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Lu Zhu,1,&ast; Jing Li,1,&ast; Zhao-Qin Wang,1,2,&ast; Yun-Jia Gu,1 Guo-Na Li,3 Wen-Jia Wang,1 Guang-Bin Pen,1 Qi Li,1 Meng-Die Wu,1 Hui-Rong Liu,1,2 Yan Huang,1,2 Lu-Yi Wu1 1Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2Shanghai Research Institute of Acupuncture and Meridian, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 3School of Acupuncture, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lu-Yi Wu, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, No. 110 Ganhe Road, Hongkou District, Shanghai City, 200437, People’s Republic of China, Email luyitcm@163.com Yan Huang, Shanghai Research Institute of Acupuncture and Meridian, Shanghai University of Traditional Chinese Medicine, No. 650 Wanping South Road, Xuhui District, Shanghai City, 200030, People’s Republic of China, Email huangyan@shutcm.edu.cnObjective: Moderate-to-severe pain is the most common clinical symptom in patients with hepatocellular carcinoma (HCC).This trial aimed to analyze the clinical efficacy of Transcutaneous electrical acupoint stimulation (TEAS) in patients of HCC with severe pain and provide a reliable reference for optimizing the clinical diagnostic and therapeutic strategies of HCC.Methods: A total of 104 eligible patients were randomly allocated to experimental and control groups in a ratio of 1:1.The treatment was administered for 1 week continuously. Patients in both groups were followed up 1 week after the end of the treatment.The primary outcome measure was the Numerical Rating Scale (NRS) score, whereas the secondary outcome measures included Brief Pain Inventory BPI-Q3, Q4, Q5 scores, analgesic dose, frequency of opioid-induced gastrointestinal side effects, Karnofsky Performance Status (KPS), Quality of Life Scale - Liver Cancer (QOL-LC), and Brief Fatigue Inventory (BFI) scores.Results: The NRS scores of experimental group was significantly lower after treatment and at the follow-up than baseline (average P< 0.01), there were also statistical differences between the groups at the above time points (average P< 0.01). BPI-Q3, -Q4, and -Q5 scores in the experimental group were decreased after treatment when compared with those before treatment (average P< 0.01). Furthermore, there were significant improvements of gastrointestinal side effects, KPS, QOL-LC and BPI in the experimental group after treatment, and the above results were statistically significant compared to the control group.Conclusion: 7-day TEAS treatment can significantly enhance the analgesic effect and maintain for the following week, also reduce the incidence of gastrointestinal side effects caused by opioids, and improve the quality of life of patients with moderate-to-severe HCC-related pain, which has reliable safety and certain clinical promotion value.Keywords: hepatocellular carcinoma pain, transcutaneous electrical acupoint stimulation, cancer pain, randomized controlled trial

Yan Lan,1,2,&ast; Yu-Kun Zheng,3,&ast; Liu-Yi Wu,3 Zi-Jun Zhou,3 Ruo-Xin Guan,3 Heng Xu,3 Ji-Yuan Tu,3 Xin Gu,3 Rui Wang,3 Nan Jiang,3 Yuan Wu,4 Cheng-Ren Shu,1,2 Zhong-Shi Zhou3 1Department of Pharmacy, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Huangshi, Hubei, People’s Republic of China; 2Hubei Key Laboratory of Kidney Disease Pathogenesis and Intervention, Hubei, People’s Republic of China; 3College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei, People’s Republic of China; 4Department of Radiation Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Cheng-Ren Shu, Department of Pharmacy, Huangshi Central Hospital, NO. 141, Tianjin Road, Huangshi, Hubei, People’s Republic of China, Tel +86-27-13986590438, Email 397112615@qq.com Zhong-Shi Zhou, College of Pharmacy, Hubei University of Chinese Medicine, No. 1, Huangjiahu West Road, Hongshan District, Wuhan City, Hubei Province, People’s Republic of China, Tel +86-27-15871745189, Email monkeyzzs@126.comObjective: Traditional Chinese medicine Polygonum cuspidatum (PC) has significant effects on reducing pain. In this study, we investigated the analgesic effects of the alcohol extract of PC on three types of inflammatory pain and explored its mechanism.Methods: Potential targets for the analgesic effects of the main active components of PC alcohol extract were screened by network pharmacology and molecular docking. Three different inflammatory pain mouse models (acetic acid twisting, formalin foot swelling, and xylene ear swelling) were used to study the analgesic effects of PC. The expression of latent signaling pathways in L4-6 spinal cord tissues in formalin foot swelling mice was evaluated using real-time qPCR (RT-qPCR), Western blot (WB), and immunohistochemistry (IHC) analyses.Results: Network pharmacology analysis shows that PC analgesic mechanism is related to the MAPK/ERK signaling pathway. The five main active components of PC have good docking ability with JNK and p38. PC alcohol extract significantly reduced the pain behavior and alleviated inflammatory reactions in three mouse models, inhibited the mRNA and protein phosphorylation levels of JNK, ERK, p38, and CREB in spinal cord tissues.Conclusion: PC alcohol extract can inhibit inflammation and alleviate pain, which is related to its inhibition of the MAPK/ERK signaling pathway in spinal cord. Thus, PC alcohol extract is a promising candidate for pain treatment.Keywords: Polygonum cuspidatum, network pharmacology, MAPK/ERK, analgesic

Li-Ying Wu,1 Shih-Chieh Shao,2 Shu-Chen Liao1,3 1Department of Emergency Medicine, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan; 2Department of Pharmacy, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan; 3Chang Gung University College of Medicine, Taoyuan, TaiwanCorrespondence: Shih-Chieh Shao, Department of Pharmacy, Keelung Chang Gung Memorial Hospital, 222 Maijin Road, Keelung, Taiwan, Email scshao@cgmh.org.tw Shu-Chen Liao, Department of Emergency Medicine, Keelung Chang Gung Memorial Hospital, 222 Maijin Road, Keelung, Taiwan, Email ermdsusan@gmail.comPurpose: The validity of the diagnosis codes to identify myocarditis cases in healthcare databases research remains unclear, and this study aimed to determine the coding accuracy of myocarditis in Taiwan.Methods: We conducted a cross-sectional study based on Taiwan’s largest multi-institutional healthcare system to identify inpatients newly diagnosed with ICD-10-CM myocarditis codes at discharge between January 1st, 2017 and March 31st, 2022. We ascertained the myocarditis diagnosis by a gold standard biopsy or by review of electronic medical records, and the positive predictive values (PPV) with 95% confidence intervals (CI) of the ICD-10-CM codes for myocarditis were determined.Results: We included a total of 498 inpatients (mean age: 33.8 years old; female: 38.8%) with new myocarditis diagnosis at discharge. Codes I409 (30.1%) and I514 (45.4%) constituted the majority of myocarditis diagnostic codes in any coding position, and the overall PPV of the myocarditis codes was 73.5% (95% CI: 69.6– 77.4%). However, the highest PPV (96.6%) for myocarditis diagnosis was noted with code I409 as the primary diagnosis. We found 132 inpatients (26.5%) who were false-positive myocarditis cases, identified by the ICD-10-CM codes, and potential reasons for misclassification included other inflammation diseases (n=35, 26.5%), pre-existing heart failure (n= 25, 18.9%) and acute myocardial infarction (n=16, 12.1%).Conclusion: The PPV of ICD-10-CM codes for myocarditis in Taiwan was acceptable, but some other inflammation diseases and pre-existing heart diseases may be falsely coded as myocarditis. Our results may serve future secondary database studies as a fundamental reference on the validity of myocarditis diagnosis codes.Keywords: ICD-CM-10 codes, positive predictive value, myocarditis, multi-institutional study, Chang Gung Research Database

