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Abstract Multiple receptor analysis-based DNA molecular computation has been developed to mitigate the off-target effect caused by nonspecific expression of cell membrane receptors. However, it is quite difficult to involve nanobodies into molecular computation with programmed recognition order because of the “always-on” response mode and the inconvenient molecular programming. Here we propose a spatial segregation-based molecular computing strategy with a shielded internal computing layer termed DNA nano-phage (DNP) to program nanobody into DNA molecular computation and build a series of kinetic models to elucidate the mechanism of microenvironment-confinement. We explain the contradiction between fast molecular diffusion and effective DNA computation using a “diffusion trap” theory and comprehensively overcome the kinetic bottleneck of DNP by determining the rate-limiting step. We predict and verify that identifying trace amount of target cells in complex cell mixtures is an intrinsic merit of microenvironment-confined DNA computation. Finally, we show that DNP can efficiently work in complex human blood samples by shielding the interference of erythrocytes and enhance phagocytosis of macrophages toward target cells by blocking CD47-SIRPα pathway.

Abstract Background Mobile technology offers great potential for physical activity promotion, especially by facilitating online communication, however, the impact of group communication norms on intervention effectiveness remains unclear. This study aimed to evaluate the effect on daily steps of a team-based social norms-related intervention using a mobile application. Methods The 13-week quasi-experimental study was conducted in Shanghai, China, from September to November 2019, involving 2,985 employees from 32 worksites. For the intervention group (n = 2,049), participants set a goal of 10,000 steps per day. The teams and individual members would receive points for meeting the daily goal, contributing to team-based rankings and financial rewards for the teams and their members. In addition, the intervention teams created dedicated WeChat groups to facilitate communication, which were also used to collect group chat messages. The communication type in these groups was classified into four types: (1) nudging – encouraging team members to be more active, (2) sharing – exchanging the completion of daily step goals, (3) feedback – providing responses or suggestions to team members, and (4) other -diverse topics that could not be classified otherwise. The control group only tracked their steps online. Results The weekly average steps of the intervention group increased by 2,523 steps, while the control group increased by 470 steps. In the first 3 weeks of follow-up, the frequency of nudging of 7–18 times/week had a positive cumulative effect on the step counts. Sharing more than 3 times/week had a positive cumulative effect. Over 6 and 13 weeks of follow-up, nudging 19 times/week or more had a positive cumulative effect while sharing and feedback at any frequency negatively affected average weekly steps. Conclusions Communication types within a team affected team-based step counts in a financial incentive intervention. The team-level social norms related to communications might have different cumulative effects on team-level physical activity. ‘nudging’ messages had a significant association with the change in individual-level step counts in the medium or long term. Trial registration Pilot Project of the application of walking incentive technology in occupational groups, 2019, ChiCTR1900023813. Registered 13 June 2019, https://www.chictr.org.cn/showproj.html?proj=39858 .

Abstract Background Polymicrobial pulmonary infections, common in immunocompromised patients, often manifest more severe symptoms than monomicrobial infections. Clinical diagnosis delays may lead to mortality, emphasizing the importance of fast and accurate diagnosis for these patients. Metagenomic next-generation sequencing (mNGS), as an unbiased method capable of detecting all microbes, is a valuable tool to identify pathogens, particularly in cases where infections are difficult to diagnosis using conventional methods. Case presentation A 50-year-old male patient was admitted due to cough, expectoration and dyspnea. CT scan revealed diffuse inflammatory and cavernous lung lesion, and blood examination suggested a polymicrobial infection. However, no etiology was found by routine examination. mNGS of bronchoalveolar lavage fluid(BALF)simultaneously detected the presence of Pneumocystis jirovecii (P.jirovecii), Aspergillus fumigates (A.fumigates), Nocardia farcinica (N.farcinica), Salmonella enterica subsp. enterica (S.enterica subsp. enterica), and cytomegalovirus (CMV). The patient was successfully treated with compound sulfamethoxazole (SMZ-TMP), cefoperazone/sulbactam (SCF), moxifloxacin (MXF), voriconazole (VCZ), and ganciclovir. The patient recovered after two weeks of anti-infection therapy and maintained good health at a six-month follow-up. Conclusion For immunocompromised patients with multiple infections and atypical symptoms, mNGS emerged as a reliable approach to pathogen detection and guiding antibiotic therapy.

Abstract Mecoptera is a small relict order of insects within the Holometabola. Panorpidae is the most speciose family in Mecoptera. They are also known as scorpion flies due to the enlarged and upward recurved male genital bulb. Panorpa liui Hua, 1997, a member of Panorpidae, is a bivoltine species of seasonal color polyphenism in the lowland plain of northeastern China. In this study, we applied PacBio HiFi and Hi–C sequencing technologies to generate a chromosome-level genome reference of P. liui. The assembled genome is 678.26 Mbp in size, with 91.3% being anchored onto 23 pseudo–chromosomes. Benchmarking Universal Single–Copy Orthologs (BUSCO) estimation reveals the completeness of this assembly as 95.1%. By integrating full-length transcriptome and homologs of related species, we generated full annotation of this assembly, yielding a total of 15,960 protein–coding genes, of these, 15,892 genes were anchored on the 23 chromosomes. The high-quality genome provides critical genomic resources for population genetics and phylogenetic research on Mecoptera. It also offers valuable information for exploring the mechanisms underlying seasonal color polymorphism.

This study estimated population normalized mass loads (PNML) of quaternary ammonium compounds (QACs) including alkyltrimethylammonium chloride (ATMAC), benzylalkyldimethylammonium chloride (BAC), and dialkyldimethylammonium chloride (DADMAC) and assessed their associations with COVID-19 containment policies. We collected daily sludge specimens from five wastewater treatment plants in Beijing from July 2020 to May 2022. Using liquid chromatography-tandem mass spectrometry, we determined QAC concentrations and backward-estimated their PNML. We used COVID-19 Oxford Stringency Index and its metrics to measure containment policies. We analysed the relationship between QACs and containment measures using linear regression models. Among QACs categories, ΣBAC had median PNML of 94.54 μg/person/day, ΣDADMAC had 282.36 μg/person/day, and ΣATMAC had 802.55 μg/person/day. The ΣQACs median PNML was 1186.12 μg/person/day. The PNML of QACs appeared to have general increasing trend over time and were significantly different across seasons. PNML increased on average by 11 μg/person/day (95 % CI: 3.2, 19) for ΣBAC per 10-unit increase in Stringency Index score. Notably, higher stringency levels in three index indicators — workplace closures, internal movement restrictions, and public gathering restriction were positively associated with higher ΣQACs PNML. Sludge derived QACs may reflect the magnitude of disinfectant use at different stages of pandemic control response.

Fei Chen,1,2,&ast; Jie Zhao,1,&ast; Rubing Mo,1 Xiuxiu Ding,1 Yue Zhang,1 Linhui Huang,1 Tian Xie,1 Yipeng Ding1 1Department of Respiratory and Critical Care Medicine, Hainan Affiliated Hospital of Hainan Medical University, Hainan General Hospital, Haikou City, Hainan Province, People’s Republic of China; 2Department of General Practice, Bai Majing Town Central Health Center, Danzhou City, Hainan Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yipeng Ding; Tian Xie, Department of Respiratory and Critical Care Medicine, Hainan Affiliated Hospital of Hainan Medical University, Hainan General Hospital, Haikou City, Hainan Province, People’s Republic of China, No. 19 Xiuhua Road, Xiuying District, Email ypding1961@163.com; hpphxietian@163.comBackground: Mutations in ADGRG6 are associated with a variety of cancers and multiple types of diseases. However, the impact of genetic variations in ADGRG6 on chronic obstructive pulmonary disease (COPD) susceptibility has not yet been evaluated.Methods: Considering the high prevalence of COPD among the elderly population in China, this study specifically targets the elderly Han population in Southern China as the study subject. Following the acquisition of participants’ whole-genome DNA, genotyping was conducted using the Agena MassARRAY platform. The online tool ‘SNPStats’, which utilizes logistic regression, was employed to analyze and assess the correlation. Multi-factor dimensionality reduction was utilized to clarify the impact of “SNP-SNP” interactions on COPD risk. The False-Positive Report Probability (FPRP) was applied to determine whether significant results are noteworthy findings.Results: The mutant allele “C” of rs11155242 was a protective genetic factor against COPD susceptibility (OR = 0.57, 95% CI = 0.36 to 0.91, p = 0.017). The heterozygous mutant genotype “CA” of rs11155242 was found to be significantly associated with reduced COPD risk (CA Vs AA: OR = 0.53, 95% CI = 0.32 to 0.90, p = 0.018). ADGRG6-rs11155242 was found to be strongly associated with a reduced risk of COPD in males, non-smokers, and subjects with a BMI below 24 kg/m2 (OR < 1, p < 0.05). The FPRP analysis indicated that the positive results identified in this study are noteworthy new findings.Conclusion: The mutant allele “C” and mutant genotype “CA” of rs11155242 act as protective genetic factors against COPD susceptibility. This study will provide a new research direction for the personalized prevention and treatment of COPD in the elderly Han population in southern China, and lay a potential scientific basis.Keywords: COPD, ADGRG6, genetic variants, mutant allele

Abstract Background ADAM19 (ADAM Metallopeptidase Domain 19) is known to be involved in extracellular matrix (ECM) remodeling, yet its specific function in systemic sclerosis (SSc) fibrosis remains unclear. Objectives This study sought to clarify the role and underlying mechanism of ADAM19 in SSc skin fibrosis. Methods The expression of ADAM19 was assessed in skin tissues of SSc and wound healing using publicly available transcriptome datasets. This analysis was further validated through real-time PCR, western blot, and immunostaining in our SSc cohort, as well as in a mouse model of hypochlorite (HOCl)-induced fibrosis. To downregulate the expression of ADAM19, ADAM19 siRNA was employed. The influence of ADAM19 on fibroblast transcriptomics was examined using bulk RNA-seq. Data analysis and visualization were conducted using R packages, including edgeR, limma, clusterProfiler, ggplot2, gseaplot2, and complexheatmap. Results ADAM19 exhibited a significant upregulation in skin tissues of SSc patients, as well as in wound healing and a HOCl-induced fibrosis mouse model. Additionally, there was a notable positive correlation between ADAM19 and fibrosis-related genes, local skin score, Modified Rodnan skin score, skin thickness progression rate, and the presence of ARA antibodies in SSc patients. Furthermore, ADAM19 levels were markedly elevated in SSc primary dermal fibroblasts and TGF-β-stimulated healthy controls primary dermal fibroblasts. The downregulation of ADAM19 resulted in the repression of TGF-β-induced ECM deposition and fibroblast activation. ADAM19 was identified as a mediator for the shedding of neuregulin-1 (NRG1) in fibroblasts, a pro-fibrotic cytokine that must be cleaved to exert its function. Conclusion ADAM19 plays a role in TGF-β-induced ECM deposition and fibroblast activation by mediating the shedding of NRG1, ultimately contributing to the development of skin fibrosis in SSc.

