa. Herein, the magnetic 3D ordered macroporous zeolitic imidazolate framework-8 (magMZIF-8) is synthesized and used for efficient urinary exosome isolation. Notably, beyond retaining the single crystals and micropores of conventional ZIF-8, MZIF-8 is further enhanced with highly oriented and ordered macropores (150 nm) and the large specific surface area (973 m2·g–1), which could enable the high purity and yield separation of exosomes via leveraging the combination of size exclusion, affinity, and electrostatic interactions between magMZIF-8 and the surfaces of exosome. Furthermore, the magnetic and hydrophilic properties of magMZIF-8 will further simplify the process and enhance the efficiency of separation. After conditional optimization, a 50 mL of urine is sufficient for exosome metabolomics analysis, and the time for isolating exosomes from 42 urine samples was 2 hours only. Incorporating machine learning algorithms with LC-MS/MS analysis of the metabolic patterns obtained from isolated exosomes, early-stage BCa patients were differentiated from healthy controls, with area under the curve (AUC) value of 0.844–0.9970 in the training set and 0.875-1.00 in the test set, signifying its potential as a reliable diagnostic tool. This study offers a promising approach for the non-invasive and efficient diagnosis of BCa on a large scale via exosome metabolomics. Graphical Abstract

Objective When the initial parking of an FAO (fully automatic operation) train in station exceeds the permitted range for door opening, the ATO (automatic train operation) system needs to re-benchmark accurately. The conventional ATO re-benchmarking method using only traction and braking commands is time-consuming, and the distance of train single movement does not meet performance requirements, affecting operational service. Therefore, it is necessary to optimize the ATO re-benchmarking method based on light braking commands. Method By considering the delays in the traction and air brake systems during actual train operation, the reason for train single move distance exceeding 1 m in case of the above-mentioned ATO method using only traction and braking commands is analyzed, and the ATO re-benchmarking method is optimized based on light braking commands. The optimized one applies fixed-level braking in advance, eliminates delays caused by air brake system during the parking process， making the process of a single movement involve only the traction system delay, thereby shortening the single move distance and meeting the performance requirements of the ATO re-benchmarking function. The feasibility of the optimized ATO re-benchmarking method based on light braking commands is validated through theoretical calculations of a single move distance. Result & Conclusion At present, the door opening authorization accuracy range is ±0.5 m, and the re-benchmarking function must achieve a train single move distance of less than 1.0 m to meet the stopping accuracy correction requirements. In the conventional ATO re-benchmarking method, the longer response time and execution time of the air brake system result in single move distances exceeding 1.0 m, failing to meet the stopping accuracy correction requirements. Theoretical calculations indicate that the optimized ATO re-benchmarking method based on light braking commands can meet the requirements for a train single move distance within 1.0 m.

Objective Under extreme line and weather conditions, urban rail transit trains often experience low adhesion leading to wheel-rail slip or slide phenomena in mainline operation, making it necessary to optimize the train anti-slip control strategy. Method Based on the adhesion model and slip determination, the typical anti-slip control logics of current urban rail transit vehicle and signaling system, and the interaction principles between vehicle and signaling system anti-slip controls are analyzed. A feasible multi-system anti-slip control strategy is developed. This strategy makes optimization in three aspects: increasing the safety envelope of the train position in the signal anti-slip strategy; matching speed measurement system linkage and tolerance thresholds in vehicle and signaling system interactions; and optimizing the wheel flange lubrication strategy in track work system. Result & Conclusion After optimizing the signaling system anti-slip control strategy, trains are still allowed to continue operating within the maximum safety envelope when the train slips, thus reducing the impact of slip incidents on the following trains and overall operations. The optimized interaction strategy between vehicle and signaling system improves speed measurement accuracy and tolerance threshold ranges. Disabling the rail-wheel flange lubrication device during rain and snow weather further reduces the probabilities of slipping. The results of same period operational data after the implementation of multi-system anti-slip control strategy in mainline operation shows a 34% reduction in emergency braking events due to train slipping and a 64% decrease in the number of affected operational trains.

