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Abstract Background Veno-arterial (V-A) and veno-venous (V-V) extracorporeal membrane oxygenation (ECMO) are crucial support modalities during lung transplantation, yet their comparative effectiveness remains unclear. Methods We conducted an 8-year retrospective analysis of 62 lung transplant recipients who received intraoperative ECMO (29 V-A, 33 V-V). Baseline characteristics, surgical parameters, and clinical outcomes were compared. To address potential selection bias, we employed entropy weighted inverse probability of treatment weighting (IPTW-EW). Results After IPTW-EW adjustment, V-A ECMO was associated with superior hemodynamic and respiratory parameters, including lower systolic pulmonary artery pressure (30 vs. 37 mmHg, p = 0.007), higher arterial oxygen partial pressure (119 vs. 78 mmHg, p = 0.002), and less severe pulmonary edema (Grade 1: 50% vs. 3%, Grade 2: 45% vs. 38%, Grade 3: 5% vs. 59%, p

Abstract Sjögren’s syndrome (SS) is a prevalent systemic autoimmune disease with substantial impacts on women’s health worldwide. Although oral Haemophilus parainfluenzae is reduced in SS, its significance remains unclear. This study aimed to elucidate the pathophysiological role of H. parainfluenzae in SS. Reduced salivary H. parainfluenzae levels in SS patients were confirmed through quantitative PCR. Oral H. parainfluenzae inoculation in NOD mice alleviated focal sialadenitis, improved salivary function, and reduced IFN-γ+CD3+ and IFN-γ+CD8+ T cells in salivary gland-draining lymph nodes, maintaining immune homeostasis against a biased type 1 response. Inoculation also enhanced salivary microbiota diversity, balanced the Firmicutes-to-Proteobacteria ratio, and reduced the overwhelming presence of Pseudomonas mendocina. In vitro, H. parainfluenzae-preconditioned A253 cells limited CD8 T cell expansion with reduced IFN-γ production. These findings suggest that H. parainfluenzae improves oral microbial diversity, promotes homeostatic T-cell immunity, and protects against SS, supporting its potential as a next-generation probiotic.

Abstract Background Blood glucose levels can fluctuate for many reasons. This study is to discuss conditions in assessing blood glucose in C57BL/6J mice, providing references to help increase the success of blood glucose testing in mouse experiments. Methods Animals were fed common chow or high-fat diet, without fasting or with a fasting duration of 6 h in the daytime or overnight before the test. During the test, animals were awake or under good anesthesia induced by intraperitoneal (IP) injection of sodium pentobarbital, interfered by a record of construction noise or not, in grouped cages or individual cages. Blood glucose measurements by glucose meters and insulin tolerance tests (ITT) were performed. Results Both IP injection and noise independently raised blood glucose levels in conscious mice, while neither of these two interferences affected blood glucose levels in mice under good anesthesia. In an ITT, a fasting of 6 h in the daytime worked well, while an overnight fasting was at higher risk of hypoglycemia. During conscious ITT, animals housed in isolated cages were more likely to have smoothly decreased levels of blood glucose with a lower minimal value as compared to those in social cages. Blood glucose tested during different stages of blood sampling varied greatly, where values of blood collected by inferior vena cava puncture were significantly higher than those of tail-tip blood, and values of serum samples after immediate centrifugation of blood were the highest, followed by those of serum samples underwent a common clotting process of 2 h. Conclusions Interferences of IP injection and noise can be reduced by anesthesia. 6-h fasting in the daytime is suitable for mouse ITT. Single housing works better than group housing during serial measurements of blood glucose in conscious mice. Tail-tip blood rather than serum or blood from sampling processes with big surgery invasion is recommended for blood glucose testing.

Abstract Neutrophilic inflammation contributes to multiple chronic inflammatory airway diseases, including asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), and is associated with an unfavorable prognosis. Here, using single-cell RNA sequencing (scRNA-seq) to profile human nasal mucosa obtained from the inferior turbinates, middle turbinates, and nasal polyps of CRSwNP patients, we identify two IL-1 signaling-induced cell subsets—LY6D + club cells and IDO1 + fibroblasts—that promote neutrophil recruitment by respectively releasing S100A8/A9 and CXCL1/2/3/5/6/8 into inflammatory regions. IL-1β, a pro-inflammatory cytokine involved in IL-1 signaling, induces the transdifferentiation of LY6D + club cells and IDO1 + fibroblasts from primary epithelial cells and fibroblasts, respectively. In an LPS-induced neutrophilic CRSwNP mouse model, blocking IL-1β activity with a receptor antagonist significantly reduces the numbers of LY6D + club cells and IDO1 + fibroblasts and mitigates nasal inflammation. This study implicates the function of two cell subsets in neutrophil recruitment and demonstrates an IL-1-based intervention for mitigating neutrophilic inflammation in CRSwNP.