Yue-Rong Zhang,1 Hui Wang,2 Ning Zhou,2 Yao-Di Zhang,1,2 Yan Lin,1,2 Li-Yang Wu,1,2 Shi-Fang Wei,2 Yan-Yun Ma,2,3 Chun-Xia Wang3 1Department of Gastroenterology, University-Town Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Department of Infectious Diseases, The First People’s Hospital of Lanzhou, Gansu, 730050, People’s Republic of China; 3Department of Laboratory, The First People’s Hospital of Lanzhou, Gansu, 730050, People’s Republic of ChinaCorrespondence: Yue-Rong ZhangDepartment of Gastroenterology, University-Town Hospital of Chongqing Medical University, No. 55 University Town Middle Road, Shapingba District, Chongqing, 401331, People’s Republic of ChinaTel/Fax +86 102365714142Email zhang_yue_rong@163.comObjective: To explore the feasibility of treating cirrhosis using a multidisciplinary team approach (MDT) and to pinpoint the key factors influencing its implementation.Methods: The data of 307 patients with decompensated cirrhosis were studied retrospectively. Patients who received more than two treatment measures were assigned to the MDT group (n=228), and patients who received symptomatic medical drug treatment only were assigned to the traditional treatment group (n=79). The follow-up period ranged from 4 to 10 years, and the average follow-up period was 5.7 years. The results of the biochemical tests for hepatitis B virus deoxyribonucleic acid, hepatitis C virus ribonucleic acid, and autoantibodies to liver disease were analyzed.Results: The differences in gender and Child–Pugh grade of liver function between the two groups were not statistically significant. The MDT group had obvious advantages over the traditional treatment group in occupational composition, etiology composition, 5-year survival rate and annual hospitalization times. The leading causes of death in the MDT group, in descending order, were liver cancer, infection, mesenteric thrombosis, and non-hepatic disease, and, in the medical treatment group, they were liver failure, gastrointestinal bleeding, infection, and liver cancer. There was a significant statistical difference between the two groups (p < 0.05). In the multidisciplinary treatment, etiological treatment was the most widely used treatment, accounting for 79.8%, followed by endoscopic treatment (33.3%), peritoneal drainage and ascites reinfusion (25%), splenectomy combined with devascularization (11.4%) and stem cell transplantation and liver transplantation (1.8%).Conclusion: An MDT can improve the efficacy and prognosis of patients with cirrhosis and improve patient compliance. After multi-disciplinary intervention, the mortality spectrum of long-term survival patients with cirrhosis changes, and the mortality rate of liver cancer and non-liver disease increases.Keywords: liver cirrhosis, decompensated period, multidisciplinary team mode, traditional treatment, retrospective study

Xing-Hua Xiao,* Qi-Yuan Huang,* Xian-Ling Qian,* Jing Duan, Xue-Qiao Jiao, Long-Yuan Wu, Qing-Yun Huang, Jun Li, Xing-Ning Lai, Yu-Bo Shi, Li-Xia Xiong Department of Pathophysiology, Medical College, Nanchang University, Nanchang 330006, People’s Republic of China*These authors contributed equally to this workCorrespondence: Li-Xia XiongDepartment of Pathophysiology, Medical College, Nanchang University, 461 Bayi Road, Nanchang 330006, People’s Republic of ChinaTel +86-791-8636-0556Email xionglixia@ncu.edu.cnPurpose: Type 1 diabetes mellitus (T1DM) is characterized by irreversible islet β cell destruction. Accumulative evidence indicated that Cdc42 and Wnt/β-catenin signaling both play a critical role in the pathogenesis and development of T1DM. Further, bio-molecular mechanisms in adipose-derived mesenchymal stem cells (ADSCs)-derived insulin-producing cells (IPCs) remain largely unknown. Our aim was to investigate the underlying mechanism of Cdc42/Wnt/β-catenin pathway in ADSC-derived IPCs, which may provide new insights into the therapeutic strategy for T1DM patients.Methods: ADSC induction was accomplished with DMSO under high-glucose condition. ML141 (Cdc42 inhibitor) and Wnt-3a (Wnt signaling activator) were administered to ADSCs from day 2 until the induction finished. Morphological changes were determined by an inverted microscope. Dithizone staining was employed to evaluate the induction of ADSC-derived IPCs. qPCR and Western blotting were employed to measure the mRNA and protein expression level of islet cell development-related genes and Wnt signaling-related genes. The proliferation ability of ADSC-derived IPCs was also detected with a cell counting kit (CCK) assay. The expression and secretion of Insulin were detected with immunofluorescence test and enzyme-linked immunosorbent assay (ELISA) respectively.Results: During induction, morphological characters of ADSCs changed into spindle and round shape, and formed islet-line cell clusters, with brown dithizone–stained cytoplasm. Expression levels of islet cell development-related genes were up-regulated in ADSC-derived IPCs. Wnt-3a promoted Wnt signaling markers and islet cell development-related gene expression at mRNA and protein levels, while ML141 played a negative effect. Wnt-3a promoted ADSC-derived IPC proliferation and glucose-stimulated insulin secretion (GSIS), while ML141 played a negative effect.Conclusion: Our research demonstrated that DMSO and high-glucose condition can induce ADSCs into IPCs, and Wnt signaling promotes the induction. Cdc42 may promote IPC induction, IPC proliferation and insulin secretion via Wnt/β-catenin pathway, meaning that Cdc42 may be regarded as a potential target in the treatment of T1DM.Keywords: Cdc42, ML141, ADSCs, IPCs, Wnt signaling, insulin

Wen-Peng Wang,1 Ning Li,1 Yuan-Yuan Zhang,1 Yu-Tao Gao,2 Yang-Chun Sun,1 Li Ge,1 Ling-Ying Wu1 1Department of Gynecologic Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; 2Department of Gynecology, First Affiliated Hospital of Kunming Medical University, Kunming, China Background: The role that lymph node dissection (LND) plays in the management of ovarian carcinosarcoma (OCS) is unclear due to its rarity. This study investigated lymph node metastasis (LNM) prevalence in women with early OCS and effects of LND and LNM on survival. Methods: Data of women diagnosed with OCS, whose primary tumor was confined to ovaries (American Joint Committee on Cancer [AJCC] T1) or pelvic cavity (AJCC T2), between 1988 and 2010 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. Patients were classified into lymphadenectomy (LND [+]) and no lymphadenectomy (LND [−]) groups. Results: A total of 363 women were included. The prevalence of LNM was 9.6% in AJCC T1 and 16.3% in AJCC T2. Multivariate analysis showed that LND and AJCC T categories were independent prognostic variables, irrespective of cancer-specific survival (CSS) or overall survival (OS). Subgroup analysis by AJCC T categories revealed that LND (+) group in AJCC T2 had a better survival outcome compared to LND (−) group (CSS, HR [95% CI] = 0.61 [0.43–0.87]; OS, HR [95% CI] = 0.59 [0.42–0.83]). There was no survival difference between groups in AJCC T1 (CSS, HR [95% CI] = 0.96 [0.56–1.65]; OS, HR [95% CI] = 0.88 [0.56–1.38]). Multivariate analysis was further carried out in LND (+) group and demonstrated that LNM and AJCC T2 had poor CSS and OS. Subgroup analysis by AJCC T categories showed that worse survival was observed in LNM (+) group compared to LNM (-) group in AJCC T2 (CSS, HR [95% CI] = 3.62 [1.50–8.73]; OS, HR [95% CI] = 3.71 [1.59–8.68]) but not in AJCC T1 (CSS, HR [95% CI] = 1.78 [0.50–6.37]; OS, HR [95% CI] = 1.97 [0.61–6.39]). Conclusion: Regional lymphadenectomy should be performed in patients with AJCC T2 OCS. LND and LNM were not significantly associated with prognosis in AJCC T1 while LNM had a trend toward worse survival. Keywords: ovarian mesodermal mixed tumor, ovarian müllerian mixed tumor, lymph node examined, lymphatic metastasis

Muhammad Saif Ur Rahman,1 Ling Zhang,2 Lingyan Wu,1 Yuqiong Xie,1 Chunchun Li,1 Jiang Cao1 1Clinical Research Center, 2Cardiovascular Key Laboratory of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People’s Republic of China Abstract: Severe side effects are major problems with chemotherapy of gastric cancer (GC). These side effects can be reduced by using sensitizing agents in combination with therapeutic drugs. In this study, the low/nontoxic dosage of glaucocalyxin B (GLB) was used with other DNA linker agents mitomycin C (MMC), cisplatin (DDP), or cyclophosphamide (CTX) to treat GC cells. Combined effectiveness of GLB with drugs was determined by proliferation assay. The molecular mechanisms associated with cell proliferation, migration, invasion, cell cycle, DNA repair/replication, apoptosis, and autophagy were investigated by immunoblotting for key proteins involved. Cell cycle and apoptosis analysis were performed by flow cytometry. Reactive oxygen species level was also examined for identification of its role in apoptosis. Proliferation assay revealed that the addition of 5 µM GLB significantly sensitizes gastric cancer SGC-7901 cells to MMC, DDP, and CTX by decreasing half-maximal inhibitory concentration (IC50) by up to 75.40%±5%, 45.10%±5%, and 52.10%±5%, respectively. GLB + drugs decreased the expression level of proteins involved in proliferation and migration, suggesting the anticancer potential of GLB + drugs. GLB + MMC, GLB + CTX, and GLB + DDP arrest the cells in G0/G1 and G1/S phase, respectively, which may be the consequence of significant decrease in the level of enzymes responsible for DNA replication and telomerase shortening. Combined use of GLB with these drugs also induces DNA damage and apoptosis by activating caspase/PARP pathways and increased production of reactive oxygen species and increased autophagy in GC cells. GLB dosage sensitizes GC cells to the alkylating agents via arresting the cell cycle and enhancing cell death. This is of significant therapeutic importance in the reduction of side effects associated with these drugs. Keywords: glaucocalyxin B, mitomycin C, cisplatin, cyclophosphamide, DNA linkers, side effects, gastric cancer