AIM: To investigate the effects of insulin-like growth factor 1(IGF-1)on the secretion of transforming growth factor β2(TGF-β2), matrix metalloproteinase 2(MMP-2)and hypoxia-inducible factor 1α(HIF-1α)in human scleral fibroblasts(HSF)and their mechanism.METHODS: The cells were cultured with IGF-1 and PI3K/AKT pathway inhibitor LY294002, respectively. CCK-8 method was used to detect cell viability and determine the optimal concentration and time of drug action. Cell migration activity was observed by cell scratch method. To determine the effects of IGF-1 on HSF cells and the regulatory role of PI3K/AKT pathway, HSF cells were divided into control group(without drugs), IGF-1(80 μg/L)group, IGF-1+LY294002(80 μg/L+5 mmol/L)group, and LY294002(5 mmol/L)group, and were cultured for 24 h; the protein expression levels of TGF-β2, MMP-2, HIF-1α, PI3K and AKT were detected by Western blot; the fluorescence expression of TGF-β2, MMP-2 and HIF-1α was detected by cellular immunofluorescence.RESULTS: The results of CCK-8 showed that the cell viability of the 80 μg/L IGF-1 group cultured with different concentrations of IGF-1 was the highest(all P

Ling Wang,1,2,&ast; Xuemei Deng,1,&ast; Jiaxi Tang,3 Yi Gong,2 Shaojin Bu,4 Zuli Li,1 Bin Liao,2 Yao Ding,2 Tingting Dai,1,5 Yong Liao,1 Yongsheng Li2,6 1Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, People’s Republic of China; 2Department of Phase I Clinical Trial Ward, Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, People’s Republic of China; 3Department of Anesthesiology, Chongqing University Cancer Hospital, Chongqing, China; 4Department of Anesthesiology, Fengdu People’s Hospital, Chongqing, People’s Republic of China; 5Department of Medical Oncology, Chongqing University Fuling Hospital, Chongqing, China; 6Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yong Liao, Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, NO. 288 Chayuan Astronomy Avenue, Nanan District, Chongqing, 401336, People’s Republic of China, Email yongliao@cqmu.edu.cn Yongsheng Li, Department of Medical Oncology, Chongqing University Cancer Hospital, No. 181 hanyu Road, Shapingba District, Chongqing, 400030, People’s Republic of China, Email yongshengli2005@163.comPurpose: Colorectal cancer (CRC) is a prevalent malignancy, and lactate metabolism significantly influences tumorigenesis and progression. This study identifies key genes associated with lactic acid metabolism and explore their impact on CRC.Patients and Methods: This study utilized data from The Cancer Genome Atlas, Gene Expression Omnibus, other public databases, and our institutional resources. Machine learning identified key lactate metabolism-related genes. Receiver Operating Characteristic analysis, Kaplan-Meier analysis, and the construction of a nomogram model were conducted to assess the diagnostic and prognostic significance of the key lactate metabolism-related gene EARS2. EARS2 expression in colorectal tissue was validated using both publicly available external data and samples from our institution. To investigate the mechanisms underlying EARS2 in CRC, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, Gene Set Enrichment Analysis, and Protein-Protein Interaction analyses were performed, alongside the construction of miRNA-mRNA interaction networks. Additionally, the relationships between EARS2 and immune cell infiltration, as well as responses to drug therapy, were examined. Following the knockdown of EARS2, we assessed cell proliferation, migration capabilities, and apoptosis. Statistical analyses were conducted using R and GraphPad Prism software.Results: ERAS2 was overexpressed in CRC tissues compared to normal and adenoma tissues, with higher expression levels correlating with aberrant lactate metabolism and poorer patient prognosis. EARS2 was involved in pathways such as neuroactive ligand-receptor interactions, protein digestion, and cholesterol metabolism, and it was associated with immune cell infiltration and responses to drug treatment. Additionally, the knockdown of EARS2 inhibited the proliferation, migration, and invasion of CRC cells while enhancing their apoptosis.Conclusion: Elevated expression of EARS2 is associated with abnormal lactate metabolism, immune cell infiltration, altered therapeutic sensitivity, and poorer survival outcomes in CRC. This correlation suggests that EARS2 may serve as a potential target for the diagnosis, prognosis, and therapeutic intervention in 0CRC. Keywords: biomarker, CRC, EARS2, lactic acid, prediction model

Yang Tao,&ast; Wen-Tao Zhang,&ast; Can Ding, Bin-Jie Fu, Fa-Jin Lv, Zhi-Gang Chu Department of Radiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fa-Jin Lv; Zhi-Gang Chu, Department of Radiology, The First Affiliated Hospital of Chongqing Medical University, 1&num; Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, People’s Republic of China, 400016, Tel +86 18723032809, Fax +86 23 68811487, Email cyscitg@hospital.cqmu.edu.cn; chuzg0815@163.comPurpose: To determine the significance of lesion–pleura relationship in differentiating peripheral inflammatory lesions (PILs) and peripheral lung cancers (PLCs).Patients and Methods: From January 2017 to April 2022, a total of 743 patients with 501 PLCs and 292 PILs (≥ 1.5 cm) were retrospectively enrolled. The patients’ clinical characteristics and CT features of lesions in these two groups were analyzed and compared, and the impact of the lesion–pleura relationship (broad or narrow basement and distance between lesion and pleura) on differentiation was specifically assessed.Results: Lesions attached to pleura were more frequent in PILs (188, 64.4%) than in PLCs (244, 48.7%) (P < 0.001), and those with broad basement-to-pleura were also more common in PILs (133, 70.7%) than in PLCs (47, 19.3%) (P < 0.001). Among the 296 lesions with a lesion-pleura distance ≤ 16 mm, the optimal cutoff value of distance was ≤ 8.9 mm (area under curve [AUC], 0.733; sensitivity: 0.770; specificity: 0.623; P < 0.001) for predicting PLCs. Regarding the 728 lesions attached to pleura or with a lesion-pleura distance ≤ 16 mm, the AUC of the model based on the clinical and CT features for predicting PLCs significantly increased from 0.812 to 0.879 after including lesion-pleura relationship (narrow basement or lesion-pleura distance ≤ 8.9 mm) (P < 0.001). Additionally, the lesion–pleura relationship was one of independent indicators for differentiation (odds ratio, 9.433; P < 0.001).Conclusion: When differentiating peripheral lesions (≥ 1.5 cm), it is crucial to consider the basement-to-pleura and lesion-pleura distance besides patients’ clinical characteristics, laboratory parameters and morphological features.Keywords: lung neoplasms, diagnosis, differential, tomography, X-ray computed

Jun Wang,1,&ast; Yulong Li,1,&ast; Chunyu Tan,1,&ast; Jinlian Shao,1 Weitai Tang,2 Quan Kong,3 Wenqianjun Sheng,1 Zhiquan Ding,1 Feng Li,1 Jifeng Piao,1 Dingyi Lv,1 Libin Hu,1 Qinghua Wang,1 Xiaodan Jiang1 1Neuromedicine Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, People’s Republic of China; 2Department of Neurosurgery, The People’s Hospital of Luoding & Affiliated Luoding Hospital of Guangdong Medical University, Luoding, 527200, People’s Republic of China; 3Neurosurgery Department of Zengcheng Campus, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qinghua Wang; Xiaodan Jiang, Email wqh1123@126.com; jiangxiao_dan@163.comBackground: Neuroinflammatory reactions are crucial factors in secondary brain damage following intracerebral hemorrhage (ICH). Although previous studies have shown that IRAK3 is involved in immune responses, the potential effects of IRAK3 on ICH remain unclear.Methods: Collagenase IV–induced ICH mouse model. Western blotting was used to determine the expression of IRAK3 at different time points following ICH. Immunofluorescence was used to investigate the cellular localization of IRAK3. The ICH model was treated with recombinant human IRAK3 (rh-IRAK3) or IRAK3 siRNA via an intracerebroventricular injection. The effect of IRAK3 on ICH mice was assessed by Western blotting and short-term and long-term neurological function evaluation. RNA-seq was performed to explore the mechanism by which IRAK3 promotes inflammation after ICH. The mechanisms of IRAK3 and neuroinflammation will be further investigated by Western blotting, qRT-PCR and immunofluorescence. Recombinant IL-17A was used to investigate the connection between IRAK3 and the NF-κB/IL-17A signaling pathway in vivo and in vitro experiments.Results: The expression of IRAK3 increased, peaking at 24 h, followed by a subsequent decrease after ICH. IRAK3 is mainly expressed in the microglia. RNA-seq analysis revealed 1,797 differentially expressed genes around the perihematomal brain tissue after IRAK3 siRNA treatment, with multiple inflammatory pathways being downregulated. Rh-IRAK3 treatment resulted in upregulation of the levels of inflammatory cytokines around the perihematomal tissue and exacerbated neurological function deficits. Furthermore, IRAK3 siRNA treatment markedly decreased the expression of inflammatory cytokines and microglial activation via the NF-κB/IL-17A signaling pathway. Recombinant IL-17A exacerbated the inflammatory response in vivo and in vitro; however, IRAK3 knockdown reversed this process.Conclusion: IRAK3 aggravates neuroinflammation by activating the NF-κB/IL-17A signaling pathway, thereby exacerbating neurological deficits following ICH. Therefore, inhibition IRAK3 may be a promising approach for treating ICH.Keywords: IRAK3, neuroinflammation, intracerebral hemorrhage, microglia, NF-κB/IL-17A pathway

Fangfang Xiang,1– 4,&ast; Zhen Zhang,1,&ast; Yuxin Nie,1 Xuesen Cao,1 Yang Li,1 Xiaohong Chen,1 Shaomin Gong,1 Jianzhou Zou,1 Jie Teng,1 Xiaoqiang Ding,1– 4 Bo Shen1– 4 1Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 2Shanghai Key Laboratory of Renal Disease and Blood Purification, Shanghai, People’s Republic of China; 3Shanghai Medical Center of Kidney, Shanghai, People’s Republic of China; 4Shanghai Institute of Kidney and Dialysis, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bo Shen, Department of Nephrology, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, People’s Republic of China, Email shen.bo@zs-hosptial.sh.cnPurpose: Infection is the most common cause of hospitalization and the second most common cause of mortality among patients undergoing hemodialysis (HD). The enzyme CD73, a cell surface 5′-nucleotidase, regulates the balance between pro-inflammatory nucleotides and anti-inflammatory adenosine. Diminished CD73-adenosine signaling contributes to severe infections.Methods: In this prospective cohort study, 393 patients who underwent HD for over six months were evaluated for CD73+Tcell ratios and were followed up for three years to track infection events. Kaplan–Meier curves and Cox regression analyses were used to evaluate the relationship between CD73+T cells and infections; meanwhile, multiple logistic regression analysis was used to analyze differences among infection groups. In addition, a 5/6 nephrectomy (5/6 Nx) rat model and cecal ligation and puncture (CLP) were used to verify the effect of chronic kidney disease (CKD) and sepsis on CD73-adenosine signaling.Results: Decreased CD73+ T cells were independently associated with increased infection risk over one and three years. The hazard ratios for one- and three-year infection incidences were 3.173 (95% CI 1.782– 5.650, p < 0.001) and 1.429 (95% CI 1.052– 1.992, p = 0.035), respectively. Furthermore, they were associated with recurrent and fatal severe infections. Animal models demonstrated reduced CD73 mRNA transcript and adenosine receptor levels, along with decreased serum adenosine levels in CKD. Impairment of CD73-adenosine signaling was more pronounced after CLP in CKD rats.Conclusion: Lower CD73+T cell levels are strongly associated with infection complications in patients undergoing HD. Altered CD73-adenosine signaling likely plays a substantial role in immune dysfunction in CKD. Keywords: adenosine, CD73, hemodialysis, infection, T cell dysfunction