Abstract Nucleotide-binding oligomerization domain 2 (NOD2) is an immune sensor crucial for eliciting the innate immune responses. Nevertheless, discrepancies exist regarding the effect of NOD2 on different types of cancer. This study aimed to investigate these function of NOD2 in melanoma and its underlying mechanisms. We have validated the tumor suppressor effect of NOD2 in melanoma. NOD2 inhibited the proliferation of melanoma cells, hindering their migration and invasion while promoting the onset of apoptosis. Our study showed that NOD2 expression is closely related to pyrimidine and folate metabolism. NOD2 inhibits thymidylate synthase (TYMS) expression by promoting K48-type ubiquitination modification of TYMS, thereby decreasing the resistance of melanoma cells to 5-fluorouracil (5-FU) and capecitabine (CAP). TYMS was identified to form a complex with Polo-like Kinase 1 (PLK1) and activate the PLK1 signaling pathway. Furthermore, we revealed that the combination of the PLK1 inhibitor volasertib (BI6727) with 5-FU or CAP had a synergistic effect repressing the proliferation, migration, and autophagy of melanoma cells. Overall, our research highlights the protective role of NOD2 in melanoma and suggests that targeting NOD2 and the TYMS/PLK1 signaling axis is a high-profile therapy that could be a prospect for melanoma treatment.

Abstract Background We investigated the associations between IgM, IgG, IgA, and IgE levels and all-cause mortality risk in Chinese centenarians. Methods All participants were from the China Hainan Centenarian Cohort Study. Eligible participants were divided into quartiles based on their IgM, IgG, IgA, and IgE levels. We used restricted cubic spline analyses, Cox regression analyses, and Kaplan–Meier survival curves to analyze associations between IgM, IgG, IgA, and IgE and all-cause mortality risk. Results A total of 906 centenarian participants were included in this study (81.2% female; median age, 102 years). During a median follow-up of 30.1 months, 838 (92.5%) participants died. Restricted cubic spline analysis revealed a nonlinear relationship (“L” type) between serum IgM level and all-cause mortality. Compared with the higher three quartiles of serum IgM level, the lowest quartile was associated with a higher risk of death (Q1 versus Q2-Q4: HR, 1.365; 95% CI, 1.166–1.598; P

Abstract Background Podocyte injury causes proteinuria and accelerates glomerular sclerosis during diabetic kidney disease (DKD). Disruptor of telomeric silencing 1-like (DOT1L), an evolutionarily conserved histone methyltransferase, has been reported in preventing kidney fibrosis in chronic kidney disease models. However, whether DOT1L exerts beneficial effects in diabetes induced podocyte injury and the underlying molecular mechanisms need further exploration. Methods The expression of DOT1L was confirmed by Western blotting in MPC-5 cells and cortex of kidney from db/db mice, as well as immunofluorescence staining in human renal biopsy samples. The effect of DOT1L on podocyte injury was obtained using MPC-5 cells and db/db mice. The potential target genes regulated by DOT1L was measured by RNA-sequencing. Then, a series of molecular biological experiments was performed to investigate the regulation of PLCL1 by DOT1L in MCP-5 cells and db/db mice. Lipid accumulation was assessed by UPLC-MS/MS analysis and Oil Red O staining. Results DOT1L expression was significantly declined in high glucose (HG)-treated MPC-5 cells, podocyte regions of kidney tissues from db/db mice and human renal biopsy samples. Subsequent investigations revealed that upregulation of DOT1L ameliorated HG-induced cell apoptosis in MPC-5 cells as well as primary podocytes. Furthermore, podocyte-specific DOT1L overexpression inhibited diabetic podocyte injury in db/db mice. Mechanistically, we revealed that DOT1L upregulated phospholipase C-like 1 (PLCL1) expression by mediating H3K79me2 at its promoter and PLCL1 silencing suppressed the protective role of DOT1L on podocyte injury. Moreover, DOT1L improved diabetes induced abnormal fatty acid metabolism in podocytes and PLCL1 knockdown reversed its protective effects. Conclusions Taken together, our results indicate that DOT1L protects podocyte injury via PLCL1-mediated fatty acid metabolism and provides new insights into the therapeutic target of DKD.