Chuiguo Huang,1,* Naijun Yuan,2,* Liying Wu,3 Xiaofu Wang,1 Junqiang Dai,4 Pan Song,5 Fengxi Li,6 Changbao Xu,1 Xinghua Zhao1 1Department of Urology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, 2College of Traditional Chinese Medicine of Jinan University, Institute of Integrated Traditional Chinese and Western Medicine of Jinan University, Guangzhou, 3Department of Nephrology, The Second Affiliated Hospital of Hainan Medical College, Hainan, 4Department of Neurosurgery, The Second Affiliated Hospital of Lanzhou University, Lanzhou, 5Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 6Department of General Surgery, The First Affiliated Hospital of Guangxi Medical University, Guangxi, People’s Republic of China *These authors contributed equally to this work Abstract: Papillary renal cell carcinoma (PRCC) is the second most common subtype of renal cell carcinoma, and it lacks effective therapeutic targets and prognostic molecular biomarkers. Attention has been increasingly focused on long noncoding RNAs (lncRNAs), which can act as competing endogenous RNA (ceRNA) to compete for shared microRNAs (miRNAs) in the tumorigenesis of human tumors. Therefore, to clarify the functional roles of lncRNAs with respect to the mediated ceRNA network in PRCC, we comprehensively integrated expression profiles, including data on mRNAs, lncRNAs and miRNAs obtained from 289 PRCC tissues and 32 normal tissues in The Cancer Genome Atlas. As a result, we identified 2,197 differentially expressed mRNAs (DEmRNAs) and 84 differentially expressed miRNAs (DEmiRNAs) using a threshold of |log2 (fold change)| >2.0 and an adjusted P-value

This article presents an in-depth analysis of global research trends in Geosciences from 2014 to 2023. By integrating bibliometric analysis with expert insights from the Deeptime Digital Earth (DDE) initiative, this article identifies key emerging themes shaping the landscape of Earth Sciences①.

Epidemiological evidence showed that serum high perfluorooctane sulfonate (PFOS) levels are associated with multiple eye related diseases, but the potential underlying molecular mechanisms remain poorly understood. Zebrafish and photoreceptor cell (661w) models were used to investigate the molecular mechanism of PFOS induced eye development defects. Our results showed a novel molecular mechanism of PFOS-induced inflammation response-mediated photoreceptor cell death associated with eye development defects. Inhibition of Caspase-8 activation significantly decreased photoreceptor cell death in PFOS exposure. Mechanistically, Toll-like receptor 4 (TLR4) mediates activation of Caspase-8 promote activation of NLR family pyrin domain-containing 3 (NLRP3) inflammasome to elicit maturation of interleukin-1 beta (IL-1β) via Caspase-1 activation, facilitating photoreceptor cell inflammation damage in PFOS exposure. In addition, we also made a novel finding that Caspase-3 activation was increased via Caspase-8 activation and directly intensified cell death. Our results show the important role of Caspase-8 activation in PFOS induced eye development defects and highlight Caspase-8 mediated activation of the NLRP3 inflammation triggers activation of Caspase-1 and promote the maturation of IL-1β in retinal inflammatory injury., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Soft-matter-based photonic crystals like blue-phase liquid crystals (BPLC) have potential applications in wide-ranging photonic and bio-chemical systems. To date, however, there are limitations in the fabrication of large monocrystalline BPLCs. Traditional crystal-growth process involves the transition from a high-temperature disordered phase to an ordered (blue) phase and is generally slow (takes hours) with limited achievable lattice structures, and efforts to improve molecular alignment through post-crystallization field application typically prove ineffective. Here we report a systematic study on the molecular self-assembly dynamics of BPLC starting from a highly ordered phase in which all molecules are unidirectionally aligned by a strong electric field. We have discovered that, near the high-temperature end of the blue phase, if the applied field strength is then switched to an intermediate level or simply turned off, large-area monocrystalline BPLCs of various symmetries (tetragonal, orthorhombic, cubic) can be formed in minutes. Subsequent temperature tuning of the single crystal at a fixed applied field allows access to different lattice parameters and the formation of never-before-seen monoclinic structures. The formed crystals remain stable upon field removal. The diversity of stable monocrystalline BPLCs with widely tunable crystalline symmetries, band structures, and optical dispersions will significantly improve and expand their application potentials., (© 2024. The Author(s).)

Considering the frequency of ethylene oxide (EtO) residues found in food, the health effects of EtO have become a concern. Between 2022 and 2023, 489 products were inspected using the purposive sampling method in Taiwan, and nine unqualified products were found to have been imported; subsequently, border control measures were enhanced. To ensure the safety of all imported foods, the current study used the K-means clustering method for identifying EtO residues in food. Data on finished products and raw materials with EtO residues from international public opinion bulletins were collected for analysis. After matching them with the Taiwan Food Cloud, 90 high-risk food items with EtO residues and 1388 manufacturers were screened. The Taiwan Food and Drug Administration set up border controls and grouped the manufacturers using K-means clustering in the unsupervised learning algorithm. For this study, 37 manufacturers with priority inspections and 52 high-risk finished products and raw materials with residual EtO were selected for inspection. While EtO was not detected, the study concluded the following: 1. Using international food safety alerts to strengthen border control can effectively ensure domestic food safety; 2. K-means clustering can validate the risk-based purposive sampling results to ensure food safety and reduce costs.

Background: The Comprehensive Geriatric Assessment (CGA) was introduced late in China and is primarily used for investigating and evaluating health problems in older adults in outpatient and community settings. However, there are few reports on its application in hospitalized patients, especially older patients with diabetes and hypertension., Aim: To explore the nursing effect of CGA in hospitalized older patients with diabetes and hypertension., Methods: We performed a retrospective single-center analysis of patients with comorbid diabetes mellitus and hypertension who were hospitalized and treated in the Jiangyin Hospital of Traditional Chinese Medicine between September 2020 and June 2022. Among the 80 patients included, 40 received CGA nursing interventions (study group), while the remaining 40 received routine nursing care (control group). The study group's comprehensive approach included creating personalized CGA profiles, multidisciplinary assessments, and targeted interventions in areas, such as nutrition, medication adherence, exercise, and mental health. However, the control group received standard nursing care, including general and medical history collection, fall prevention measures, and regular patient monitoring. After 6 months of nursing care implementation, we evaluated the effectiveness of the interventions, including assessments of blood glucose levels fasting blood glucose, 2-h postprandial blood glucose, and glycated hemoglobin, type A1c (HbA1c); blood pressure indicators such as diastolic blood pressure (DBP) and systolic blood pressure (SBP); quality of life as measured by the 36-item Short Form Survey (SF-36) questionnaire; and treatment adherence., Results: After 6 months, the nursing outcomes indicated that patients who underwent CGA nursing interventions experienced a significant decrease in blood glucose indicators, such as fasting blood glucose, 2-h postprandial blood glucose, and HbA1c, as well as blood pressure indicators, including DBP and SBP, compared with the control group ( P < 0.05). Quality of life assessments, including physical health, emotion, physical function, overall health, and mental health, showed marked improvements compared to the control group ( P < 0.05). In the study group, 38 patients adhered to the clinical treatment requirements, whereas only 32 in the control group adhered to the clinical treatment requirements. The probability of treatment adherence among patients receiving CGA nursing interventions was higher than that among patients receiving standard care (95% vs 80%, P < 0.05)., Conclusion: The CGA nursing intervention significantly improved glycemic control, blood pressure management, and quality of life in hospitalized older patients with diabetes and hypertension, compared to routine care., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Motivation: Gene regulatory networks (GRNs) are vital tools for delineating regulatory relationships between transcription factors and their target genes. The boom in computational biology and various biotechnologies has made inferring GRNs from multi-omics data a hot topic. However, when networks are constructed from gene expression data, they often suffer from false-positive problem due to the transitive effects of correlation. The presence of spurious noise edges obscures the real gene interactions, which makes downstream analyses, such as detecting gene function modules and predicting disease-related genes, difficult and inefficient. Therefore, there is an urgent and compelling need to develop network denoising methods to improve the accuracy of GRN inference., Results: In this study, we proposed a novel network denoising method named REverse Network Diffusion On Random walks (RENDOR). RENDOR is designed to enhance the accuracy of GRNs afflicted by indirect effects. RENDOR takes noisy networks as input, models higher-order indirect interactions between genes by transitive closure, eliminates false-positive effects using the inverse network diffusion method, and produces refined networks as output. We conducted a comparative assessment of GRN inference accuracy before and after denoising on simulated networks and real GRNs. Our results emphasized that the network derived from RENDOR more accurately and effectively captures gene interactions. This study demonstrates the significance of removing network indirect noise and highlights the effectiveness of the proposed method in enhancing the signal-to-noise ratio of noisy networks., Availability and Implementation: The R package RENDOR is provided at https://github.com/Wu-Lab/RENDOR and other source code and data are available at https://github.com/Wu-Lab/RENDOR-reproduce., (© The Author(s) 2024. Published by Oxford University Press.)