Baoyue Ding,1,2,&ast; Mingjuan Li,2,&ast; Jie Zhang,2,&ast; Xiaojuan Zhang,2 Huan Gao,2 Jianqing Gao,3 Chunyan Shen,4 Yan Zhou,4 Fanzhu Li,5 Ailin Liu1 1Department of Pharmaceutical Analysis, Higher Educational Key Laboratory for Nano Biomedical Technology of Fujian Province, The School of Pharmacy, Fujian Medical University, Fuzhou, 350122, People’s Republic of China; 2Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, Jiaxing University College of Medicine, Jiaxing, Zhejiang, People’s Republic of China; 3Institute of Pharmaceutics, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058 People’s Republic of China; 4Jiaxing Institute for Food, Drug and Product Quality Control, Jiaxing, Zhejiang, People’s Republic of China; 5Zhejiang Chinese Medical University, School of Pharmaceutical Science, Hangzhou, 310053, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fanzhu Li; Ailin Liu, Email lifanzhu@zcmu.edu.cn; ailinliu@mail.fjmu.edu.cnPurpose: The incidence of malignant melanoma (MM) has risen over the past three decades, and despite advancements in treatment, there is still a need to improve treatment modalities. This study developed a promising strategy for tumor-targeted co-delivery of Dacarbazine (DTIC) and miRNA 34a-loaded PHRD micelles (Co-PHRD) for combination treatment of MM.Methods: To construct the dual drug-loaded delivery system Co-PHRD, poly (L-arginine)-poly (L-histidine)-polylactic acid (PLA) was employed as a building block. In this system, poly (L-arginine) and PLA function as hydrophilic and hydrophobic blocks, respectively, which self-assemble into micelles in aqueous solution. Poly(L-arginine) and poly(L-histidine) are efficiently taken up by cells and perform efficient gene condensation, which facilitate the release of encapsulated miRNA 34a into the cytoplasm. Due to its lipophilic properties, PLA can effectively encapsulate DTIC. The polypeptide aptamer DR5-TAT (D21) was used as a targeting ligand. The properties of Co-PHRD and its in vitro release behaviour were characterized. Additionally, the synergetic effects of DTIC and miRNA 34a in melanoma therapy were investigated in vitro and in vivo.Results: Compared to DTIC treatment alone, Co-PHRD treatment exhibited 1.84-fold greater cytotoxicity in A375 cells, demonstrating that miRNA 34a enhanced the efficacy of DTIC. The particle size of Co-PHRD at an N/P ratio of 10 was 164.1 ± 4.5 nm, and the zeta potential of Co-PHRD was 27.3 ± 1.38 mV. The flow cytometry and CLSM results revealed both DTIC and miRNA 34a were avidly taken up by A375 cells at 1 h and 4 h in PHRD. In addition, in vivo results indicated that Co-PHRD micelles can significantly inhibit tumor growth without causing significant damage to major organs.Conclusion: Co-delivery of DTIC and miRNA 34a via polypeptide micelles showed synergistic effects against MM, offering a new strategy for gene and chemotherapy.Keywords: nano micelle, DTIC, miRNA 34a, co-delivery, malignant melanoma

Xiaoshan Yang,1– 3,&ast; Yang Zhou,2,3,&ast; Fuxing Zhou,4,&ast; Lili Bao,2,3 Zhengyan Wang,5 Zihan Li,2,3 Feng Ding,2,3 Huijuan Kuang,6,7 Huan Liu,8 Shenglong Tan,1 Xinyuan Qiu,1 Huan Jing,9 Shiyu Liu,2,3 Dandan Ma1 1Department of Endodontics, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, People’s Republic of China; 2State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Department of Oral Biology, School of Stomatology, The Fourth Military Medical University, Xi’an, 710032, People’s Republic of China; 3State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi’an, 710032, People’s Republic of China; 4Department of Gynecology and Obstetrics, Xijing Hospital, The Fourth Military Medical University, Xi’an, 710032, People’s Republic of China; 5Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, 250012, People’s Republic of China; 6Department of Orthopaedics, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, People’s Republic of China; 7State Key Laboratory for Manufacturing System Engineering, Xi’an Jiaotong University, Xi’an, 710054, People’s Republic of China; 8Department of Otolaryngology Head and Neck Surgery, Peking University Third Hospital, Beijing, 100871, People’s Republic of China; 9Department of Endodontics, Guangdong Provincial High-level Clinical Key Specialty, Guangdong Province Engineering Research Center of Oral Disease Diagnosis and Treatment, Peking University Shenzhen Hospital, Shenzhen, 518036, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dandan Ma, Stomatological Hospital, Southern Medical University, S366 Jiangnan Boulevard, Guangzhou, Guangdong, 510280, People’s Republic of China, Tel +86-20-34152996, Email mdd@smu.edu.cn Shiyu Liu, School of Stomatology, The Fourth Military Medical University, No. 145, West Changle Road, Xi’an, Shaanxi, 710032, People’s Republic of China, Tel +86-29-84772645, Email liushiyu@vip.163.comBackground: Osteoporosis is a major public health concern characterized by decreased bone density. Among various therapeutic strategies, apoptotic extracellular vesicles (ApoEVs) have emerged as promising agents in tissue regeneration. Specifically, T cell-derived ApoEVs have shown substantial potential in facilitating bone regeneration. However, it remains unclear whether ApoEVs can promote bone mass recovery through enzymatic activity mediated by membrane surface molecules. Therefore, this study aimed to investigate whether T cell-derived ApoEVs could promote bone mass recovery in osteoporosis mice and reveal the underlying mechanisms.Methods: ApoEVs were isolated through sequential centrifugation, and their proteomic profiles were identified via mass spectrometry. Western blot and immunogold staining confirmed the enrichment of CD39 and CD73 on ApoEVs. The role of CD39 and CD73 in hydrolyzing adenosine triphosphate (ATP) to adenosine was evaluated by quantifying the levels of ATP and adenosine. Inhibitors of CD39 and CD73, and an A2BR antagonist were used to explore the molecular mechanism of ApoEVs in promoting bone regeneration.Results: ApoEVs significantly reduced bone loss and promote the osteogenic differentiation of BMMSCs in ovariectomy (OVX) mice. We observed increased levels of extracellular ATP and a decrease in CD39 and CD73, key enzymes in ATP-to-adenosine conversion in bone marrow of OVX mice. We found that ApoEVs are enriched with CD39 and CD73 on their membranes, which enable the hydrolysis of extracellular ATP to adenosine both in vitro and in vivo. The adenosine generated by ApoEVs inhibits the inflammatory response and promotes osteogenesis through A2BR and downstream PKA signaling.Conclusion: T cell-derived ApoEVs are enriched with CD39 and CD73, enabling them to hydrolyze extracellular ATP to adenosine, thereby promoting bone regeneration via A2BR and PKA signaling pathway. Our data underscore the substantive role of T cell-derived ApoEVs to treat osteoporosis, thus providing new ideas for the development of ApoEVs-based therapies in tissue regeneration. Keywords: T cell apoptosis, apoptotic extracellular vesicles, CD39, CD73, adenosine, bone regeneration

Xiaowei Li,&ast; Kunkun Cao,&ast; Zhigang Fu,&ast; Xiaoxia Chen, Jiaming Zhong, Li Liu, Ning Ding, Xiaoli Zhang, Zengqiang Qu, Lijun Zhu, Jian Zhai Department II of Interventional Radiology, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, 200438, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jian Zhai; Lijun Zhu, Department II of Interventional Radiology, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, 200438, People’s Republic of China, Email jianzhai1979@126.com; lijun_zhush@163.comPurpose: To assess the activity and toxicity of hepatic arterial infusion chemotherapy (HAIC)+tislelizumab+lenvatinib (HAIC+tisle+len) in hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) type IV (Vp4 hCC) in a real-world context.Methods: Fifty-five patients, with Vp4 hCC receiving HAIC+tisle+len therapy from April 2021 to December 2022, were analyzed retrospectively. Data on patient characteristics, adverse events (AEs), treatment, and survival were collected. Outcomes were disease control rate (DCR), overall response rate (ORR), overall survival (OS), progression-free survival (PFS), and treatment-related AEs (TRAEs).Results: As of December 20, 2023, the median follow-up was 17.5 months (95% confidence interval [CI]: 14.7– 22.5). The ORR was 52.7% (3 complete response [CR], 26 partial response [PR]) as per RECIST v1.1 and 65.5% (12 CR, 24 PR) as per mRECIST. The DCR was 94.5% using both RECIST v1.1 and mRECIST. The median PFS and the median OS were 8.0 months (95% CI: 6.2– 12.3) and 16.7 months (95% CI: 12.0-not reached), respectively. Additionally, PFS was independently predicted only by the best tumor response. In patients with the best tumor response (PR or CR), the median PFS was 11.7 months (95% CI: 8.02-not reached) by mRECIST and 15.4 months (95% CI: 7.39-not reached) by RECIST v1.1. Hypertension (14.5%), decreased albumin levels (10.9%) and anorexia (9.1%) were the most frequently observed grade 3– 4 TRAEs.Conclusion: HAIC+tisle+len regimen demonstrated a promising efficacy and favorable safety for patients with HCC and Vp4, providing valuable real-world evidence to complement the trial data for Vp4 hCC.Keywords: tislelizumab, portal vein tumor thrombus, lenvatinib, hepatocellular carcinoma, hepatic artery infusion chemotherapy

Deep brain stimulation (DBS) is recognized as one of the prominent solutions to treat Parkinson’s disease. In the DBS, an accelerometer sensor is often adopted to measure the value of the tremor and then wirelessly transmit the measured signals to the programming device using a communication network. False data injection (FDI) attacks are among the most prevalent attacks in DBS, where the attacker injects false data into the communication infrastructure. In this paper, an event triggered adaptive defense mechanism is designed to mitigate the effect of FDI attacks in the DBS system. To the best of our knowledge, this is the first work focusing on the design of defense mechanisms against cybersecurity threats directed toward deep brain stimulation systems. To this end, a fractional order extended state observer (FOESO) is adopted to predict the tremor measurement signals of the accelerometer sensor. To achieve accurate prediction, Heuristic Adaptive Dynamic Programming (HADP) is utilized to adjust the coefficients embedded in the FOESO structure. Using a neural networks-based approach, the HADP agent regulates the parameters of the FOESO by maximizing a reward (reinforcement) signal according to the desired system requirements. An event-triggered mechanism is also utilized to mitigate manipulated signals measured by sensors and this strategy can address challenges such as bandwidth limitations and high network traffic. The comprehensive simulations of DBS under various levels of FDI threats reveal the feasibility of the suggested defense mechanism against cyber threats. Moreover, comparative dynamic responses and real-time examination of tremors demonstrate that by adopting the suggested adaptive defense, a superior performance than other state-of-the-art schemes can be achieved.

Abstract Environmental pollution represents a significant public health concern, with the potential health risks associated with environmental pollutants receiving considerable attention over an extended period. In recent years, a substantial body of research has been dedicated to this topic. Since the discovery of ferroptosis, an iron-dependent programmed cell death typically characterized by lipid peroxidation, in 2012, there have been significant advances in the study of its role and mechanism in various diseases. A growing number of recent studies have also demonstrated the involvement of ferroptosis in the damage caused to the organism by environmental pollutants, and the molecular mechanisms involved have been partially elucidated. The targeting of ferroptosis has been demonstrated to be an effective means of ameliorating the health damage caused by PM2.5, organic and inorganic pollutants, and ionizing radiation. This review begins by providing a summary of the most recent and important advances in ferroptosis. It then proceeds to offer a critical analysis of the health effects and molecular mechanisms of ferroptosis induced by various environmental pollutants. Furthermore, as is the case with all rapidly evolving research areas, there are numerous unanswered questions and challenges pertaining to environmental pollutant-induced ferroptosis, which we discuss in this review in an attempt to provide some directions and clues for future research in this field.