Abstract Metal oxide nanostructures with single-atomic heteroatom incorporation are of interest for many applications. However, a universal and scalable synthesis approach with high heteroatom concentrations represents a formidable challenge, primarily due to the pronounced structural disparities between Mhetero–O and Msub–O units. Here, focusing on TiO2 as the exemplified substrate, we present a diethylene glycol-assisted synthetic platform tailored for the controlled preparation of a library of M1-TiO2 nanostructures, encompassing 15 distinct unary M1-TiO2 nanostructures, along with two types of binary and ternary composites. Our approach capitalizes on the unique properties of diethylene glycol, affording precise kinetic control by passivating the hydrolytic activity of heteroatom and simultaneously achieving thermodynamic control by introducing short-range order structures to dissipate the free energy associated with heteroatom incorporation. The M1-TiO2 nanostructures, characterized by distinctive and abundant M–O–Ti units on the surface, exhibit high efficiency in photochromic photothermal catalysis toward recycling waste polyesters. This universal synthetic platform contributes to the preparation of materials with broad applicability and significance across catalysis, energy conversion, and biomedicine.

The traditional finite element model has the problems of high computational cost，more black-box operation，and lack of independent intellectual right. The analytical method is used to study the prediction of the vibration response of aircraft wall panels with macro fiber composite（MFC）patches under basic harmonic excitation. Based on classical laminate plate theory，electro mechanical coupling constitutive equations，and the energy method，the analytical model of the MFC-panel system under basic harmonic excitation is established. By employing velocity feedback control method and modal superposition principle，the vibration response of the structure system before and after active control under such an excitation load is successfully solved. The analytical model and its predictive results are extensively validated through the integration of literature data and experimental data obtained from a vibration testing system that is assembled. The results show that，compared to the literature results，the maximum deviation in the calculation of natural frequencies by the proposed model is less than 2%. Additionally，the maximum error in predicting the first two order resonance responses by the model is less than 8.6 %，and both of them are within an acceptable range.

Abstract Background and aim Appendiceal adenocarcinoma, an exceedingly rare malignancy, sparks debate on the optimal surgical approach—appendectomy or right hemicolectomy—for early-stage cases. This study aims to investigate the impact of these two surgical methods on the survival prognosis of patients with early appendiceal adenocarcinoma. Method Utilizing a multicenter medical database, we gathered data from 168 patients diagnosed with T1 stage appendiceal adenocarcinoma admitted between January 2008 and January 2015. This study aims to compare the impact of different treatment modalities on the prognosis of appendiceal adenocarcinoma in these two groups. Result In patients diagnosed with T1 appendiceal adenocarcinoma, the survival prognosis was not significantly improved with right hemicolectomy compared to appendectomy. Out of one hundred twenty-seven patients undergoing right colon resection, only three exhibited lymphatic metastasis, resulting in a rate of 2.3%. Conclusion Simple appendectomy can fulfill the objective of achieving radical tumor resection, rendering right hemicolectomy unnecessary.

Abstract The metabolomic profile of aging is complex. Here, we analyse 325 nuclear magnetic resonance (NMR) biomarkers from 250,341 UK Biobank participants, identifying 54 representative aging-related biomarkers associated with all-cause mortality. We conduct genome-wide association studies (GWAS) for these 325 biomarkers using whole-genome sequencing (WGS) data from 95,372 individuals and perform multivariable Mendelian randomization (MVMR) analyses, discovering 439 candidate “biomarker - disease” causal pairs at the nominal significance level. We develop a metabolomic aging score that outperforms other aging metrics in predicting short-term mortality risk and exhibits strong potential for discriminating aging-accelerated populations and improving disease risk prediction. A longitudinal analysis of 13,263 individuals enables us to calculate a metabolomic aging rate which provides more refined aging assessments and to identify candidate anti-aging and pro-aging NMR biomarkers. Taken together, our study has presented a comprehensive aging-related metabolomic profile and highlighted its potential for personalized aging monitoring and early disease intervention.