Chlorinated polyfluorinated ether sulfonate, commercially known as F-53B, has been associated with adverse birth outcomes. However, the reproductive toxicology of F-53B on the placenta remains poorly understood. To address this gap, we examined the impact of F-53B on placental injury and its underlying molecular mechanisms in vivo. Pregnant C57BL/6 J female mice were randomly allocated to three groups: the control group, F-53B 0.8 µg/kg/day group, and F-53B 8 µg/kg/day group. After F-53B exposure through free drinking water from gestational day (GD) 0.5-14.5, the F-53B 8 µg/kg/day group exhibited significant increases in placental weights and distinctive histopathological alterations, including inflammatory cell infiltration, heightened syncytiotrophoblast knots, and a loosened trophoblastic basement membrane. Within the F-53B 8 µg/kg/day group, placental tissue exhibited increased apoptosis, as indicated by increased caspase3 activation. Furthermore, F-53B potentially induced the NF-κB signaling pathway activation through IκB-α phosphorylation. Subsequently, this activation upregulated the expression of inflammatory cytokines and components of the NLRP3 inflammasome, including activated caspase1, IL-1β, IL-18, and cleaved gasdermin D (GSDMD), ultimately leading to pyroptosis in the mouse placenta. Our findings reveal a pronounced inflammatory injury in the placenta due to F-53B exposure, suggesting potential reproductive toxicity at concentrations relevant to the human population. Further toxicological and epidemiological investigations are warranted to conclusively assess the reproductive health risks posed by F-53B., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Cognitive impairment and brain atrophy are common in chronic kidney disease patients. It remains unclear whether differences in renal function, even within normal levels, influence hippocampal volume (HCV) and cognition. We aimed to investigate the association between estimated glomerular filtration rate (eGFR), HCV and cognition in outpatients., Methods: This single-center retrospective study enrolled 544 nonrenal outpatients from our hospital. All participants underwent renal function assessment and 3.0 T magnetic resonance imaging (MRI) in the same year. HCV was also measured, and cognitive assessments were obtained. The correlations between eGFR, HCV, and cognitive function were analyzed. Logistic regression analysis was performed to identify the risk factors for hippocampal atrophy and cognitive impairment. Receiver-operator curves (ROCs) were performed to find the cut-off value of HCV that predicts cognitive impairment., Results: The mean age of all participants was 66.5 ± 10.9 years. The mean eGFR of all participants was 88.5 ± 15.1 mL/min/1.73 m 2 . eGFR was positively correlated with HCV and with Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores. Univariate and multivariate logistic regression analysis showed Age ≥ 65 years, eGFR < 75 mL/min/1.73 m 2 , Glucose ≥6.1 mmol/L and combined cerebral microvascular diseases were independent risk factors for hippocampal atrophy and Age ≥ 65 years, left hippocampal volume (LHCV) <2,654 mm 3 were independent risk factors for cognitive impairment in outpatients. Although initial unadjusted logistic regression analysis indicated that a lower eGFR (eGFR < 75 mL/min/1.73 m 2 ) was associated with poorer cognitive function, this association was lost after adjusting for confounding variables. ROC curve analysis demonstrated that LHCV <2,654 mm 3 had the highest AUROC [(0.842, 95% CI: 0.808-0.871)], indicating that LHCV had a credible prognostic value with a high sensitivity and specificity for predicting cognitive impairment compared with age in outpatients., Conclusion: Higher eGFR was associated with higher HCV and better cognitive function. eGFR < 75 mL/min/1.73 m 2 was an independent risk factor for hippocampal atrophy after adjusting for age. It is suggested that even eGFR < 75 mL/min/1.73 m 2 , lower eGFR may still be associated with hippocampal atrophy, which is further associated with cognitive impairment. LHCV was a favorable prognostic marker for predicting cognitive impairment rather than age., Competing Interests: The authors declare that this study was conducted in the absence of any commercial or financial relationships that could be interpreted as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Wu, Lu, Zheng, Cui, Lu and Zhang.)

Up to 80% of Parkinson's disease patients develop dementia, but time to dementia varies widely from motor symptom onset. Dementia with Lewy bodies presents with clinical features similar to Parkinson's disease dementia, but cognitive impairment precedes or coincides with motor onset. It remains controversial whether dementia with Lewy bodies and Parkinson's disease dementia are distinct conditions or represent part of a disease spectrum. The biological mechanisms underlying disease heterogeneity, in particular the development of dementia, remain poorly understood, but will likely be the key to understanding disease pathways and, ultimately, therapy development. Previous genome-wide association studies in Parkinson's disease and dementia with Lewy bodies/Parkinson's disease dementia have identified risk loci differentiating patients from controls. We collated data for 7804 patients of European ancestry from Tracking Parkinson's, The Oxford Discovery Cohort, and Accelerating Medicine Partnership-Parkinson's Disease Initiative. We conducted a discrete phenotype genome-wide association study comparing Lewy body diseases with and without dementia to decode disease heterogeneity by investigating the genetic drivers of dementia in Lewy body diseases. We found that risk allele rs429358 tagging APOEe4 increases the odds of developing dementia, and that rs7668531 near the MMRN1 and SNCA-AS1 genes and an intronic variant rs17442721 tagging LRRK2 G2019S on chromosome 12 are protective against dementia. These results should be validated in autopsy-confirmed cases in future studies., Competing Interests: H.R.M. is employed by UCL. In the last 12 months, he reports paid consultancy from Roche, Aprinoia, AI Therapeutics and Amylyx; lecture fees/honoraria from BMJ, Kyowa Kirin and Movement Disorders Society; and research grants from Parkinson's UK, Cure Parkinson's Trust, PSP Association, Medical Research Council and Michael J. Fox Foundation. H.R.M. is a co-applicant on a patent application related to C9ORF72—Method for diagnosing a neurodegenerative disease (PCT/GB2012/052140)., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Melanoma is commonly diagnosed in a younger population than most other solid malignancies and, in Australia and most of the world, is the leading cause of skin-cancer-related death. Melanoma is a cancer type with high immunogenicity; thus, immunotherapies are used as first-line treatment for advanced melanoma patients. Although immunotherapies are working well, not all the patients are benefitting from them. A lack of a comprehensive understanding of immune regulation in the melanoma tumour microenvironment is a major challenge of patient stratification. Overexpression of CD155 has been reported as a key factor in melanoma immune regulation for the development of therapy resistance. A more thorough understanding of the actions of current immunotherapy strategies, their effects on immune cell subsets, and the roles that CD155 plays are essential for a rational design of novel targets of anti-cancer immunotherapies. In this review, we comprehensively discuss current anti-melanoma immunotherapy strategies and the immune response contribution of different cell lineages, including tumour endothelial cells, myeloid-derived suppressor cells, cytotoxic T cells, cancer-associated fibroblast, and nature killer cells. Finally, we explore the impact of CD155 and its receptors DNAM-1, TIGIT, and CD96 on immune cells, especially in the context of the melanoma tumour microenvironment and anti-cancer immunotherapies.

Background: Understanding the molecular mechanisms of Alzheimer's disease (AD) has important clinical implications for guiding therapy. Impaired amyloid beta (Aβ) clearance is critical in the pathogenesis of sporadic AD, and blood monocytes play an important role in Aβ clearance in the periphery. However, the mechanism underlying the defective phagocytosis of Aβ by monocytes in AD remains unclear., Methods: Initially, we collected whole blood samples from sporadic AD patients and isolated the monocytes for RNA sequencing analysis. By establishing APP/PS1 transgenic model mice with monocyte-specific cystatin F overexpression, we assessed the influence of monocyte-derived cystatin F on AD development. We further used a nondenaturing gel to identify the structure of the secreted cystatin F in plasma. Flow cytometry, enzyme-linked immunosorbent assays and laser scanning confocal microscopy were used to analyse the internalization of Aβ by monocytes. Pull down assays, bimolecular fluorescence complementation assays and total internal reflection fluorescence microscopy were used to determine the interactions and potential interactional amino acids between the cystatin F protein and Aβ. Finally, the cystatin F protein was purified and injected via the tail vein into 5XFAD mice to assess AD pathology., Results: Our results demonstrated that the expression of the cystatin F protein was specifically increased in the monocytes of AD patients. Monocyte-derived cystatin F increased Aβ deposition and exacerbated cognitive deficits in APP/PS1 mice. Furthermore, secreted cystatin F in the plasma of AD patients has a dimeric structure that is closely related to clinical signs of AD. Moreover, we noted that the cystatin F dimer blocks the phagocytosis of Aβ by monocytes. Mechanistically, the cystatin F dimer physically interacts with Aβ to inhibit its recognition and internalization by monocytes through certain amino acid interactions between the cystatin F dimer and Aβ. We found that high levels of the cystatin F dimer protein in blood contributed to amyloid pathology and cognitive deficits as a risk factor in 5XFAD mice., Conclusions: Our findings highlight that the cystatin F dimer plays a crucial role in regulating Aβ metabolism via its peripheral clearance pathway, providing us with a potential biomarker for diagnosis and potential target for therapeutic intervention., (© 2024. The Author(s).)