Abstract This study aims to examine the relationship between physical activity and inhibitory function in college students with depressive symptoms and to explore the role of resting EEG as a mediator in this relationship. Specifically, it analyzes how physical activity correlates with inhibitory function and identifies potential routes through which physical activity impacts inhibitory function. A cross-sectional study was conducted involving 154 college students with depressive symptoms. Participants completed the Basic Information Questionnaire, the Beck Depression Inventory-II, and the Physical Activity Rating Scale. Five-minute EEG signals were recorded, and participants performed behavioral tasks to assess inhibitory function. Data were analyzed using independent samples t-tests, χ2 tests, Pearson correlation analysis, and structural equation modeling. Significant differences were found between the adequate and inadequate physical activity groups in BDI scores and response inhibition (P 0.05). There is a close relationship between physical activity, specific EEG indicators, and response inhibition. The central, parietal, and temporal regions serve as potential routes linking physical activity and response inhibition. Delta band lateralization (in the central, parietal, and temporal regions) may be the route through which physical activity influences response inhibition.

Abstract Glutamine is the most abundant amino acid in human serum, and it can provide carbon and nitrogen for biosynthesis, which is crucial for proliferating cells. Moreover, it is widely known that glutamine metabolism is reprogrammed in cancer cells. Many cancer cells undergo metabolic reprogramming targeting glutamine, increasing its uptake to meet their rapid proliferation demands. An increasing amount of study is being done on the particular glutamine metabolic pathways in cancer cells. Further investigation into the function of glutamine in immune cells is warranted given the critical role these cells play in the fight against cancer. Immune cells use glutamine for a variety of biological purposes, including the growth, differentiation, and destruction of cancer cells. With the encouraging results of cancer immunotherapy in recent years, more investigation into the impact of glutamine metabolism on immune cell function in the cancer microenvironment could lead to the discovery of new targets and therapeutic approaches. Oral supplementation with glutamine also enhances the immune capabilities of cancer patients, improves the sensitivity to chemotherapy and radiotherapy, and improves prognosis. The unique metabolism of glutamine in cancer cells, its function in various immune cells, the impact of inhibitors of glutamine metabolism, and the therapeutic use of glutamine supplements are all covered in detail in this article.

Abstract Background Arthrogryposis multiplex congenita (AMC) is a congenital disorder characterized by multiple joint involvement, primarily affecting limb mobility and leading to various tissue contractures. Variations in the RIPK4 gene may impact connective tissues, thereby resulting in a spectrum of malformations. This study aimed to identify the genetic etiologies of AMC patients and provide genetic testing information for further diagnosis and treatment of AMC. Methods We recruited a Chinese female patient with hand-related AMC and her family members. Whole-exome sequencing (WES) was employed to determine the genetic etiologies of the patient’s disease. The pathogenic mechanisms of the identified variations were analyzed using protein tolerance profiling and modeling. Results We identified two novel RIPK4 variants (c.1354G > A, p.E452K; c.1558A > T, p.T520S). Pathogenicity studies indicated that the c.1354G > A, p.E452K variant changed the charge from negative to positive and altered the chemical properties from acidic to alkaline, potentially significantly affecting protein function. Conclusions We reported the discovery of two novel RIPK4 variants (c.1354G > A, p.E452K; c.1558A > T, p.T520S) in a Chinese AMC female patient’s family. Our study enhances the genetic repository for AMC and highlights the pathogenicity of RIPK4 variants, underscoring the significance of comprehensive management for genetic-related diseases, particularly the critical roles of prenatal diagnosis and genetic counseling. Trial registration The research protocol received approval from the Ethics Review Committee of Xiangya Hospital of Central South University in China (approval number: 202103427), registered in March 2021, with all participants providing duly signed informed consent forms.

The study employed three methods—odium tripolyphosphate method, neutral protease method, and ultrasonic treatment to modify the Chlorella protein in this paper. The investigation focused on changes in particle size, zeta potential distribution, antioxidant activity, functional properties, thermal stability, and structural characteristics before and after modification. The analysis revealed that compared to unmodified Chlorella protein, all three modification methods significantly reduced particle size and zeta potential. Additionally, significant improvements were observed in solubility, emulsification, emulsion stability, microstructure, and thermal stability. Overall, all three modification methods effectively improved the Chlorella protein. However, the sodium tripolyphosphate method showed only slight improvement in hydrophobicity and fluorescence intensity, with no significant overall improvement observed. The neutral protease method exhibited the most significant improvements in antioxidant activity, water-holding capacity, oil-holding capacity, thermal stability, and secondary structure of the Chlorella protein. For instance, the ABTS free radical scavenging rate increased from 22.95% to 35.72%, and the thermal stability improved by 11.48 ℃ compared to the control. The ultrasonic method significantly increased the solubility of Chlorella protein from 23.56% to 69.66%, emulsification from 70.29 m2/g to 95.25 m2/g, and emulsion stability from 10.74 min to 39.47 min. Additionally, reductions in particle size and improvements in zeta potential were observed.

Yujing Li,1,2,&ast; Xindie Ren,3,&ast; Qianqian Wang,4,&ast; Songying Shen,2,&ast; Yihao Li,1,2 Xinling Qian,2 Yufei Tang,2 Jinguang Jia,2 Hao Zhang,2 Junjie Ding,2 Yinsen Song,1 Sisen Zhang,1 Shengfeng Wang,5 Yinghe Xu,6 Yongpo Jiang,6 Xuwei He,7 Muhua Dai,8 Lin Zhong,9 Yonghui Xiong,10 Yujie Pan,11 Mingqiang Wang,12 Huanzhang Shao,12 Hongliu Cai,3 Lingtong Huang,3 Hongyu Wang1,2 1Department of Critical Care Medicine, The Fifth Clinical Medical College of Henan University of Chinese Medicine, Zhengzhou, Henan Province, People’s Republic of China; 2Department of Critical Care Medicine, People’s Hospital of Henan University of Chinese Medicine/People’s Hospital of Zhengzhou, Zhengzhou, Henan Province, People’s Republic of China; 3Department of Critical Care Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People’s Republic of China; 4Department of Critical Care Medicine, The First Hospital of Jiaxing, Jiaxing, Zhejiang Province, People’s Republic of China; 5Department of Critical Care Medicine, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of China; 6Department of Critical Care Medicine, Taizhou Hospital of Zhejiang Province affiliated with Wenzhou Medical University, Taizhou, Zhejiang Province, People’s Republic of China; 7Department of Critical Care Medicine, Lishui People’s Hospital, Lishui, Zhejiang Province, People’s Republic of China; 8Department of Critical Care Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang Province, People’s Republic of China; 9Department of Critical Care Medicine, The First People’s Hospital of Pinghu, Pinghu, Zhejiang Province, People’s Republic of China; 10Department of Critical Care Medicine, Lanxi Hospital of Traditional Chinese Medicine, Lanxi, Zhejiang Province, People’s Republic of China; 11Department of Critical Care Medicine, Wenzhou Central Hospital, Wenzhou, Zhejiang Province, People’s Republic of China; 12Department of Critical Care Medicine, Henan Key Laboratory for Critical Care Medicine, Zhengzhou Key Laboratory for Critical Care Medicine, Henan Provincial People’s Hospital; Zhengzhou University People’s Hospital, Henan University People’s Hospital, Zhengzhou, Henan Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lingtong Huang, Department of Critical Care Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China, Email lingtonghuang@zju.edu.cn Hongyu Wang, Department of Critical Care Medicine, People’s Hospital of Henan University of Chinese Medicine/People’s Hospital of Zhengzhou, Zhengzhou, Henan Province, People’s Republic of China, Email hongyu260@163.comBackground: Several predictive models for invasive pulmonary aspergillosis (IPA) based on clinical characteristics have been reported. Nevertheless, the significance of other concurrently detected microorganisms in IPA patients is equally noteworthy. This study aimed to develop a risk prediction model for IPA by integrating clinical and microbiological characteristics.Methods: This retrospective study was conducted in adult intensive care units (ICUs) of 17 medical centers in China. Clinical data were collected from patients with severe pneumonia who underwent clinical metagenomics of bronchoalveolar lavage fluid between January 1, 2019, and June 30, 2023. Subsequently, patients were randomly assigned to training and validation cohorts in a 7:3 ratio. In the training cohort, potential influencing factors were identified through univariate analysis, clinical practice, and existing literature, and a risk prediction model was constructed using multivariate logistic regression analysis. The performance of this model was then assessed and validated in the validation cohort.Results: Out of 1737 patients initially included in the study, 898 were ultimately analyzed, of which 100 (11%) were diagnosed with IPA. The risk prediction model for IPA, incorporating microbiological characteristics, identified six independent risk factors, namely age, immunosuppression, chronic kidney disease, connective tissue disease, liver failure, and cytomegalovirus positivity. The model demonstrated a superior discriminative ability, with area under the curve (AUC) values of 0.791 and 0.792 in the training and validation cohorts, respectively. Sensitivity and specificity reached 73.1% and 74.9%, respectively, and the model demonstrated good calibration.Conclusion: This study developed a novel risk prediction model for IPA incorporating microbiological characteristics based on clinical metagenomics. The model exhibited good discriminative ability and calibration.Keywords: CAP, community-acquired pneumonia, IPA, invasive pulmonary aspergillosis, prediction model, microbiological characteristics, clinical metagenomics

Yu Ding,1 Yuxia Liu,2 Jianjian Yu,2 Chengsen Cai,2 Lina Fu,2 Jie Zhu,3 Shengzhen Yang,4 Yu Jiang,1 Jun Wang2 1The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, People’s Republic of China; 3Department of Pharmacy, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, People’s Republic of China; 4Department of Pulmonary, Rizhao Hospital of Traditional Chinese Medicine, Rizhao, People’s Republic of ChinaCorrespondence: Jun Wang, Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, People’s Republic of China, Email jnwj660606@163.comPurpose: The C-reactive protein (CRP)–albumin–lymphocyte (CALLY) index is a newly developed biomarker that combines measurements of CRP, serum albumin, and lymphocyte count. This index provides a thorough assessment of a patient’s inflammation level, nutritional condition, and immunological function. The objective of this study is to examine the correlation between the CALLY index and all-cause mortality in COPD patients.Methods: We calculated the CALLY index using data from the National Health and Nutrition Examination Survey (NHANES) for the 2007– 2008 and 2009– 2010 cycles, extracted from the participants’ peripheral blood samples. The study utilized Kaplan-Meier curves, restricted cubic spline (RCS) curves, and Cox regression analysis to evaluate the relationship between the CALLY index and the risk of all-cause mortality in COPD patients. To assess the predictive accuracy of the CALLY index, we calculated the area under the receiver operating characteristic (ROC) curve (AUC).Results: The study included 1,048 participants and found a significant negative correlation between the CALLY index and all-cause mortality in patients with COPD. The CALLY index was a major predictor of survival in COPD patients [fully adjusted model: in the 3rd quartile, HR = 1.61, 95% CI: 1.02– 2.52, p = 0.039; in the 2nd quartile, HR = 2.11, 95% CI: 1.22– 3.65, p = 0.008; in the 1st quartile, HR = 3.12, 95% CI: 2.00– 4.85, p < 0.001]. The RCS curves demonstrated a non-linear association between the CALLY index and all-cause mortality in COPD patients. The areas under the curve (AUC) in predicting 5- and 10-year all-cause mortality were 0.693 and 0.656.Conclusion: The CALLY index has a strong relationship with all-cause mortality in patients with COPD in the US and could serve as a prognostic biomarker for these patients.Keywords: chronic obstructive pulmonary disease, the C-reactive protein–albumin–lymphocyte index, national health and nutrition examination survey, biomarker