Abstract The Tatun Volcano Group (TVG) is located at the northern end of Taiwan, ~ 15 km from the center of Taipei, a metropolitan area of over seven million inhabitants. A volcanic eruption by the TVG of any type or scale could cause catastrophic human and economic impacts. This paper summarizes previous geochemical, geophysical, and geochronological reports and highlights why the widely accepted age model does not comport with the latest observations. This study also reports novel 40Ar/39Ar ages for two andesite samples and one basalt sample from the TVG. A sample collected from Chihsingshan yields a robust 40Ar/39Ar age of 0.081 ± 0.005 Ma. This provides the first direct evidence of TVG volcanic activity after 0.1 Ma. Two samples yield 0.28 ± 0.02 Ma for Tatunshan and 0.159 ± 0.017 Ma for Honglushan. The younger ages refute previously proposed age models for the TVG. Along with new drone photos and LiDAR images, the age data help resolve eruptive history and advance understanding of volcanic hazards and hazard mitigation in Taiwan and surrounding areas.

This study constructs a directed weighted network among traditional village buildings based on directional similarity and utilizes social network analysis to identify influential buildings affecting spatial order. Key findings include: 1) Centrality Measures; Weighted degree, eigenvector, and betweenness centrality quantify the influence of building nodes in terms of quantity, quality, and importance, respectively. 2) Influential Buildings; High centrality buildings are not necessarily ‘star buildings’. Their impact is implicit and local, contrasting with the explicit and holistic influence of ‘star buildings’. 3) Community Structure; The village forms seven sub-communities with a modularity of 0.681, reflecting ideal community division. Community consistency is influenced by factors like size, the presence of ancient buildings, and morphology. 4) Spatial Order; Centrality distribution among nodes varies between communities. Communities rich in ancient buildings show a complex, organic order, suggesting self-organization, while those with modern buildings exhibit a more rigid layout, indicating imposed order. This research offers methodological insights for traditional village spatial morphology and provides guidance for conservation and planning.

Abstract This case report presents the clinical findings of a female patient diagnosed with Wernicke’s encephalopathy, characterized by pinpoint pupils. While pupillary changes can occur in Wernicke’s encephalopathy, the presence of pinpoint pupils is exceedingly rare. In this report, we aim to document and discuss this unusual presentation, as well as speculate on the potential mechanisms underlying this atypical manifestation of the disease.

Objective To study the effectiveness and safety of ultrasound-guided pectoral nerve block combined with no background patient controlled intravenous analgesia (PCIA) in postoperative pain control of partial mastectomy patients. Methods A total of 60 patients who underwent elective partial mastectomy at Pukou Traditional Chinese Medicine Hospital Affiliated to China Pharmaceutical University from May 2022 to May 2023 were selected and divided into group M and group N, with 30 cases in each growp. Both groups received no background PCIA. Patients in M group received 0.2% ropivacaine 30 mL for pectoral nerve block, while patients in group N did not receive any other treatment. The outcome measures were VAS scores during static and coughing at the time point of patient leaving resuscitation room (T0), 4 hours (T1), 12 hours (T2), 24 hours (T3), and 48 hours (T4) after surgery, as well as the total analgesia consumption and rescue analgesia dosage. Results Patients in group M showed a lower rest VAS at T0, T1, T2, and T3 time point (P＜0.05), and lower cough VAS at T0, T1, and T2 time point than patients in group N (P＜0.05). In group M, the total intravenous analgesia consumption and number of presses were significantly less than group N at 48 hours after surgery (P＜0.05). There was no statistically significant difference in the incidence of postoperative adverse reactions between the two groups (P＞0.05), and there was no complication related to nerve block in group M. Conclusion Ultrasound-guided pectoral nerve block combined with no background PCIA is able to provide potent postoperative pain control, reduce analgesia consumption in partial mastectomy patients.

Abstract Background Currently, no normal ultrasound data of the fetuses during the 20–40 gestation have been obtained for references of fetal growth and development. If such ultrasound data existed for prenatal diagnosis of possible diseases and abnormalities, neonates would be able to get timely treatment immediately after birth. This study was thus performed to obtain ultrasound parameters of normal fetuses during the 20–40 week gestation and the distribution of ultrasound parameters with the gestational age for references of detecting potential fetal diseases and abnormalities. Methods Normal fetuses without any abnormalities were enrolled, and the ultrasound parameters of the general biology, arteries, and aorta were measured and analyzed. Results 417 normal fetuses were enrolled. A significant (P