Background: Adverse drug reactions (ADRs), which are the phenotypic manifestations of clinical drug toxicity in humans, are a major concern in precision clinical medicine. A comprehensive evaluation of ADRs is helpful for unbiased supervision of marketed drugs and for discovering new drugs with high success rates., Objective: In current practice, drug safety evaluation is often oversimplified to the occurrence or nonoccurrence of ADRs. Given the limitations of current qualitative methods, there is an urgent need for a quantitative evaluation model to improve pharmacovigilance and the accurate assessment of drug safety., Methods: In this study, we developed a mathematical model, namely the Adverse Drug Reaction Classification System (ADReCS) severity-grading model, for the quantitative characterization of ADR severity, a crucial feature for evaluating the impact of ADRs on human health. The model was constructed by mining millions of real-world historical adverse drug event reports. A new parameter called Severity&#95;score was introduced to measure the severity of ADRs, and upper and lower score boundaries were determined for 5 severity grades., Results: The ADReCS severity-grading model exhibited excellent consistency (99.22%) with the expert-grading system, the Common Terminology Criteria for Adverse Events. Hence, we graded the severity of 6277 standard ADRs for 129,407 drug-ADR pairs. Moreover, we calculated the occurrence rates of 6272 distinct ADRs for 127,763 drug-ADR pairs in large patient populations by mining real-world medication prescriptions. With the quantitative features, we demonstrated example applications in systematically elucidating ADR mechanisms and thereby discovered a list of drugs with improper dosages., Conclusions: In summary, this study represents the first comprehensive determination of both ADR severity grades and ADR frequencies. This endeavor establishes a strong foundation for future artificial intelligence applications in discovering new drugs with high efficacy and low toxicity. It also heralds a paradigm shift in clinical toxicity research, moving from qualitative description to quantitative evaluation., (©Qi-Xuan Yue, Ruo-Fan Ding, Wei-Hao Chen, Lv-Ying Wu, Ke Liu, Zhi-Liang Ji. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 03.05.2024.)

Exercise has beneficial effects on emotional cognitive control for the majority of the population. However, the impact of exercise on cognitive processes in perimenopausal women remains unclear. Therefore, this study investigated the effect of aerobic exercise on the cognitive processes of perimenopausal women using an emotional Stroop task (EST)., Method: A quasi-experimental pilot study was conducted involving 14 perimenopausal women (Peri-MG) and 13 healthy young women (YG) who completed an EST before and after an aerobic cycling exercise. Mixed-effects models for repeated measures were used to analyze reaction times (RTs) and error rates (ERs) during emotional word processing (positive, negative, and neutral) for both groups., Results: Compared with the YG, the Peri-MG showed significantly shortened RTs for positive and negative emotions ( p < 0.05) post-exercise, but not for neutral words. In addition, the Peri-MG exhibited significantly increased ERs for negative words at baseline compared with the YG ( p < 0.05), but this difference was not observed during the post-exercise test., Conclusion: The findings suggest that aerobic exercise can enhance executive control performance in perimenopausal women. The Peri-MG exhibited marked behavioral plasticity in the form of reduced bias to salient cues that were significantly more sensitive to alterations due to exercise. This new evidence enhances the understanding of emotional vulnerability and beneficial susceptibility to exercise in perimenopausal women.

Background: As most viruses remain uncultivated, metagenomics is currently the main method for virus discovery. Detecting viruses in metagenomic data is not trivial. In the past few years, many bioinformatic virus identification tools have been developed for this task, making it challenging to choose the right tools, parameters, and cutoffs. As all these tools measure different biological signals, and use different algorithms and training and reference databases, it is imperative to conduct an independent benchmarking to give users objective guidance., Results: We compare the performance of nine state-of-the-art virus identification tools in thirteen modes on eight paired viral and microbial datasets from three distinct biomes, including a new complex dataset from Antarctic coastal waters. The tools have highly variable true positive rates (0-97%) and false positive rates (0-30%). PPR-Meta best distinguishes viral from microbial contigs, followed by DeepVirFinder, VirSorter2, and VIBRANT. Different tools identify different subsets of the benchmarking data and all tools, except for Sourmash, find unique viral contigs. Performance of tools improved with adjusted parameter cutoffs, indicating that adjustment of parameter cutoffs before usage should be considered., Conclusions: Together, our independent benchmarking facilitates selecting choices of bioinformatic virus identification tools and gives suggestions for parameter adjustments to viromics researchers., (© 2024. The Author(s).)

Background and Aims: We aimed to define gender-specific, optimal alanine aminotransferase (ALT) cut-off values for the prediction of significant liver histological changes (SLHC) in Chinese patients with grey zone (GZ) chronic hepatitis B (CHB) and normal ALT., Methods: In a retrospective study, we included 1101 consecutive patients with GZ CHB and normal ALT assigned to training or internal validation cohorts. We included an independent cohort of 842 patients for external validation. We performed receiver operating characteristic (ROC) curve, smoothed curve fitting, and threshold effect analyses to determine optimal ALT cut-off values. Area under the curve (AUC) values were calculated to assess their predictive performance., Results: A proportion of 79.3% of patients with GZ CHB and normal ALT (≤40 U/L) had SLHC. ROC curve analysis initially identified optimal ALT cut-off values of 29 U/L (male) and 22 U/L (female). After smoothed curve fitting and threshold effect analyses, new optimal cut-off values were 27 U/L for males and 24 U/L for females. AUCs for these values were 0.836 (male) and 0.833 (female) in the internal validation cohort, and 0.849 (male) and 0.844 (female) in the external validation cohort. The accuracy and discriminative ability of the newly defined ALT cut-off values were greater than those of the current recommendations., Conclusion: This study established novel optimal ALT cut-off values for more precise prediction of SLHC among Chinese patients with GZ CHB and normal ALT levels. This may help identify individuals who will benefit from timely antiviral therapy., (© 2024 John Wiley & Sons Ltd.)

Background: Currently, there has been observed a significant alteration in the composition of the gut microbiome (GM) and serum metabolites in patients with psoriatic arthritis (PsA) compared to healthy individuals. However, previous observational studies have shown inconsistent results regarding the alteration of gut microbiota/metabolites. In order to shed light on this matter, we utilized Mendelian randomization to determine the causal effect of GM/metabolites on PsA., Methods: We retrieved summary-level data of GM taxa/metabolites and PsA from publicly available GWAS statistics. Causal relationships between GM/metabolites and PsA were determined using a two-sample MR analysis, with the IVW approach serving as the primary analysis method. To ensure the robustness of our findings, we conducted sensitivity analyses, multivariable MR analysis (MVMR), and additional analysis including replication verification analysis, LDSC regression, and Steiger test analysis. Furthermore, we investigated reverse causality through a reverse MR analysis. Finally, we conducted an analysis of expression quantitative trait loci (eQTLs) involved in the metabolic pathway to explore potential molecular mechanisms of metabolism., Results: Our findings reveal that eight GM taxa and twenty-three serum metabolites are causally related to PsA ( P < 0.05). Notably, a higher relative abundance of Family Rikenellaceae (OR IVW : 0.622, 95% CI: 0.438-0.883, FDR = 0.045) and elevated serum levels of X-11538 (OR IVW : 0.442, 95% CI: 0.250-0.781, FDR = 0.046) maintain significant causal associations with a reduced risk of PsA, even after adjusting for multiple testing correction and conducting MVMR analysis. These findings suggest that Family Rikenellaceae and X-11538 may have protective effects against PsA. Our sensitivity analysis and additional analysis revealed no significant horizontal pleiotropy, reverse causality, or heterogeneity. The functional enrichment analysis revealed that the eQTLs examined were primarily associated with glycerolipid metabolism and the expression of key metabolic factors influenced by bacterial infections ( Vibrio cholerae and Helicobacter pylori ) as well as the mTOR signaling pathway., Conclusion: In conclusion, our study demonstrates that Family Rikenellacea e and X-11538 exhibit a strong and negative causal relationship with PsA. These particular GM taxa and metabolites have the potential to serve as innovative biomarkers, offering valuable insights into the treatment and prevention of PsA. Moreover, bacterial infections and mTOR-mediated activation of metabolic factors may play an important role in this process., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xu, Wu, Wang, Yan, Wang, Li, Sun and Zhao.)