Zhe Xu,1 Yi Ding,1 Xue-Mei Deng,1 Xiu-Xiu Mao,1 Ping-Fan Xia,1 Deng-Ran Li,1 Yong-Ping Lu2 1Department of Pediatrics, Guangyuan Central Hospital, Guangyuan, People’s Republic of China; 2Science & Technology Innovation Center, Guangyuan Central Hospital, Guangyuan, People’s Republic of ChinaCorrespondence: Yong-Ping Lu, Science & Technology Innovation Center, Guangyuan Central Hospital, Guangyuan, People’s Republic of China, Email luyongping_lyp@163.comObjective: To explore the application of short-peptide enteral nutrition formulation in mechanically ventilated pediatric patients with severe pneumonia and its impact on rehabilitation outcomes, providing practical clinical evidence for the nutritional support strategy in critically ill pneumonia children.Methods: This study retrospectively analyzed the clinical data of 90 neonatal pneumonia patients undergoing mechanical ventilation from May 2022 to December 2023. The patients were divided into an experimental group receiving short peptide enteral nutrition formulation via nasogastric tube and a control group receiving whole-protein enteral nutrition formulation via nasogastric tube. The nutritional risk was assessed using STRONGkids, and the nutritional status was analyzed through biochemical protein indicators. Additionally, mechanical ventilation time, hospitalization duration, incidence of ventilator-associated pneumonia (VAP), and disease outcomes were recorded and compared between the two groups.Results: Both groups were assessed with medium to high nutritional risk, with no significant difference in the degree of nutritional risk (P > 0.05). After intervention, total protein, albumin, and prealbumin levels increased in both groups, with the experimental group showing significantly higher levels than the control group (P < 0.05). VAP predominantly occurred in the control group, with an incidence rate of 7% (3/45), showing a statistically significant difference between the two groups (P < 0.05). The experimental group exhibited significantly shorter Length of hospital stay and mechanical ventilation duration compared to the control group (P < 0.05). Moreover, there was no statistically significant difference in disease outcomes between the two groups (P > 0.05).Conclusion: Short peptide enteral nutrition formulation contributes to improving the treatment outcomes of mechanically ventilated pneumonia patients, providing a therapeutic approach for the nutritional support of critically ill children requiring mechanical ventilation.Keywords: short peptide enteral nutrition formulation, mechanical ventilation, pediatric patients with severe pneumonia, nutritional status

Bing Liu,1– 3,&ast; Zhiyao Bao,1– 3,&ast; Wei Chen,1– 3,&ast; Xiaotong Xi,4,5,&ast; Xiao Ge,1– 3 Jun Zhou,1– 3 Xiaoyan Zheng,6 Peipei Zhang,4,5 Wanglong Deng,4,5 Ran Ding,4,5 Min Zhou,1– 3 Jie Fang7 1Department of Pulmonary and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People’s Republic of China; 2Institute of Respiratory Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People’s Republic of China; 3Shanghai Key Laboratory of Emergency Prevention, Diagnosis and Treatment of Respiratory Infectious Diseases, Shanghai, 200025, People’s Republic of China; 4State Key Laboratory of Neurology and Oncology Drug Development, Jiangsu Simcere Diagnostics Co., Ltd., Nanjing Simcere Medical Laboratory Science Co., Ltd., Nanjing, 210018, People’s Republic of China; 5Nanjing Simcere Medical Laboratory Science Co., Ltd., Nanjing, 210018, People’s Republic of China; 6Department of Pulmonary and Critical Care Medicine, Zhoushan Branch of Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Zhoushan, 316000, People’s Republic of China; 7Department of Pharmacy, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jie Fang, Department of Pharmacy, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Rui Jin 2nd Road, Shanghai, 200025, People’s Republic of China, Email fj40517@rjh.com.cn Min Zhou, Department of Pulmonary and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Rui Jin 2nd Road, Shanghai, 200025, People’s Republic of China, Email doctor_zhou_99@163.comBackground: Targeted next-generation sequencing (tNGS) is a high-throughput and cost-effective diagnostic alternative for pneumonia, with the ability to simultaneously detect pathogens, antimicrobial resistance genes, and virulence genes. We aimed to explore the applicability of tNGS in the co-detection of the responsible pathogens, antimicrobial resistance (AMR) genes, and virulence genes in patients with pneumonia.Methods: A prospective study was conducted among patients with suspected pneumonia at Ruijin Hospital from March 1 to May 31, 2023. Bronchoalveolar lavage fluid (BALF) or sputum samples were collected and sent for tNGS, metagenomic next-generation sequencing (mNGS), and conventional microbiological tests (CMTs).Results: In total, 67 BALF and 11 sputum samples from 78 patients were included in the analyses. According to the composite reference standards, the accuracy of tNGS in the detection of responsible pathogens was 0.852 (95% confidence interval 0.786– 0.918), which resembled that of mNGS and remarkably exceeded that of CMTs. In addition, 81 AMR genes associated with responsible pathogens were reported, and 75.8% (25/33) priority drug-resistant pathogens could be directly identified. A total of 144 virulence genes were detected for four common pathogens. And patients with virulence genes detected were of higher proportions of severe pneumonia (95.0% vs 42.9%, P = 0.009), acute respiratory distress syndrome (55.0% vs 0%, P = 0.022), and neutrophils (82.3% vs 62.2%, P = 0.026) than those not.Conclusion: In patients with pneumonia, tNGS could detect the responsible pathogens, AMR genes, and virulence genes simultaneously, serving as an efficient and cost-effective tool for the diagnosis, treatment, and severity indication of pneumonia.Keywords: targeted next-generation sequencing, pneumonia, pathogen, antimicrobial resistance, virulence

Qin Guo,1,&ast; Shengying Xia,2,&ast; Yan Ding,3 Fan Liu3 1Department of General Surgery, Wuhan Children’s Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, 430016, People’s Republic of China; 2Department of Emergency and Critical Care Center, Wuhan Children’s Hospital, Tongji Medical College, Huazhong University of Science &Technology, Wuhan, 430016, People’s Republic of China; 3Department of Rheumatology and Immunology, Wuhan Children’s Hospital, Tongji Medical College, Huazhong University of Science &Technology, Wuhan, 430016, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fan Liu; Yan Ding, Department of Rheumatology and Immunology, Wuhan Children’s Hospital, Tongji Medical College, Huazhong University of Science &Technology, No. 100 hong Kong Road, Jiang’an District, Wuhan, 430016, People’s Republic of China, Tel +86 02782824022, Email LFwhetyy@outlook.com; DYwhetyy@outlook.comBackground: Henoch-Schönlein Purpura (HSP) is a common systemic vasculitis in children that often involves the gastrointestinal system (GIS). Identifying reliable predictive markers for GIS complications is crucial for early intervention and improved patient outcomes.Objective: This study aims to identify laboratory markers predictive of GIS complications in children with HSP using a machine learning approach.Methods: This retrospective study included children diagnosed with HSP and a control group from May 2020 to January 2024. Detailed demographic and laboratory data, including WBC count, lymphocyte count, neutrophil count, platelet count, hemoglobin, NLR, PLR, MPV, MPR, C-reactive protein, ESR, albumin, BUN, creatinine, sodium, potassium, calcium, IgA, PT, aPTT, and INR, were collected. GIS complications was classified based on clinical symptoms and diagnostic findings. Patients were categorized into groups without GIS complications, with mild GIS complications, and with severe GIS complications. We compared laboratory parameters across these groups to identify significant differences associated with GIS complications. Furthermore, a predictive model was developed by a Random Forest classifier to identify key markers and assess their ability to distinguish between patients with and without GIS complications.Results: Significant differences were observed in several laboratory parameters between HSP patients and the control group, and between patients with and without GIS complications. Key predictive markers identified included neutrophil count, NLR, WBC count, PLR, and platelet count. The RandomForest model achieved an accuracy of 91% and an AUC of 0.90.Conclusion: Our findings highlight the importance of specific laboratory markers in predicting GIS complications in HSP. The use of machine learning models can enhance the early identification and management of high-risk patients, potentially improving clinical outcomes.Keywords: Henoch-Schönlein Purpura, gastrointestinal complications, laboratory markers, machine learning, random forest classifier

Abstract The current single-cell analysis technologies such as fluorescence-activated cell sorting (FACS) and fluorescence-activated droplet sorting (FADS) could decipher the cellular heterogeneity but were constrained by low sorting performance and cell viability. Here, an ultra-sensitive single-cell sorting platform has been developed by integrating the FADS technology with Tetramer-HCR-EvaGreen (THE) fluorescence signal amplification. The THE system produced much higher fluorescence signal than that of the single Tetramer or Tetramer-HCR signal amplification. Upon application to target MCF-7 cells, the platform exhibited high efficacy and selectivity while maintaining more than 95% cell viability. The THE-FADS achieved sorting efficiencies of 55.5% and 50.3% with purities of 91% and 85% for MCF-7 cells in PBS solutions and simulated serum samples, respectively. The sorted MCF-7 cells showed similar proliferation together with CK19 and EGFR mRNA expression compared with the control cells. The established THE-FADS showed the promising prospects to cellular heterogeneity understanding and personalized medicine.

Shuzhe Xiao,1,* Yue Ding,1,* Chen Du,1,* Yiting Lv,1 Shumei Yang,1,2 Qi Zheng,3 Zhiqiu Wang,3 Qiaoli Zheng,3 Meifang Huang,1 Qingyan Xiao,1 Zhuxiao Ren,2 Guangliang Bi,1 Jie Yang1,2 1Department of Neonatology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of China; 2Department of Neonatology, Guangdong Women and Children Hospital, Guangzhou, 511442, People’s Republic of China; 3The First Clinical Medical College of Southern Medical University, Guangzhou, 510515, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jie Yang; Guangliang Bi, Email Jieyang0830@126.com; bader515@163.comBackground: Autophagy and immunity play important regulatory roles in lung developmental disorders. However, there is currently a lack of bioinformatics analysis on autophagy-related genes (ARGs) and immune infiltration in bronchopulmonary dysplasia (BPD). We aim to screen and validate the signature genes of BPD by bioinformatics and in vivo experiment.Methods: GSE8586 was obtained from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified using the R program. Using cell-type identification with CIBERSORT to analyze the inflammatory and immune status of BPD. Subsequently, the hub genes were identified by Lasso and Cytoscape with three machine-learning algorithms (MCC, Degree and MCODE). In addition, hub genes were validated with ROC, single-cell sequence and IHC in hyperoxia mice. Finally, we searched the drug targets of these hub genes, and established a nomogram model for predicting the risk of BPD.Results: There were 73 the differentially expressed and autophagy-related genes (DE-ARGs) by overlapping the DEGs in GSE8586 and ARGs. Five hub genes, BRIX1, JUN, PES1, NR4A1 and RRP9, were lowly expressed in the BPD group and had high diagnostic value in the diagnostic model. All hub genes are mainly located in B cell, epithelial cell, fibroblast, endothelial cell, smooth muscle cell and pneumocyte in lung single-cell sequencing. Moreover, immune infiltration analysis showed immune cells were higher in the BPD group and were closely associated with hub genes. We also predict the drug targets of the genes. Finally, the IHC result in mice showed that expression of PES1, BRX1, RRP9, JUN, NR4A1 was lower in the hyperoxia group compared to the normoxia group.Conclusion: BRIX1, JUN, PES1, NR4A1, RRP9, may be promising therapeutic targets for BPD. Our findings provided researchers and clinicians with more evidence regarding immunotherapeutic strategies for BPD treatment.Keywords: BPD, autophagy, immune cell infiltration, single cell sequencing, biomarkers

The problem of data privacy protection in the information age deserves people’s attention. As a distributed machine learning technology, federated learning can effectively solve the problem of privacy security and data silos. Differential privacy(DP) technology is applied in federated learning(FL). By adding noise to raw data and model parameters, it can further enhance the degree of data privacy protection. Over the years, differential privacy technology based on federated learning framework has been developed, which is divided into central differential privacy federated learning(CDPFL) and local differential privacy federated learning(LDPFL). Although differential privacy may reduce the accuracy and convergence of federated learning models while protecting data privacy, researchers have proposed a variety of optimization methods to balance privacy protection and model performance. This paper comprehensively expounds the research status of differential privacy techniques based on the federated learning framework, first providing detailed introductions to federated learning and differential privacy technologies, and then summarizing the development status of two types of federated learning differential privacy(DPFL) techniques respectively; for CDPFL, the paper divides the discussion into first proposal of CDP and typical application examples, the impact of Gaussian mechanisms on model accuracy, optimization based on asynchronous differential privacy, and insights from other scholars; for LDPFL, the paper divides the discussion into first proposal of LDP and typical application examples, processing multidimensional data and improving model accuracy, existing methods and optimization for reducing communication costs, balancing privacy protection and data usability, LDPFL based on the Shuffle model, and insights from other scholars; following this, the paper addresses and summarizes the unique challenges introduced by incorporating differential privacy into federated learning and proposes solutions; finally, based on a summary of existing optimization techniques, the paper outlines future directions and specifically discusses three research ideas for enhancing the optimization effects of federated differential privacy: advanced optimization strategies combining Bayesian methods and the Alternating Direction Method of Multipliers (ADMM), integrating lattice homomorphic encryption techniques from cryptography to achieve more efficient differential privacy protection in federated learning, and exploring the application of zero-knowledge proof techniques in federated learning for privacy protection.