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

The PCHE is a critical component in the intermediate heat exchanger of mobile micro-reactors. This study conducts a numerical investigation of the flow and heat transfer characteristics of helium-air within the zigzag channels of the PCHE under 69 different thermal-hydraulic operating conditions. The results reveal that the model validation shows good agreement, with maximum errors in the Nu and f of 10.75 % and 4.81 %, respectively. Changes in thermal-hydraulic parameters exert negligible effects on the inlet and outlet pressure drops for both helium and air (ΔPₕₑ ≈ 10 kPa, ΔPₐᵢᵣ ≈ 100 kPa). The helium-side inlet temperature and mass flow play a dominant role in determining the heat transfer characteristics of the PCHE. The Nu and h for variations in the helium-side inlet temperature are 19.66 % and 25.98 % higher, respectively, compared to the air-side. For variations in the inlet mass flow, the Nu and h are approximately 1.2 times greater on the helium-side than on the air-side. As both parameters increase, the overall heat transfer capacity of the PCHE is significantly enhanced. This study provides valuable theoretical insights for future experimental investigations and optimization designs of the flow and heat transfer characteristics of helium and air within the PCHE.

Objectives SLE is a multifaceted autoimmune disorder with a complex pathogenesis involving genetic, environmental and hormonal factors, which converge on immune dysregulation. The T cell receptor (TCR) repertoire’s role in SLE has garnered significant interest due to its potential in both diagnostics and therapeutics. Our study aimed to delineate the variances in the TCRβ repertoire between patients with SLE and healthy individuals, correlating these differences with the severity and subtypes of SLE.Methods We conducted an analysis of blood samples from 50 treatment-naive patients with SLE and 50 healthy donors, employing RNA extraction, high-throughput sequencing and subsequent bioinformatics analysis.Results Our findings revealed significant alterations in TRBV and TRBJ gene usage frequencies, indicative of a skewed TCR repertoire in patients with SLE. Notably, nine hub TRBV genes were identified as potential biomarkers for SLE with high diagnostic accuracy. Furthermore, we observed a reduction in TCR diversity, characterised by a lower diversity 50 value and increased clonal expansion, which correlated with disease severity.Conclusions The TCRβ repertoire is significantly altered in SLE, with potential implications for diagnostics and therapeutics. The identified hub genes may serve as novel biomarkers for SLE, and the findings contribute to the understanding of the immunopathogenesis of the disease.

BackgroundRheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and progressive joint destruction. Neutrophil extracellular traps (NETs), a microreticular structure formed after neutrophil death, have recently been implicated in RA pathogenesis and pathological mechanisms. However, the underlying molecular mechanisms and key genes involved in NET formation in RA remain largely unknown.MethodsWe obtained single-cell RNA sequencing data of synovial tissues from the Gene Expression Omnibus (GEO) database and performed cellular annotation and intercellular communication analyses. Subsequently, three microarray datasets were collected for a training cohort and correlated with a bulk RNA-seq dataset associated with NETs. Differentially expressed genes were identified, and weighted gene correlation network analysis was used to characterize gene association. Using three machine learning techniques, we identified the most important hub genes to develop and evaluate a nomogram diagnostic model. CIBERSORT was used to elucidate the relationship between hub genes and immune cells. An external validation dataset was used to verify pivotal gene expression and to construct co-regulatory networks using the NetworkAnalyst platform. We further investigated hub gene expression using immunohistochemistry (IHC) in an adjuvant-induced arthritis rat model and real-time quantitative polymerase chain reaction (RT-qPCR) in a clinical cohort.ResultsSeven cellular subpopulations were identified through downscaling and clustering, with neutrophils likely the most crucial cell clusters in RA. Intercellular communication analysis highlighted the network between neutrophils and fibroblasts. In this context, 4 key hub genes (CRYBG1, RMM2, MMP1, and SLC19A2) associated with NETs were identified. A nomogram model with a diagnostic value was developed and evaluated. Immune cell infiltration analysis indicated associations between the hub genes and the immune landscape in NETs and RA. IHC and RT-qPCR findings showed high expression of CRYBG1, RMM2, and MMP1 in synovial and neutrophilic cells, with lower expression of SLC19A2. Correlation analysis further emphasized close associations between hub genes and laboratory markers in patients with RA.ConclusionThis study first elucidated neutrophil heterogeneity in the RA synovial microenvironment and mechanisms of communication with fibroblasts. CRYBG1, RMM2, MMP1, and SLC19A2 were identified and validated as potential NET-associated biomarkers, offering insights for diagnostic tools and immunotherapeutic strategies in RA.