Purpose: To improve the effectivity of patient-specific finite element analysis (FEA) to predict refractive power change (RPC) in rigid Ortho-K contact lens fitting. Novel eyelid boundary detection is introduced to the FEA model to better model the effects of the lid on lens performance, and stress and strain outcomes are investigated to identify the most effective FEA components to use in modelling., Methods: The current study utilises fully anonymised records of 249 eyes, 132 right eyes, and 117 left eyes from subjects aged 14.1 ± 4.0 years on average (range 9 to 38 years), which were selected for secondary analysis processing. A set of custom-built MATLAB codes was built to automate the process from reading Medmont E300 height and distance files to processing and displaying FEA stress and strain outcomes. Measurements from before and after contact lens wear were handled to obtain the corneal surface change in shape and power. Tangential refractive power maps were constructed from which changes in refractive power pre- and post-Ortho-K wear were determined as the refractive power change (RPC). A total of 249 patient-specific FEA with innovative eyelid boundary detection and 3D construction analyses were automatically built and run for every anterior eye and lens combination while the lens was located in its clinically detected position. Maps of four stress components: contact pressure, Mises stress, pressure, and maximum principal stress were created in addition to maximum principal logarithmic strain maps. Stress and strain components were compared to the clinical RPC maps using the two-dimensional (2D) normalised cross-correlation and structural similarity (SSIM) index measure., Results: On the one hand, the maximum principal logarithmic strain recorded the highest moderate 2D cross-correlation area of 8.6 ± 10.3%, and contact pressure recorded the lowest area of 6.6 ± 9%. Mises stress recorded the second highest moderate 2D cross-correlation area with 8.3 ± 10.4%. On the other hand, when the SSIM index was used to compare the areas that were most similar to the clinical RPC, maximum principal stress was the most similar, with an average strong similarity percentage area of 26.5 ± 3.3%, and contact pressure was the least strong similarity area of 10.3 ± 7.3%. Regarding the moderate similarity areas, all components were recorded at around 34.4% similarity area except the contact pressure, which was down to 32.7 ± 5.8%., Conclusions: FEA is an increasingly effective tool in being able to predict the refractive outcome of Ortho-K treatment. Its accuracy depends on identifying which clinical and modelling metrics contribute to the most accurate prediction of RPC with minimal ocular complications. In terms of clinical metrics, age, Intra-ocular pressure (IOP), central corneal thickness (CCT), surface topography, lens decentration and the 3D eyelid effect are all important for effective modelling. In terms of FEA components, maximum principal stress was found to be the best FEA barometer that can be used to predict the performance of Ortho-K lenses. In contrast, contact pressure provided the worst stress performance. In terms of strain, the maximum principal logarithmic strain was an effective strain barometer.

Single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq) data provided new insights into the understanding of epigenetic heterogeneity and transcriptional regulation. With the increasing abundance of dataset resources, there is an urgent need to extract more useful information through high-quality data analysis methods specifically designed for scATAC-seq. However, analyzing scATAC-seq data poses challenges due to its near binarization, high sparsity and ultra-high dimensionality properties. Here, we proposed a novel network diffusion-based computational method to comprehensively analyze scATAC-seq data, named Single-Cell ATAC-seq Analysis via Network Refinement with Peaks Location Information (SCARP). SCARP formulates the Network Refinement diffusion method under the graph theory framework to aggregate information from different network orders, effectively compensating for missing signals in the scATAC-seq data. By incorporating distance information between adjacent peaks on the genome, SCARP also contributes to depicting the co-accessibility of peaks. These two innovations empower SCARP to obtain lower-dimensional representations for both cells and peaks more effectively. We have demonstrated through sufficient experiments that SCARP facilitated superior analyses of scATAC-seq data. Specifically, SCARP exhibited outstanding cell clustering performance, enabling better elucidation of cell heterogeneity and the discovery of new biologically significant cell subpopulations. Additionally, SCARP was also instrumental in portraying co-accessibility relationships of accessible regions and providing new insight into transcriptional regulation. Consequently, SCARP identified genes that were involved in key Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways related to diseases and predicted reliable cis-regulatory interactions. To sum up, our studies suggested that SCARP is a promising tool to comprehensively analyze the scATAC-seq data., (© The Author(s) 2024. Published by Oxford University Press.)

In the brain, the extracellular matrix (ECM) composition shapes the neuronal microenvironment and can undergo substantial changes with cerebral pathology. Brevican is integral to the formation of the ECM's neuroprotective perineuronal nets (PNNs). Decreased brevican levels were reported in vascular dementia (VaD) but not in Alzheimer's disease (AD). However, the status of brevican in clinical cohorts with high concomitance of AD pathological burden and cerebrovascular disease (CeVD) is unclear. In this study, 32 non-cognitively impaired (NCI), 97 cognitively impaired no dementia (CIND), 46 AD, and 23 VaD participants recruited from memory clinics based in Singapore underwent neuropsychological and neuroimaging assessments, together with measurements of serum brevican. Association analyses were performed between serum brevican and neuroimaging measures of CeVDs, including white matter hyperintensities (WMHs), lacunes, cortical infarcts, and cerebral microbleeds. Using an aggregated score for CeVD burden, only CIND participants showed lower brevican levels with higher CeVD compared to those with lower CeVD burden ( p = 0.006). Among the CeVD subtypes assessed, only elevated WMH burden was associated with lower brevican levels (OR = 2.7; 95% CI = 1.3-5.5). Our findings suggest that brevican deficits may play a role in early cerebrovascular damage in participants at risk of developing dementia.

Objectives: This study was performed to explore the preventive and therapeutic effects of Lactobacillus plantarum ZFM4 on H. pylori infections of the stomach tissue in C57BL/6 mice., Methods: In this study, 40 specific-pathogen-free female C57BL/6 mice were randomly divided into five groups, namely, the control, ZFM4 pretreatment) ZFM4 pretreatment before H. pylori infected), model ( H. pylori infected), triple therapy ( H. pylori infected and treated with triple therapy), and ZFM4 treatment groups ( H. pylori infected and treated with ZFM4). The preventive and therapeutic effects of Lactobacillus plantarum ZFM4 were evaluated in H. pylori- infected C57BL/6 mice by assessing gastric tissue morphology, inflammatory cytokine levels, microbial composition, and microbial diversity., Results: Lactobacillus plantarum ZFM4 was able to survive in low gastric pH and play a role in preventing H. pylori infection. This was evident from a reduction in both, the gastric inflammatory response and expression of inflammatory factors caused by H. pylori infection. Lactobacillus plantarum ZFM4 could also inhibit the growth of H. pylori via its beneficial impact on the gastric microbiota., Conclusion: Our findings suggest that Lactobacillus plantarum ZFM4 offers superior preventive effects against H. pylori infections when used alone. However, the therapeutic effect on established infections is weaker. Further clinical trials are needed to confirm the specific dosage, duration, and other aspects of administration., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yu, Wu, Sun, Gu and Zhou.)

Probiotics, live microorganisms that confer health benefits to the host when administered in adequate amounts, have gained considerable attention for their potential role in maintaining women's health. This overview summarizes key clinical findings on the beneficial effects of probiotics in various aspects of women's health. Probiotics, particularly Lactobacillus species, contribute to vaginal health by promoting a balanced vaginal microbiome to prevent infections and maintain an acidic environment. In gynecologic conditions, probiotics show potential in preventing and managing bacterial vaginosis, vulvovaginal candidiasis, and sexually transmitted infections. Probiotic supplementation has also been associated with improvements in metabolic parameters and menstrual irregularities in polycystic ovary syndrome patients. During pregnancy, probiotics may be helpful in reducing the risk of gestational diabetes, maternal group B streptococcal colonization, obstetric anemia, and postpartum mastitis. In recent years, the potential role of probiotics in the prevention and management of gynecologic cancer has gained attention. Further research is needed to better understand the specific mechanisms and determine the optimal Lactobacillus strains and dosages regimens for gynecologic cancer prevention and therapy. In conclusion, probiotics offer a non-invasive and cost-effective approach to support women's health and prevent obstetric and gynecologic complications., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2023. Published by Elsevier B.V.)

Myelodysplastic syndrome (MDS) is a group of clonal hematopoietic neoplasms originating from hematopoietic stem progenitor cells (HSPCs). We previously identified frequent roundabout guidance receptor 1 ( ROBO1 ) mutations in patients with MDS, while the exact role of ROBO1 in hematopoiesis remains poorly delineated. Here, we report that ROBO1 deficiency confers MDS-like disease with anemia and multilineage dysplasia in mice and predicts poor prognosis in patients with MDS. More specifically, Robo1 deficiency impairs HSPC homeostasis and disrupts HSPC pool, especially the reduction of megakaryocyte erythroid progenitors, which causes a blockage in the early stages of erythropoiesis in mice. Mechanistically, transcriptional profiling indicates that Cdc42 , a member of the Rho-guanosine triphosphatase family, acts as a downstream target gene for Robo1 in HSPCs. Overexpression of Cdc42 partially restores the self-renewal and erythropoiesis of HSPCs in Robo1 -deficient mice. Collectively, our result implicates the essential role of ROBO1 in maintaining HSPC homeostasis and erythropoiesis via CDC42 .