Texture and anisotropy control of rolled strip have always been a technical problem in titanium alloy industry, especially for near-alpha titanium alloys. In order to solve the above problems, we innovatively propose a process method for efficiently preparing weakly anisotropic alloy strips. In this paper, the texture evolution and anisotropy of TA18 titanium alloy strip under various rolling and heat treatment conditions were systematically studied by EBSD and other technical means. The results have showed that the hot-rolled TA18 titanium alloy has a distinct band microstructure along the RD. The obvious tensile properties anisotropy of hot-rolled TA18 titanium alloy is mainly due to the non-uniform microstructure formed and strong T-type micro-texture. The hot-rolled TA18 titanium alloy after 700 °C/3h heat treatment occurred complete recrystallization process, which formed the fine and uniform equiaxed grains. Texture components distribution of the titanium alloy changed from typical bimodal texture to the tendency of //normal direction (ND) base plane texture. The hot-rolled TA18 titanium alloy after heat treatment at 700 °C/3h, followed by rolling to 4.8 mm at room temperature and annealing at 730 °C/1h, could effectively reduce the anisotropy of titanium alloys. Finally, the formation of anisotropy of yield strength was considered as the different slip activation behaviors due to the influence of micro-texture orientation. This study innovatively proposes an efficient method for fabricating alloy strips with reduced anisotropy forTA18 titanium alloy strips.

Introduction: Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer after hepatocellular carcinoma. Through data mining of publicly available iCCA transcriptomic datasets from the Gene Expression Omnibus, we identified SFN as the most significantly up-regulated gene in iCCA compared to normal tissue, focusing on the Gene Ontology term ''cell proliferation'' (GO:0008283). SFN encodes the 14-3-3σ protein, also known as stratifin, which plays crucial roles in various cellular processes. Materials and methods: Immunohistochemistry was used to assess stratifin expression in 182 patients with localized iCCAs undergoing surgical resection. Patients were divided into low and high expression groups, and the association between stratifin expression and clinicopathological features was analyzed. Univariate and multivariate survival analyses were performed to assess overall survival (OS), disease-specific survival (DSS), local recurrence-free survival (LRFS), and metastasis-free survival (MeFS). Results: Elevated stratifin expression in iCCAs was significantly associated with the absence of hepatitis, positive surgical margins, advanced primary tumor stages, and higher histological grades (all p ≤ 0.011). Survival analyses demonstrated a significant negative association between stratifin expression and all prognostic indicators, including OS, DSS, LRFS, and MeFS (all p ≤ 0.0004). Multivariate analysis revealed that stratifin overexpression was significantly correlated with poorer outcomes in terms of DSS, LRFS, and MeFS (all p

Jiayi Ding,1 Xueliang Zhang,2 Le Guo,1 Jiabao Xiong,3 Chi Zhang,1 Zhong Du,3 Lijun Zhu,3 Nuernisha Alifu,1– 3 Biao Dong2,4 1Institute of Public Health, Xinjiang Medical University, Urumqi, 830011, People’s Republic of China; 2State Key Laboratory of Pathogenesis Prevention and Treatment of High Incidence Diseases in Central Asia, School of Medical Engineering and Technology Xinjiang Medical University, Urumqi, 830011, People’s Republic of China; 3Second Clinical Medical College, Xinjiang Medical University, Urumqi, 830011, People’s Republic of China; 4State Key Laboratory on Integrated Optoelectronics, College of Electronic Science and Engineering, Jilin University, Changchun, 130012, People’s Republic of ChinaCorrespondence: Nuernisha Alifu, State Key Laboratory of Pathogenesis Prevention and Treatment of High Incidence Diseases in Central Asia, School of Medical Engineering and Technology Xinjiang Medical University, Urumqi, 830011, People’s Republic of China, Tel +86-18799167931, Email nens_xjmu@126.com Biao Dong, State Key Laboratory on Integrated Optoelectronics, College of Electronic Science and Engineering, Jilin University, Changchun, 130012, People’s Republic of China, Tel +86-13504329842, Email dongb@jlu.edu.cnPurpose: A synergistic treatment strategy of phototherapy and chemotherapy has been shown to improve efficacy and offer unique advantages over monotherapy. The purpose of this study is to explore a new nanocarrier system with liposome as the inner membrane and erythrocyte membrane as the outer membrane, which aims to realize the leak-free load of phototherapy drug indocyanine green (ICG) and chemotherapy drug doxorubicin (DOX), prolong the circulation time in vivo and improve the therapeutic effect.Patients and Methods: In this study, bilayer membrane-loaded ICG and DOX nanoparticles (RBC@ICG-DOX NPs) were prepared and characterized. For in vitro analysis, the biocompatibility and tumor inhibition properties of the nanoparticles were evaluated. For in vivo analysis, the antitumor properties of the nanoparticles were explored in a mouse subcutaneous tumor model.Results: RBC@ICG-DOX NPs were successfully prepared with strong safety and good blood compatibility, which can effectively reduce drug leakage and prolong drug circulation time in the body. In vitro performance evaluation showed that RBC@ICG-DOX NPs obtained excellent photothermal conversion ability and well reactive oxygen generation performance under near-infrared laser irradiation. Both in vitro and in vivo experiments showed well phototherapy-chemotherapy effect of RBC@ICG-DOX NPs with low toxic side effects.Conclusion: Drug delivery, imaging and tumor synergies were accomplished through combinatorial strategies as well as bilayer membrane encapsulation, opening up a new platform for the design of future tumor combination therapies.Keywords: erythrocyte membrane modification, indocyanine green, adriamycin, combination therapy, cervical cancer

Yuwei Jiang,1,&ast; Jiaoya Xu,1,2,&ast; Junyao Ding,1,&ast; Tao Liu,1 Yang Liu,1,3 Ping Huang,1 Qianlei Wang,1 Peiyong Zheng,1 Haiyan Song,1 Lili Yang1 1Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2Department of Gout, Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 3Teaching Experiment Center, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Haiyan Song; Lili Yang, Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai, 200032, People’s Republic of China, Email songhy@126.com; yanglili76@126.comPurpose: Mitochondrial dysfunction mediated by c-Jun N-terminal kinase (JNK) plays an important role in lipotoxic liver injury in nonalcoholic steatohepatitis (NASH). This study aims to investigate the pharmacological mechanism of Jiangzhi Granule (JZG), a Chinese herbal formula against NASH, with a focus on its regulation of JNK signaling-mediated mitochondrial function.Methods: Hepatocytes were induced by palmitic acid (PA) for 24 h to establish an in vitro lipotoxic model, which was simultaneously treated with either JZG or vehicle control. Male C57BL/6J mice were fed a high-fat diet (HFD) for 22 weeks and then treated with JZG via gavage for additional 8 weeks. Lipotoxic injury in hepatocytes or mice liver tissues, as well as JNK signaling-related molecules, were further investigated.Results: JZG improved PA-induced lipid deposition, cell viability, apoptosis, and mitochondrial dysfunction in hepatocytes. In NASH mice, JZG reduced hepatosteatosis, and inflammatory infiltration, and improved mitochondrial morphology and quantity in liver tissues. Additionally, elevated phosphorylation ratio of non-receptor tyrosine kinase c-Src (Src) and reduced phosphorylation ratio of JNK and SH2-containing protein tyrosine phosphatase (SHP-1) were found in both hepatocytes and mice liver tissues treated with JZG versus those with the vehicle.Conclusion: Taken together, JZG could improve mitochondrial dysfunction and reduce lipotoxic liver injury in NASH in vivo and in vitro models. The inhibition of the JNK signaling pathway may contribute to the underlying mechanism of JZG in preventing and reversing NASH development. Keywords: nonalcoholic steatohepatitis, Jiangzhi Granule, c-Jun N-terminal kinase, mitochondrial dysfunction, lipotoxic injury

Abstract. Background:. As an essential part of health services, rehabilitation is of great significance to improve the health and quality of life of the whole population. Accelerating aging calls for a significant expansion of rehabilitation services in China, but rehabilitation needs remain unclear. We conducted the study to explore the rehabilitation needs in China and project the trend of rehabilitation needs from 2020 to 2034. Methods:. The data of health conditions that might potentially benefit from rehabilitation were obtained from Global Burden of Disease (GBD) study. Estimated annual percentage changes (EAPCs) were calculated to quantify the trends of the age-standardized rates. Projections of rehabilitation needs were made until 2034 using Bayesian age–period–cohort analysis (BAPC). Results:. Approximately 460 million persons (33.3% of the total population) need rehabilitation in China, contributing to 63 million years lived with disabilities (YLDs) in 2019. The number of prevalent cases that need rehabilitation increased from around 268 (95% uncertainty interval [UI]: 257–282) million in 1990 to almost 460 (95% UI: 443–479) million in 2019, representing an increase of 71.3%. The highest contribution to the need for rehabilitation was musculoskeletal disorders with about 322 (95% UI: 302–343) million persons in seven aggregate disease and injury categories, and hearing loss with over 95 (95% UI: 84–107) million people among 25 health conditions. Based on the projection results, there will be almost 636 million people (45% of the total population) needing rehabilitation services in China by 2034, representing an increase of 38.3%. The rehabilitation needs of neoplasms, cardiovascular diseases, and neurological disorders are expected to increase significantly from 2019 to 2034, with increases of 102.3%, 88.8% and 73.2%, respectively. Conclusions:. The need for rehabilitation in China substantially increased over the last 30 years. It is predicted that over two in five people will require rehabilitation by 2034, thus suggesting the need to develop rehabilitation services that meet individuals’ rehabilitation needs.