Background: The neoantigen vaccine has remarkable potential in treating advanced cancer due to its tumor specificity and ability to bypass central tolerance mechanisms. However, numerous neoantigens show poor immunogenicity, and the immune inhibitory factors of present in both tumors and tumor-draining lymph nodes impair the efficacy of cancer neoantigen vaccine. Eliminating immunosuppressive cells will improve the priming and expansion of anti-tumor immune cells induced by the vaccine. Methods: In this study, a Treg-depleting regimen (consisting of CD25mAb and low-dose cyclophosphamide (LD-CTX)) was used in conjunction with a neoantigen vaccine for treating mice with solid tumors. We constructed two types of tumor models and investigated differences in therapy efficacy in the four groups (PBS, vaccine, CD25mAb+CTX and combination) at the genetic and protein levels. ELISPOT and TCR sequencing were applied to detect the expansion of neoantigen reactive T cells (NRT) and tumor antigen spreading. Results: In the combinational group, the ELISPOT results showed an obvious expansion of NRT cells induced by weak immunogenic peptides. The combinational group exhibited significant improvement in inhibiting the tumor growth extended the survival time of tumor-bearing mice, and promoted T cells infiltration into tumors. Besides, compared to the Vac group, more neoantigen-targeted and TAA-targeted T cells were detected in the combinational group by TCR sequencing. The results of transcriptomic sequencing and flow cytometry showed that the number of Tregs in the combinational group was lower, while the proportions of memory effector T cells and effector T cells were higher than those in the vaccine group. An increase in mature DCs was also observed in vaccinated mice after receiving this Treg-depleting strategy. Conclusion: Our research first revealed that inhibiting the normal function of Tregs transformed “weaker” neoantigens into “stronger” ones, while also contributing to the proliferation of NRT cells. This Treg-depleting strategy allowed neoantigens with poor immunogenicity to elicit a robust immune response, thereby augmenting the efficacy of the neoantigen vaccine in delaying tumor growth and prolonging the survival of the hosts.

Background: Stroke is the main cause of death and disability worldwide. There are divergent views regarding the effects of acupuncture in managing acute ischemic stroke (AIS). The purpose of this study was to assess the safety and effectiveness of acupuncture for acute ischemic stroke. Methods: We conducted a comprehensive search across the PubMed, Cochrane Library, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), Wanfang, and SinoMed databases from their inception until October 3, 2023. Two reviewers screened eligible randomized controlled trials (RCTs) according to criteria and extracted data using a pre-established form. Cochrane tool was used for risk of bias assessment, and Revman 5.3 was used for subsequent meta-analysis. The GRADE tool will be used to assess the quality of evidence. Results: Thirty-one RCTs were included, involving 3604 patients. Meta-analysis showed that compared with conventional treatments (CTs), acupuncture combined with CTs could improve in National Institutes of Health Stroke Scale (NIHSS) and Efficiency (MD:1.70, 95 %CI [-2.27, -1.14], P < 0.00001;RR: 1.21, 95 %CI [1.12, 1.31], P < 0.00001,);On the Chinese Stroke Scale (CSS) and effectiveness based on CSS, acupuncture showed positive effects (MD:4.33, 95 %CI [-5.67, -2.98], P < 0.00001; RR: 1.26, 95 %CI [1.13, 1.41], P < 0.0001). Furthermore, ADL, Fugl-Meyer Assessment Scale (FMA), prognosis analyses also showed the effectiveness of acupuncture. (SMD: 0.98, 95 % CI [0.64, 1.31], P < 0.00001; MD: 16.46, 95 %CI [12.56, 20.35], P < 0.00001; RR: 0.38, 95 %CI [0.16, 0.89], P = 0.03). However, the certainty of evidence was low. Conclusion: According to current evidence, Acupuncture may be effective and safe for AIS. The future still needs high-quality evidence to support this conclusion. Protocol registration: PROSPERO (CRD42023464998).