Transforming growth factor-beta 2 (TGF-β2), an important member of the TGF-β family, is a secreted protein that is involved in many biological processes, such as cell growth, proliferation, migration, and differentiation. TGF-β2 had been thought to be functionally identical to TGF-β1; however, an increasing number of recent studies uncovered the distinctive features of TGF-β2 in terms of its expression, activation, and biological functions. Mice deficient in TGF-β2 showed remarkable developmental abnormalities in multiple organs, especially the cardiovascular system. Dysregulation of TGF-β2 signalling was associated with tumorigenesis, eye diseases, cardiovascular diseases, immune disorders, as well as motor system diseases. Here, we provide a comprehensive review of the research progress in TGF-β2 to support further research on TGF-β2.

Because of the limited effectiveness of prevailing phylogenetic methods when applied to highly divergent protein sequences, the phylogenetic analysis problem remains challenging. Here, we propose a sequence-based evolutionary distance algorithm termed sequence distance (SD), which innovatively incorporates site-to-site correlation within protein sequences into the distance estimation. In protein superfamilies, SD can effectively distinguish evolutionary relationships both within and between protein families, producing phylogenetic trees that closely align with those based on structural information, even with sequence identity less than 20%. SD is highly correlated with the similarity of the protein structure, and can calculate evolutionary distances for thousands of protein pairs within seconds using a single CPU, which is significantly faster than most protein structure prediction methods that demand high computational resources and long run times. The development of SD will significantly advance phylogenetics, providing researchers with a more accurate and reliable tool for exploring evolutionary relationships., (© 2023. The Author(s).)

Background: In the field of biology and medicine, the interpretability and accuracy are both important when designing predictive models. The interpretability of many machine learning models such as neural networks is still a challenge. Recently, many researchers utilized prior information such as biological pathways to develop neural networks-based methods, so as to provide some insights and interpretability for the models. However, the prior biological knowledge may be incomplete and there still exists some unknown information to be explored., Results: We proposed a novel method, named PathExpSurv, to gain an insight into the black-box model of neural network for cancer survival analysis. We demonstrated that PathExpSurv could not only incorporate the known prior information into the model, but also explore the unknown possible expansion to the existing pathways. We performed downstream analyses based on the expanded pathways and successfully identified some key genes associated with the diseases and original pathways., Conclusions: Our proposed PathExpSurv is a novel, effective and interpretable method for survival analysis. It has great utility and value in medical diagnosis and offers a promising framework for biological research., (© 2023. The Author(s).)

Background: Previous studies have shown that F-53B exposure may be neurotoxic to animals, but there is a lack of epidemiological evidence, and its mechanism needs further investigation., Methods: Serum F-53B concentrations and Wisconsin Card Sorting Test (WCST) were evaluated in 314 growing children from Guangzhou, China, and the association between them were analyzed. To study the developmental neurotoxicity of F-53B, experiments on sucking mice exposed via placental transfer and breast milk was performed. Maternal mice were orally exposed to 4, 40, and 400 μg/L of F-53B from postnatal day 0 (GD0) to postnatal day 21 (PND 21). Several genes and proteins related to neurodevelopment, dopamine anabolism, and synaptic plasticity were examined by qPCR and western blot, respectively, while dopamine contents were detected by ELISA kit in weaning mice., Results: The result showed that F-53B was positively associated with poor WCST performance. For example, with an interquartile range increase in F-53B, the change with 95 % confidence interval (CI) of correct response (CR), and non-perseverative errors (NPE) was -2.47 (95 % CI: -3.89, -1.05, P = 0.001), 2.78 (95 % CI: 0.79, 4.76, P = 0.007), respectively. Compared with the control group, the highest exposure group of weaning mice had a longer escape latency (35.24 s vs. 51.18 s, P = 0.034) and a lesser distance movement (34.81 % vs. 21.02 %, P < 0.001) in the target quadrant, as observed from morris water maze (MWM) test. The protein expression of brain-derived neurotrophic factor (BDNF) and growth associated protein-43 (GAP-43) levels were decreased, as compared to control (0.367-fold, P < 0.001; 0.366-fold, P < 0.001; respectively). We also observed the upregulation of dopamine transporter (DAT) (2.940-fold, P < 0.001) consistent with the trend of dopamine content (1.313-fold, P < 0.001) in the hippocampus., Conclusion: Early life exposure to F-53B is associated with adverse neurobehavioral changes in developing children and weaning mice which may be modulated by dopamine-dependent synaptic plasticity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Through infection and lysis of their coexisting bacterial hosts, viruses impact the biogeochemical cycles sustaining globally significant pelagic oceanic ecosystems. Currently, little is known of the ecological interactions between lytic viruses and their bacterial hosts underlying these biogeochemical impacts at ecosystem scales. This study focused on populations of lytic viruses carrying the B 12 -dependent Class II monomeric ribonucleotide reductase (RNR) gene, ribonucleotide-triphosphate reductase (Class II RTPR), documenting seasonal changes in pelagic virioplankton and bacterioplankton using amplicon sequences of Class II RTPR and the 16S rRNA gene, respectively. Amplicon sequence libraries were analyzed using compositional data analysis tools that account for the compositional nature of these data. Both virio- and bacterioplankton communities responded to environmental changes typically seen across seasonal cycles as well as shorter term upwelling-downwelling events. Defining Class II RTPR-carrying viral populations according to major phylogenetic clades proved a more robust means of exploring virioplankton ecology than operational taxonomic units defined by percent sequence homology. Virioplankton Class II RTPR populations showed positive associations with a broad phylogenetic diversity of bacterioplankton including dominant taxa within pelagic oceanic ecosystems such as Prochlorococcus and SAR11. Temporal changes in Class II RTPR virioplankton, occurring as both free viruses and within infected cells, indicated possible viral-host pairs undergoing sustained infection and lysis cycles throughout the seasonal study. Phylogenetic relationships inferred from Class II RTPR sequences mirrored ecological patterns in virio- and bacterioplankton populations demonstrating possible genome to phenome associations for an essential viral replication gene., (© 2023. ISME Publications B.V.)

The bone marrow microenvironment (BMM) can regulate leukemia stem cells (LSCs) via secreted factors. Increasing evidence suggests that dissecting the mechanisms by which the BMM maintains LSCs may lead to the development of effective therapies for the eradication of leukemia. Inhibitor of DNA binding 1 (ID1), a key transcriptional regulator in LSCs, previously identified by us, controls cytokine production in the BMM, but the role of ID1 in acute myeloid leukemia (AML) BMM remains obscure. Here, we report that ID1 is highly expressed in the BMM of patients with AML, especially in BM mesenchymal stem cells, and that the high expression of ID1 in the AML BMM is induced by BMP6, secreted from AML cells. Knocking out ID1 in mesenchymal cells significantly suppresses the proliferation of cocultured AML cells. Loss of Id1 in the BMM results in impaired AML progression in AML mouse models. Mechanistically, we found that Id1 deficiency significantly reduces SP1 protein levels in mesenchymal cells cocultured with AML cells. Using ID1-interactome analysis, we found that ID1 interacts with RNF4, an E3 ubiquitin ligase, and causes a decrease in SP1 ubiquitination. Disrupting the ID1-RNF4 interaction via truncation in mesenchymal cells significantly reduces SP1 protein levels and delays AML cell proliferation. We identify that the target of Sp1, Angptl7, is the primary differentially expression protein factor in Id1-deficient BM supernatant fluid to regulate AML progression in mice. Our study highlights the critical role of ID1 in the AML BMM and aids the development of therapeutic strategies for AML., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Objective: This study was designed to investigate the efficacy and prognostic factors for immune checkpoint inhibitors (ICIs) combined with or without radio(chemo)therapy and to evaluate their toxicity in patients with locally advanced or recurrent/metastatic esophageal squamous cell carcinoma (LA/RM ESCC)., Methods: In this study, 198 patients with locally advanced or recurrent/metastatic (LA/RM) ESCC who received ICIs combined with or without radiotherapy/chemotherapy in the Department of Radiotherapy of the Fourth Hospital of Hebei Medical University were retrospectively analyzed. Univariate and multivariate analyses were performed to determine the prognostic factors for overall survival (OS) and progression free survival (PFS). The factors affecting treatment response and the occurrences of treatment-related adverse events (trAEs) were analyzed., Results: The median OS and PFS were 30.4 months (95% confidence interval [CI] 15.1-45.7 months) and 15.3 months (95% CI 12.8-17.8 months), respectively. Univariate and multivariate analysis showed that the number of ICI cycles, the intervention of radiotherapy and dysphagia were independent factors affecting OS (Hazard ratio [HR] = 0.39, 2.043 and 0.365, respectively; P = 0.018, 0.001 and 0.032, respectively). The intervention of radiotherapy was an independent factor for PFS (hazard ratio [HR] = 18.149, P = 0.013). The median OS and PFS for patients who had complete response and partial response (Objective response, ORR) were 50.8 months (95% CI 25.8-75.7 months) and 20.5 months (95% CI 14.1-27.0), respectively, which were significantly higher than those in the non-ORR group (OS non-ORR :17.5 months, 95% CI 14.0-21.0; χ 2  = 13.881, P < 0.001; PFS non-ORR : 12.1 months, 95% CI 10.1-14.1, χ 2  = 10.676, P = 0.001). The intervention of radiotherapy could improve treatment response (χ 2  = 47.725, P = 0.000). In entire study population, 83 patients (41.9%) had ≥ grade 2 trAEs., Conclusions: ICIs combined with radiotherapy/chemotherapy are safe and effective in LA/RM ESCC patients. Intervention of radiotherapy, the number of immunotherapy cycles and occurrence of dysphagia affecting the overall survival of LR/RM ESCC patients. Intervention of radiotherapy was an independent prognosis factor for OS and PFS and associated with better treatment response., (© 2023. Springer Science+Business Media, LLC.)