The loss of speech function following a laryngectomy usually leads to severe physiological and psychological distress for laryngectomees. In clinical practice, most laryngectomees retain intact upper tract articulatory organs, emphasizing the significance of speech rehabilitation that utilizes articulatory motion information to effectively restore speech. This study proposed a deep learning-based end-to-end method for speech reconstruction using ultrasound tongue images. Initially, ultrasound tongue images and speech data were collected simultaneously with a designed Mandarin corpus. Subsequently, a speech reconstruction model was built based on adversarial neural networks. The model includes a pretrained feature extractor to process ultrasound images, an upsampling block to generate speech, and discriminators to ensure the similarity and fidelity of the reconstructed speech. Finally, both objective and subjective evaluations were conducted for the reconstructed speech. The reconstructed speech demonstrated high intelligibility in both Mandarin phonemes and tones. The character error rate of phonemes in automatic speech recognition was 0.2605, and tone error rate obtained from dictation tests was 0.1784, respectively. Objective results showed high similarity between the reconstructed and ground truth speech. Subjective perception results also indicated an acceptable level of naturalness. The proposed method demonstrates its capability to reconstruct tonal Mandarin speech from ultrasound tongue images. However, future research should concentrate on specific conditions of laryngectomees, aiming to enhance and optimize model performance. This will be achieved by enlarging training datasets, investigating the impact of ultrasound tongue imaging parameters, and further refining this method.

Abstract We present an analysis of lepton-jet azimuthal decorrelation in deep-inelastic scattering (DIS) at next-to-next-to-next-to-leading logarithmic (N3LL) accuracy, combined with fixed-order corrections at O α s 2 $$ \mathcal{O}\left({\alpha}_s^2\right) $$ . In this study, jets are defined in the lab frame using the anti-k T clustering algorithm and the winner-take-all recombination scheme. The N3LL resummation results are derived from the transverse-momentum dependent factorization formula within the soft-collinear effective theory, while the O α s 2 $$ \mathcal{O}\left({\alpha}_s^2\right) $$ fixed-order matching distribution is calculated using the NLOJET++ event generator. The azimuthal decorrelation between the jet and electron serves as a critical probe of the three-dimensional structure of the nucleon. Our numerical predictions provide a robust framework for precision studies of QCD and the nucleon’s internal structure through jet observables in DIS. These results are particularly significant for analyses involving jets in HERA data and the forthcoming electron-ion collider experiments.

Abstract Human-machine interaction has emerged as a revolutionary and transformative technology, bridging the gap between human and machine. Gesture recognition, capitalizing on the inherent dexterity of human hands, plays a crucial role in human-machine interaction. However, existing systems often struggle to meet user expectations in terms of comfort, wearability, and seamless daily integration. Here, we propose a handwriting recognition technology utilizing an intelligent hybrid-fabric wristband system. This system integrates spun-film sensors into textiles to form the smart fabric, enabling intelligent functionalities. A thermal encapsulation process is proposed to bond multiple spun-films without additional materials, ensuring the lightweight, breathability, and stretchability of the spun-film sensors. Furthermore, recognition algorithms facilitate precise accurate handwriting recognition of letters, with an accuracy of 96.63%. This system represents a significant step forward in the development of ergonomic and user-friendly wearable devices for enhanced human-machine interaction, particularly in the virtual world.

Abstract Background Although immunotherapy has achieved great progress in advanced triple-negative breast cancer (TNBC), there are still numerous patients who do not benefit from immunotherapy. Therefore, identification of the key molecule that induces immune escape and clarification of its specific mechanism in TNBC are urgently needed. Methods In this research, single cell sequencing and bulk sequencing were conducted for biomarker screening. Immunohistochemistry, multiplex immunofluorescence, and orthotopic TNBC tumor model were applied in identifying the key molecule driving immune escape. At the mechanical level, RNA sequencing, in vitro co-culturing system, flow cytometry, Western blotting, ELISA, and real-time qPCR were carried out. Results Mortality factor 4 like 2 (MORF4L2) expression is significantly up-regulated among patients who developed anti-PD1 resistance. MORF4L2 enhances anti-PD1 resistance by inducing the chemotaxis of macrophage infiltration and promoting their polarization towards the alternative activation phenotype (M2), thus creating an immunosuppressive microenvironment. Mechanistically, MORF4L2 actes as part of NuA4 histone acetyltransferase (HAT) complex, contributes to to histone 4 lysine 12 acetylation (H4K12Ac) and activates the downstream transcription of macrophage colony-stimulating factor (CSF1). CSF1 is secreted by tumor cells and binds to the macrophage-surface CSF1 receptor (CSF1R), which chemotactically converted and polarized macrophages to the M2 phenotype. Furthermore, we revealed that grainyhead like transcription factor 2 (GRHL2) could promote MORF4L2 transcription by binding to the MORF4L2 enhancer region. Notably, BLZ549, an inhibitor of CSF1R, restored the anti-PD1 sensitivity by blocking the GRHL2/MORF4L2/H4K12Ac/CSF1 axis. Conclusions GRHL2/MORF4L2/H4K12Ac/CSF1 axis plays an important role in anti-PD1 resistance. CSF1R inhibitors can reverse GRHL2/MORF4L2-mediated anti-PD1 resistance.

Abstract Background Enteric infections are among the most common infectious diseases. The aim of this article was to track the global trends in morbidity and mortality from enteric infections in 204 countries or territories from 1990 to 2019. Methods Data were obtained from the Global Burden of Disease 2019 study. Average annual percentage changes (AAPCs) in age-standardized incidence rate (ASIR) and age-standardized mortality rate (ASMR) were calculated to quantify trends in enteric infections. Age-period-cohort models were used to estimate the annual percentage changes from 0 to 4 to 80 − 84 years (local drifts), period and cohort effects between 1990 and 2019 in different socio-demographic index (SDI) regions. Results In 2019, there were 6.59 billion incident cases of enteric infections, and caused 1,748,251 deaths worldwide. From 1990 to 2019, the trend in the global ASIR of enteric infections was relatively stable, but that of ASMR declined (AAPC=-3.30, 95% confidence interval [CI]: -3.54 to -3.07), and global mortality decreased in all age groups. Meanwhile, decreasing trends in ASMR were observed in 173 countries/territories (P

Introduction: Over decades, the source-function relationships of bioactive polysaccharides have been progressively investigated, however, it is still unclear how a defined structure may conduce to the bioactivities of polysaccharides. Objectives: To explore the structure–function relationship of fungus polysaccharides, we employed a dextran sulfate sodium (DSS)‐induced colitis mouse model to compare the anti-inflammatory activity of two fungus polysaccharides from Dictyophora indusiata (DIP) and Tremella fuciformis (TFP), which exhibit distinct glycosidic linkages. Methods: The structures of DIP and TFP were characterized through molecular weight detection, molecular morphology analysis, methylation analysis, and NMR analysis. Subsequently, we employed a DSS-induced colitis model to assess the anti-inflammatory efficacy of DIP and TFP. The colitis symptoms, histological morphology, intestinal inflammatory cytokines, and the composition and function of gut microbiota before and after polysaccharides treatment in colitis mice were also investigated. Results: DIP, l,3-β-D-glucan with 1,4-β and 1,6-β-D-Glcp as branched chains, exhibited superior therapeutic effect than that of TFP consisted of a linear 1,3-α-D-mannose backbone with D-xylose and L-fucose in the side chains. Both DIP and TFP relieved DSS-induced colitis in a gut microbiota-dependent manner. Furthermore, metagenomics showed that DIP and TFP could partially reverse the bacterial function in colitis mice. Glycoside Hydrolase 1 (GH1) and GH3 were identified as being involved in hydrolyzing the glucose linkages in DIP, while GH92 and GH29 were predicted to be active in cleaving the α-1,3-linked mannose linkages and the glycosidic bonds of L-fucose residues in TFP. Conclusion: Our findings highlight the pivotal role of glycosidic linkages in anti-inflammatory activities of fungus polysaccharides and would promote the design and discovery of polysaccharides with designated activity to be used as functional foods and/or therapeutics.

Chronic obstructive pulmonary disease (COPD) is one of the major chronic airway diseases, with the highest prevalence among individuals over 60 years old, significantly impacting the health of elderly patients. Guidelines of prevention and treatment for COPD in domestic and abroad recommend pulmonary rehabilitation as a complementary and effective adjunct to pharmacological treatment. Pulmonary rehabilitation can significantly improve patients' respiratory function and physical fitness, alleviate symptoms, reduce hospitalization and mortality rates. However, the specific contents of pulmonary rehabilitation for elderly patients with COPD in different stages were different. This expert consensus elaborates on the assessment and treatment methods of pulmonary rehabilitation for elderly patients with COPD in the acute exacerbation stage, post-exacerbation remission stage and outpatient stable stage, aiming to provide guidance for pulmonary rehabilitation treatment at different stages of COPD. This expert consensus identifies common functional impairments of elderly patients with COPD, including respiratory dysfunction, exercise tolerance impairment, psychological issues, swallowing dysfunction and cognitive impairment. It recommends a comprehensive assessment for multifaceted impairments of elderly patients with COPD based on the International Classification of Functioning, Disability and Health (ICF) framework from four aspects including body structure, body function (respiratory function, cardiac function, motor function, psychological and cognitive function, swallowing function, and nutritional factors), activity and participation, and environmental factors. Pulmonary rehabilitation is suitable for all patients with relevant symptoms of COPD and/or those at high risk of acute exacerbations (high-level evidence). The rehabilitation team, treatment plan, and treatment location should be adjusted in time as the condition evolves and changes, to establish a full-cycle rehabilitation. Smoking cessation is a crucial intervention to slow down the decline of lung function and the progression of COPD (high-level evidence). Through adequate nutritional support, elderly patients with COPD can improve nutritional status, and enhance physical strength and quality of life, so as to better manage the disease and promote rehabilitation (low to moderate-level evidence). Oxygen therapy is recommended for patients with advanced COPD who remain hypoxemic at rest (low to moderate-level evidence). Some emerging rehabilitation treatments (such as neuromuscular electrical stimulation, acupuncture and certain traditional Chinese medicines) may be beneficial for elderly patients with COPD (low to moderate-level evidence). Rehabilitation treatment process was divided into phase Ⅰ, phase Ⅱ and phase Ⅲ of pulmonary rehabilitation based on the different stages of elderly patients with COPD in this expert consensus. It further details the target population, implementation location, rehabilitation content, assessment content, participating disciplines and rehabilitation goals for each phase in the rehabilitation process. The consensus emphasizes that multidisciplinary personnel, including clinical respiratory specialists, primary care physicians, rehabilitation physicians/therapists, nurses, nutritionists, psychiatrists/psychologists and social workers should actively coordinate and collaborate in the full-cycle rehabilitation process for elderly patients with COPD.

Objective: The independent rôle of impulsivity in alcoholism patient’s suicidality is less elucidated. In this study, we intended to investigate how impulsivity and depression contribute to suicidality in patients with alcohol use disorder (AUD). Methods: We recruited 27 adult patients with AUD and major depressive disorder (AUD with MDD) and 33 with AUD only (AUD without MDD). We assessed suicidality, alcohol use severity, depression severity, impulsivity, and other psychiatric comorbidities. Suicidality was quantified for the frequency of previous history of suicide attempts and for current suicide intent/tendency. Impulsivity was measured using the Barratt Impulsiveness Scale (BIS). We addressed how impulsivity contributed to both suicidality indices in multiple ordinal regressions. Results: Patients with AUD with MDD versus those with AUD without MDD showed significantly higher suicidality (p < 0.001), significantly more severe alcohol (p < 0.01), significantly more polysubstance use (p < 0.05), significantly more anxiety comorbidities (p < 0.05), and significantly higher BIS scores (p < 0.001). In a better-fitting final model using regression with stepwise elimination, the BIS total score was independently and significantly associated with current suicide tendency (p < 0.05) and frequency of previous suicide attempts (p < 0.01). In contrast, the Hamilton Depression Rating Scale-17 score was significantly associated only with current suicidal tendencies (p < 0.01), but not with the frequency of previous attempts. Conclusion: Depressed patients relative to nondepressed individuals with AUD showed higher suicidality, Barratt impulsivity, and severity of alcohol use. Across groups, BIS impulsivity but not the severity of depression was found to predict suicidality. We suggest that suicide prevention efforts may include assessment of impulsivity in AUD patients.