Aldehyde dehydrogenase 2 (ALDH2), a pivotal enzyme in the metabolism of toxic aldehydes produced by oxidative stress, has been demonstrated to play a cardioprotective role in cardiovascular diseases. Antrodia cinnamomea triterpenoids (ACT) is a medicinal mushroom with anti-inflammatory and antioxidant properties, and our previous study found that ACT can exert anti-fatty liver effects by regulating ALDH2. This study aimed to elucidate the impact of ACT and its monomer on cardiac hypertrophy and investigate the relationship between its pharmacological mechanism and ALDH2. Through examining cardiac morphology and expression levels of hypertrophic biomarkers, ACT significantly reduced myocardial hypertrophy induced by angiotensin II (Ang II) and transverse aortic constriction (TAC)surgery in wild-type mice, but not in ALDH2 knockout mice. In vitro, ACT and its monomeric dehydrosulphurenic acid (DSA) inhibited the hypertrophic phenotype of Ang II-stimulated neonatal cardiac myocytes (NRCMs) in an ALDH2-dependent manner. Regarding the pharmacological mechanism, it was observed that ACT and DSA restored ALDH2 expression and activity in myocardial tissues of WT-Ang II/TAC mice and Ang II-induced NRCMs. Furthermore, it inhibited oxidative stress and improved mitochondrial quality control (MQC) homeostasis in an ALDH2-dependent manner. We screened SNW1, a transcriptional coactivator, as a DSA-binding protein by “target fishing” and cellular enthusiasm transfer assay techniques and validated that SNW1 promoted ALDH2 transcription and translation levels through synergistic interaction with the transcription factor RXR. In conclusion, the findings demonstrate that ACT/DSA upregulates ALDH2 expression via regulating SNW1/RXR, thereby inhibiting oxidative stress and maintaining MQC homeostasis, and then protects against cardiac hypertrophy.

Study regions: The Guizhou Province (GZP) in southwestern China, where mainly comprises Karst regions. Study focus: The rainfall records were collected from 45 rain gauges within GZP during 1960–2019 to calculate the Rainfall Erosivity (RE). In addition, the spatio-temporal characteristics of RE were analyzed using statistical analysis methods, and the effect of El Niño-Southern Oscillation (ENSO) on RE under different rainfall intensities was also explored for the first time. New hydrological insights for the region: The annual average RE was 4774 MJ·mm·hm−2·h−1, exhibiting a persistent increasing trend. RE demonstrated an increasing trend in most months, except for April and May, and the trend would continue in the future. The southern region of the GZP exhibited higher RE values, while the northern region displayed lower values. The spatial distribution varied across different seasons and months. On an annual scale, RE was significantly (P < 0.01) negatively correlated with elevation, indicating a decrease in erosive precipitation with increasing elevation. On a monthly scale, except for June to September, RE showed a significant (P < 0.001) negative correlation with elevation. Additionally, the study revealed a significant positive correlation (P < 0.05) with a lag time of 1 year between the total RE and RE under rainfall intensities exceeding 40 mm/day and the Multivariate ENSO Index (MEI). This finding provides a possibility for predicting high-intensity RE with one year ahead.

Fusobacterium nucleatum (F. nucleatum) is closely correlated with tumorigenesis in colorectal cancer (CRC). We aimed to investigate the effects of host norepinephrine on the carcinogenicity of F. nucleatum in CRC and reveal the underlying mechanism. The results revealed that both norepinephrine and bacterial quorum sensing (QS) molecule auto-inducer-2 (AI-2) were positively associated with the progression of F. nucleatum related CRC (p