Background: The phagocytosis and homeostasis of microglia play an important role in promoting blood clearance and improving prognosis after subarachnoid hemorrhage (SAH). LC3-assocaited phagocytosis (LAP) contributes to the microglial phagocytosis and homeostasis via autophagy-related components. With RNA-seq sequencing, we found potential signal pathways and genes which were important for the LAP of microglia., Methods: We used an in vitro model of oxyhemoglobin exposure as SAH model in the study. RNA-seq sequencing was performed to seek critical signal pathways and genes in regulating LAP. Bioparticles were used to access the phagocytic ability of microglia. Western blot (WB), immunoprecipitation, quantitative polymerase chain reaction (qPCR) and immunofluorescence were performed to detect the expression change of LAP-related components and investigate the potential mechanisms., Results: In vitro SAH model, there were increased inflammation and decreased phagocytosis in microglia. At the same time, we found that the LAP of microglia was inhibited in all stages. RNA-seq sequencing revealed the importance of P38 MAPK signal pathway and DAPK1 in regulating microglial LAP. P38 was found to regulate the expression of DAPK1, and P38-DAPK1 axis was identified to regulate the LAP and homeostasis of microglia after SAH. Finally, we found that P38-DAPK1 axis regulated expression of BECN1, which indicated the potential mechanism of P38-DAPK1 axis regulating microglial LAP., Conclusion: P38-DAPK1 axis regulated the LAP of microglia via BECN1, affecting the phagocytosis and homeostasis of microglia in vitro SAH model. Video Abstract., (© 2023. The Author(s).)

K V channel-interacting proteins (KChIP1-4) belong to a family of Ca 2+ -binding EF-hand proteins that are able to bind to the N-terminus of the K V 4 channel α-subunits. KChIPs are predominantly expressed in the brain and heart, where they contribute to the maintenance of the excitability of neurons and cardiomyocytes by modulating the fast inactivating-K V 4 currents. As the auxiliary subunit, KChIPs are critically involved in regulating the surface protein expression and gating properties of K V 4 channels. Mechanistically, KChIP1, KChIP2, and KChIP3 promote the translocation of K V 4 channels to the cell membrane, accelerate voltage-dependent activation, and slow the recovery rate of inactivation, which increases K V 4 currents. By contrast, KChIP4 suppresses K V 4 trafficking and eliminates the fast inactivation of K V 4 currents. In the heart, I Ks , I Ca,L , and I Na can also be regulated by KChIPs. I Ca,L and I Na are positively regulated by KChIP2, whereas I Ks is negatively regulated by KChIP2. Interestingly, KChIP3 is also known as downstream regulatory element antagonist modulator (DREAM) because it can bind directly to the downstream regulatory element (DRE) on the promoters of target genes that are implicated in the regulation of pain, memory, endocrine, immune, and inflammatory reactions. In addition, all the KChIPs can act as transcription factors to repress the expression of genes involved in circadian regulation. Altered expression of KChIPs has been implicated in the pathogenesis of several neurological and cardiovascular diseases. For example, KChIP2 is decreased in failing hearts, while loss of KChIP2 leads to increased susceptibility to arrhythmias. KChIP3 is increased in Alzheimer's disease and amyotrophic lateral sclerosis, but decreased in epilepsy and Huntington's disease. In the present review, we summarize the progress of recent studies regarding the structural properties, physiological functions, and pathological roles of KChIPs in both health and disease. We also summarize the small-molecule compounds that regulate the function of KChIPs. This review will provide an overview and update of the regulatory mechanism of the KChIP family and the progress of targeted drug research as a reference for researchers in related fields.

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease, resulting in a huge socio-economic impact. Kidney is a highly complex organ and the pathogenesis underlying kidney organization involves complex cell-to-cell interaction within the heterogeneous kidney milieu. Advanced single-cell RNA sequencing (scRNA-seq) could reveal the complex architecture and interaction with the microenvironment in early DKD. We used scRNA-seq to investigate early changes in the kidney of db/m mice and db/db mice at the 14th week. Uniform Manifold Approximation and Projection were applied to classify cells into different clusters at a proper resolution. Weighted gene co-expression network analysis was used to identify the key molecules specifically expressed in kidney tubules. Information of cell-cell communication within the kidney was obtained using receptor-ligand pairing resources. In vitro model, human subjects, and co-detection by indexing staining were used to identify the pathophysiologic role of the hub genes in DKD. Among four distinct subsets of the proximal tubule (PT), lower percentages of proliferative PT and PT containing AQP4 expression (PT AQP4+ ) in db/db mice induced impaired cell repair activity and dysfunction of renin-angiotensin system modulation in early DKD. We found that ferroptosis was involved in DKD progression, and ceruloplasmin acted as a central regulator of the induction of ferroptosis in PT AQP4+ . In addition, lower percentages of thick ascending limbs and collecting ducts with impaired metabolism function were also critical pathogenic features in the kidney of db/db mice. Secreted phosphoprotein 1 (SPP1) mediated pathogenic cross-talk in the tubular microenvironment, as validated by a correlation between urinary SPP1/Cr level and tubular injury. Finally, mesangial cell-derived semaphorin 3C (SEMA3C) further promoted endothelium-mesenchymal transition in glomerular endothelial cells through NRP1 and NRP2, and urinary SEMA3C/Cr level was positively correlated with glomerular injury. These data identified the hub genes involved in pathophysiologic changes within the microenvironment of early DKD., (© 2023. The Author(s).)

Border management serves as a crucial control checkpoint for governments to regulate the quality and safety of imported food. In 2020, the first-generation ensemble learning prediction model (EL V.1) was introduced to Taiwan's border food management. This model primarily assesses the risk of imported food by combining five algorithms to determine whether quality sampling should be performed on imported food at the border. In this study, a second-generation ensemble learning prediction model (EL V.2) was developed based on seven algorithms to enhance the "detection rate of unqualified cases" and improve the robustness of the model. In this study, Elastic Net was used to select the characteristic risk factors. Two algorithms were used to construct the new model: The Bagging-Gradient Boosting Machine and Bagging-Elastic Net. In addition, F β was used to flexibly control the sampling rate, improving the predictive performance and robustness of the model. The chi-square test was employed to compare the efficacy of "pre-launch (2019) random sampling inspection" and "post-launch (2020-2022) model prediction sampling inspection". For cases recommended for inspection by the ensemble learning model and subsequently inspected, the unqualified rates were 5.10%, 6.36%, and 4.39% in 2020, 2021, and 2022, respectively, which were significantly higher ( p < 0.001) compared with the random sampling rate of 2.09% in 2019. The prediction indices established by the confusion matrix were used to further evaluate the prediction effects of EL V.1 and EL V.2, and the EL V.2 model exhibited superior predictive performance compared with EL V.1, and both models outperformed random sampling.

As a toxic heavy metal, cadmium (Cd) is one of the principal pollutants influencing rice productivity and food security. Despite several studies, the underlying mechanism of Cd response in plants remains largely unclear. Dehydrins are part of the late embryogenesis abundant (LEA) family which protect plants against abiotic stresses. In this study, a Cd-responsive LEA gene, OsDHN2, was functionally characterized. The chromosome localization results indicated that OsDHN2 was located on chromosome 2 of rice. Meanwhile, cis-acting elements, such as MBS (MYB binding site involved in drought-inducibility), ARE (anaerobic induction), and ABRE (abscisic acid), were present in the OsDHN2 promoter region. Expression pattern analysis also showed that OsDHN2 expression was induced in both roots and shoots under Cd stress. Overexpression of OsDHN2 improved Cd tolerance and reduced Cd concentration in yeast. Moreover, increased expression levels of SOD1, CTA1, GSH1, or CTT1 were found in transgenic yeast under Cd stress, suggesting the increased antioxidant enzymatic activities. These results suggested that OsDHN2 is a Cd-responsive gene that has the potential to improve resistance to Cd in rice., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)