Abstract Cancer is among the leading causes of death related diseases worldwide, and lung cancer has the highest mortality rate in the world. Transcription factors (TFs) constitute a class of structurally and functionally intricate proteins. Aberrant expression or functional deficiencies of transcription factors may give rise to abnormal gene expression, contributing to various diseases, including tumours. In this study, we propose to elucidate the potential role and mechanism of TFAP2A in NSCLC. We found that TFAP2A levels were significantly greater in tumour tissues than para-tumour tissues, and high expression of TFAP2A was associated with poor prognosis in NSCLC patients. Additionally, TFAP2A overexpression promoted NSCLC progression both in vivo and in vitro. Mechanistically, ESR2 is a potential target regulated by TFAP2A and that TFAP2A can bind to the promoter region of ESR2. Furthermore, the overexpression of both TFAP2A and ESR2 in NSCLC cells was associated with the overactivation of MAPK signalling, and the combination of PHTPP and osimertinib had a synergistic effect on suppressing tumour growth.

Abstract Sepsis, characterized as life-threatening organ dysfunction resulting from dysregulated host responses to infection, remains a significant challenge in clinical practice. Despite advancements in understanding host-bacterial interactions, molecular responses, and therapeutic approaches, the mortality rate associated with sepsis has consistently ranged between 10 and 16%. This elevated mortality highlights critical gaps in our comprehension of sepsis etiology. Traditionally linked to bacterial and fungal pathogens, recent outbreaks of acute viral infections, including Middle East respiratory syndrome coronavirus (MERS-CoV), influenza virus, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), among other regional epidemics, have underscored the role of viral pathogenesis in sepsis, particularly when critically ill patients exhibit classic symptoms indicative of sepsis. However, many cases of viral-induced sepsis are frequently underdiagnosed because standard evaluations typically exclude viral panels. Moreover, these viruses not only activate conventional pattern recognition receptors (PRRs) and retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) but also initiate primary antiviral pathways such as cyclic guanosine monophosphate adenosine monophosphate (GMP-AMP) synthase (cGAS)-stimulator of interferon genes (STING) signaling and interferon response mechanisms. Such activations lead to cellular stress, metabolic disturbances, and extensive cell damage that exacerbate tissue injury while leading to a spectrum of clinical manifestations. This complexity poses substantial challenges for the clinical management of affected cases. In this review, we elucidate the definition and diagnosis criteria for viral sepsis while synthesizing current knowledge regarding its etiology, epidemiology, and pathophysiology, molecular mechanisms involved therein as well as their impact on immune-mediated organ damage. Additionally, we discuss clinical considerations related to both existing therapies and advanced treatment interventions, aiming to enhance the comprehensive understanding surrounding viral sepsis.

Abstract Background The modification of protein substrates by small ubiquitin-related modifier (SUMO) plays a vital role in plants subjected to biotic and abiotic stresses. However, its role in the stress responses of Brassica plants remains poorly understood. Results A genome-wide analysis revealed the presence of 30 SUMOylation genes in the Caixin genome. These results demonstrated that the Caixin genome contains all the necessary components for SUMOylation. Analysis of the cis-acting elements revealed that the promoters of SUMOylation genes presented diverse combinations of developmental and stress-related cis-regulatory elements. The RNA-seq data indicated that 23 SUMOylation genes presented relatively high expression levels under normal conditions and exhibited a notable decrease in expression following Pectobacterium carotovorum subsp. carotovorum (Pcc) infection. Additionally, dynamic alterations in SUMO conjugates were observed in response to Pcc infection. Conclusions The Caixin genome contains genes involved in SUMOylation. The majority of these genes presented multiple copies, and analyses of their transcription and protein profiles indicate that they may play a role in the response to Pcc infection.

Abstract Background We aimed to develop and validate models for predicting intensive care unit (ICU) mortality of critically ill adult patients as early as upon ICU admission. Methods Combined data of 79,657 admissions from two teaching hospitals’ ICU databases were used to train and validate the machine learning models to predict ICU mortality upon ICU admission and at 24 h after ICU admission by using logistic regression, gradient boosted trees (GBT), and deep learning algorithms. Results In the testing dataset for the admission models, the ICU mortality rate was 7%, and 38.4% of patients were discharged alive or dead within 1 day of ICU admission. The area under the receiver operating characteristic curve (0.856, 95% CI 0.845–0.867) and area under the precision-recall curve (0.331, 95% CI 0.323–0.339) were the highest for the admission GBT model. The ICU mortality rate was 17.4% in the 24-hour testing dataset, and the performance was the highest for the 24-hour GBT model. Conclusion The ADM models can provide crucial information on ICU mortality as early as upon ICU admission. 24 H models can be used to improve the prediction of ICU mortality for patients discharged more than 1 day after ICU admission.

Abstract Cranial radiation therapy (RT) for brain cancers is often associated with the development of radiation-induced cognitive dysfunction (RICD). RICD significantly impacts the quality of life for cancer survivors, highlighting an unmet medical need. Previous human studies revealed a marked reduction in plasma brain-derived neurotrophic factor (BDNF) post-chronic chemotherapy, linking this decline to a substantial cognitive dysfunction among cancer survivors. Moreover, riluzole (RZ)-mediated increased BDNF in vivo in the chemotherapy-exposed mice reversed cognitive decline. RZ is an FDA-approved medication for ALS known to increase BDNF in vivo. In an effort to mitigate the detrimental effects of RT-induced BDNF decline in RICD, we tested the efficacy of RZ in a cranially irradiated (9 Gy) adult mouse model. Notably, RT-exposed mice exhibited significantly reduced hippocampal BDNF, accompanied by increased neuroinflammation, loss of neuronal plasticity-related immediate early gene product, cFos, and synaptic density. Spatial transcriptomic profiling comparing the RT + Vehicle with the RT + RZ group showed gene expression signatures of neuroprotection of hippocampal excitatory neurons post-RZ. RT-exposed mice performed poorly on learning and memory, and memory consolidation tasks. However, irradiated mice receiving RZ (13 mg/kg, drinking water) for 6–7 weeks showed a significant improvement in cognitive function compared to RT-exposed mice receiving vehicle. Dual-immunofluorescence staining, spatial transcriptomics, and biochemical assessment of RZ-treated irradiated brains demonstrated preservation of synaptic integrity and mature neuronal plasticity but not neurogenesis and reduced neuroinflammation concurrent with elevated BDNF levels and transcripts compared to vehicle-treated irradiated brains. In summary, oral administration of RZ represents a viable and translationally feasible neuroprotective approach against RICD.

Hao Liu,1,2,&ast; Zhengze Zhang,1,2,&ast; Yuewen He,1,2 Longfei Ding,1,2 Tong Wu,1,2 Yong Wang,2,3 Wuhua Ma2 1Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China; 2Department of Anesthesiology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China; 3State Key Laboratory of Traditional Chinese Medicine Syndrome, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wuhua Ma; Yong Wang, Department of Anesthesiology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, 16 Jichang Road, Guangzhou, Guangdong, 510405, People’s Republic of China, Tel +86 13318860680 ; +86 15920382796, Email tuesdaymorninggz@126.com; wangyong@gzucm.edu.cnPurpose: Numerous studies have identified a correlation between sleep and delirium; however, the causal relationship remains ambiguous. This bidirectional two-sample Mendelian randomization (MR) study was conducted to examine the possible causal relationships between sleep traits and delirium.Patients and Methods: Utilizing genome-wide association studies (GWAS), we identified ten sleep traits: chronotype, sleep duration, short sleep duration, long sleep duration, daytime napping, daytime sleepiness, insomnia, number of sleep episodes (NSE), sleep efficiency, and rapid eye movement sleep behavior disorder (RBD). In this MR study, genetic variants independently associated with exposures were selected as instrumental variables (IVs). To establish causal inferences, three regression models were employed—inverse variance weighted (IVW), MR Egger, and weighted median (WM) —and conducted sensitivity analyses to assess the robustness of our findings.Results: Our results suggest no significant causal association between the ten sleep traits and the risk of delirium. The reverse MR analysis revealed that delirium is associated with an increased propensity for morning chronotype [ORIVW, 1.025; 95% CI, 1.012– 1.036; p = 1.50E-05; adjusted p values (padjusted)= 1.35E-04] and a decreased risk of long sleep duration [ORIVW, 0.996; 95% CI, 0.993– 0.999; p = 0.013; padjusted= 0.059]. However, no robust evidence currently exists to substantiate a causal relationship between delirium and other sleep traits.Conclusion: Our bidirectional, two-sample MR analysis study did not provide definitive evidence that sleep traits may augment the susceptibility to delirium. However, the reverse MR results indicate that delirium may predispose patients to an earlier sleep-wake cycle. Additional large-scale investigations are necessary to examine the bidirectional causality between delirium and sleep traits.Keywords: sleep traits, delirium, Mendelian randomization analysis, genome-wide association studies

Pod size is a key agronomic trait that influences peanut yield greatly. However, our understanding of the mechanisms underlying pod size is limited. In this study, we employed a segregating population derived from a cross between the small-pod line ND_S and the large-pod line ND_L to map quantitative trait loci (QTL) associated with pod size. Initial mapping performed using bulk segregant analysis revealed a candidate interval on chromosome A05 referred to as qPSW05. We refined this interval to a 256.9 kb genomic region using newly developed molecular markers. Through sequence and expression analyses, we identified the candidate gene AhXE45GC, which encodes an AN1 zinc finger protein. We discovered a 33-bp insertion in the intron of AhXE45GC in ND_S. Accessions that lack this insertion, such as ND_L, had significantly larger pods than those with the insertion, including ND_S. To facilitate marker-assisted selection for peanut pod size, we developed a molecular marker associated with this polymorphism. This marker could provide a valuable genetic resource for breeding high-yielding peanut varieties.

Xue Ding,1,&ast; Leilei Fan,2,&ast; Liran Xu,3 Xiuxia Ma,4 Pengfei Meng,4 Jie Li,4 Jiahe Li,3 Jingyu Yue4 1Department of Medicine, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, People’s Republic of China; 2Department of Cardiovascular, The First People’s Hospital of Zhengzhou, Zhengzhou, People’s Republic of China; 3Department of the First Clinical Medical College, Henan University of Chinese Medicine, Zhengzhou, People’s Republic of China; 4Department of AIDS Clinical Research Center, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jingyu Yue, Department of AIDS Clinical Research Center, The First Affiliated Hospital of Henan University of Chinese Medicine, 19 Renmin Road, Zhengzhou, People’s Republic of China, Email yuejingyu@aliyun.comAbstract: Antiretroviral therapy can reduce human immunodeficiency virus (HIV) load to undetectable levels and restore CD4+ T cells to rebuild immune function in patients with HIV. However, some patients fail to achieve immune reconstitution despite treatment. Traditional Chinese medicine is an important branch of complementary and alternative medicine for the treatment of HIV infection, and a growing number of studies has demonstrated that traditional Chinese medicine can increase CD4+ T cell counts in patients, thereby promoting immune reconstitution, ameliorating symptoms and signs, and improving quality of life. Here, we review pathogenesis in immunological non-responders and research into their treatment with traditional Chinese medicine. Furthermore, we summarize potential future research directions, including elucidation of how traditional Chinese medicine can regulate CD4+ T cells to reduce opportunistic infections and improve quality of life in immunological non-responders.Keywords: immunological non-responders, drug mechanism, traditional Chinese medicine, future research directions