To address the issue of severe mine pressure manifestations and difficult-to-control deformation in deep coal seam roadways, an orthogonal numerical simulation experiment was conducted based on the Kastner formula.This experiment examined five factors affecting the stability of roadway surrounding rock: height-to-width ratio, lateral pressure coefficient, depth, cross-sectional shape, and surrounding rock strength.Sensitivity of each factor to roadway deformation and damage was studied using variance analysis and intuitive analysis charts.The stress distribution patterns of elliptical and rectangular roadways under different lateral pressure coefficients and height-to-width ratios were analyzed using the plane elasticity complex variable function theory.Optimal designs for the height-to-width ratio and shape of elliptical and rectangular roadways were developed.The results showed that the main factors affecting the stability of surrounding rock are the strength of the surrounding rock and the lateral pressure coefficient, while depth, cross-sectional shape, and height-to-width ratio are secondary factors.Elliptical roadways exhibit the smallest difference in surrounding rock stress under isotropic stress ratios.Rectangular roadways have lower stress concentration when the width is 5 m and the height-to-width ratio is approximately 0.6.For areas with rapid stress increase in rectangular roadways, an optimized rounded rectangular roadway was designed considering bearing characteristics and cross-sectional utilization, and a calculation formula for the corner radius was established.The optimization performance of this design was verified through numerical simulation.

Abstract As major terrestrial carbon sinks, forests play an important role in mitigating climate change. The relationship between the seasonal uptake of carbon and its allocation to woody biomass remains poorly understood, leaving a significant gap in our capacity to predict carbon sequestration by forests. Here, we compare the intra-annual dynamics of carbon fluxes and wood formation across the Northern hemisphere, from carbon assimilation and the formation of non-structural carbon compounds to their incorporation in woody tissues. We show temporally coupled seasonal peaks of carbon assimilation (GPP) and wood cell differentiation, while the two processes are substantially decoupled during off-peak periods. Peaks of cambial activity occur substantially earlier compared to GPP, suggesting the buffer role of non-structural carbohydrates between the processes of carbon assimilation and allocation to wood. Our findings suggest that high-resolution seasonal data of ecosystem carbon fluxes, wood formation and the associated physiological processes may reduce uncertainties in carbon source-sink relationships at different spatial scales, from stand to ecosystem levels.

Abstract Background This study aims to investigate the role of shear wave elastography (SWE) and connective tissue growth factor (CTGF) in the assessment of papillary thyroid carcinoma (PTC) prognosis. Methods CTGF expression was detected with immunohistochemistry. Clinical and pathological data were collected. Parameters of conventional ultrasound combined with SWE were also collected. The relationship among CTGF expression, ultrasound indicators, the elastic modulus and the clinicopathological parameters were analyzed. Results Univariate analysis showed that patients with high risk of PTC were characterized with male, Uygur ethnicity, increased expression of CTGF, convex lesions, calcified, incomplete capsule, intranodular blood flow, rear echo attenuation, cervical lymph node metastasis, lesions larger than 1 cm, psammoma bodies, advanced clinical stage, increased TSH and high value in the shear modulus (P

Abstract The pathogenesis of Alzheimer's disease (AD) remains unclear, but revealing individual differences in functional connectivity (FC) may provide insights and improve diagnostic precision. A hierarchical clustering-based autoencoder with functional connectivity was proposed to categorize 82 AD patients from the Alzheimer's Disease Neuroimaging Initiative. Compared to directly performing clustering, using an autoencoder to reduce the dimensionality of the matrix can effectively eliminate noise and redundant information in the data, extract key features, and optimize clustering performance. Subsequently, subtype differences in clinical and graph theoretical metrics were assessed. Results indicate a significant inter-subject heterogeneity in the degree of FC disruption among AD patients. We have identified two neurophysiological subtypes: subtype I exhibits widespread functional impairment across the entire brain, while subtype II shows mild impairment in the Limbic System region. What is worth noting is that we also observed significant differences between subtypes in terms of neurocognitive assessment scores associations with network functionality, and graph theory metrics. Our method can accurately identify different functional disruptions in subtypes of AD, facilitating personalized treatment and early diagnosis, ultimately improving patient outcomes.

Highlights A unique approach is proposed: constructing a polymer fiber rigid network with high glass transition temperature. Frozen bulk heterojunction morphology impeded deterioration of exciton quenching, charge transport, and charge extraction properties during thermal aging. The strategy is universal and can be further optimized for enhanced thermal stability and improved mechanical resilience.