Abstract Emerging evidence demonstrates that pyroptosis has been implicated in the pathogenesis of asthma. Gasdermin D (GSDMD) is the pyroptosis executioner. The mechanism of GSDMD in asthma remains unclear. The aim of this study was to elucidate the potential role of GSDMD in asthmatic airway inflammation and remodeling. Immunofluorescence staining was conducted on airway epithelial tissues obtained from both asthma patients and healthy controls (HCs) to evaluate the expression level of N-GSDMD. ELISA was used to measure concentrations of cytokines (IL-1β, IL-18, IL-17A, and IL-10) in serum samples collected from asthma patients and healthy individuals. We demonstrated that N-GSDMD, IL-18, and IL-1β were significantly increased in samples with mild asthma compared with those from the controls. Then, wild type and Gsdmd-knockout (Gsdmd −/−) mice were used to establish asthma model. We performed histopathological staining, ELISA, and flow cytometry to explore the function of GSDMD in allergic airway inflammation and tissue remodeling in vivo. We observed that the expression of N-GSDMD, IL-18, and IL-1β was enhanced in OVA-induced asthma mouse model. Gsdmd knockout resulted in attenuated IL-18, and IL-1β production in both bronchoalveolar lavage fluid (BALF) and lung tissue in asthmatic mice. In addition, Gsdmd −/− mice exhibit a significant reduction in airway inflammation and remodeling, which might be associated with reduced Th17 inflammatory response and M2 polarization of macrophages. Further, we found that GSDMD knockout may improve asthmatic airway inflammation and remodeling through regulating macrophage adhesion, migration, and macrophage M2 polarization by targeting Notch signaling pathway. These findings demonstrate that GSDMD deficiency profoundly alleviates allergic inflammation and tissue remodeling. Therefore, GSDMD may serve as a potential therapeutic target against asthma.

We report on a previously non-HIV-diagnosed, 47-year-old male diagnosed with diabetes mellitus (DM) and cryptococcal meningoencephalitis, who was referred to our institution for antifungal treatment. During the course of treatment, due to the development of refractory intracranial hypertension, Ommaya reservoirs were employed for cranial pressure reduction. The patient gradually recovered during subsequent antifungal therapy; however, symptoms worsened in the third month of treatment, leading to consideration of post-infectious inflammatory response syndrome (PIIRS) on examination. Once diagnosed, the symptoms improved significantly after approximately 130 days of treatment with additional corticosteroids.

Apolipoprotein E (APOE)is the gene with greatest genetic risk for Alzheimer’s disease (AD). We successfully established a human induced pluripotent stem cell(iPSC) line from a woman mutated by APOE gene. The cell line was isolated from this woman’s peripheral blood mononuclear cells using a non-integrated Sendai virus, which retained the original genotype, showed a normal karyotype, highly expressed pluripotent markers and could differentiate into three germ layers.

The pollution of indoor environments and the consequent health risks associated with thirdhand smoke (THS) are increasingly recognized in recent years. However, the carcinogenic potential of THS and its underlying mechanisms have yet to be thoroughly explored. In this study, we examined the effects of short-term THS exposure on the development of gastric cancer (GC) in vitro and in vivo. In a mouse model of spontaneous GC, CC036, we observed a significant increase in gastric tumor incidence and a decrease in tumor-free survival upon THS exposure as compared to control. RNA sequencing of primary gastric epithelial cells derived from CC036 mice showed that THS exposure increased expression of genes related to the extracellular matrix and cytoskeletal protein structure. We then identified a THS exposure-induced 91-gene expression signature in CC036 and a homologous 84-gene signature in human GC patients that predicted the prognosis, with secreted phosphoprotein 1 (SPP1) and tribbles pseudokinase 3 (TRIB3) emerging as potential targets through which THS may promote gastric carcinogenesis. We also treated human GC cell lines in vitro with media containing various concentrations of THS, which, in some exposure dose range, significantly increased their proliferation, invasion, and migration. We showed that THS exposure could activate the epithelial-mesenchymal transition (EMT) pathway at the transcript and protein level. We conclude that short-term exposure to THS is associated with an increased risk of GC and that activation of the EMT program could be one potential mechanism. Increased understanding of the cancer risk associated with THS exposure will help identify new preventive and therapeutic strategies for tobacco-related disease as well as provide scientific evidence and rationale for policy decisions related to THS pollution control to protect vulnerable subpopulations such as children.

As an effective computer-aided diagnostic tool, deep learning has been successfully applied to the classification of breast histopathological images. However, the performance of the deep model is data-driven, and it is difficult to obtain satisfied results when the number of histopathological images is small and labelling histopathological images is difficult. Moreover, in traditional deep learning methods, the representation of features is monotonous, which leads to the limitation of the classification performance of the model. This study proposes an auto-encoder reconstructed semi-supervised domain adaptation for a breast histopathological image classification algorithm. First, the model was pre-trained and transferred to extract high-level features of the sample images. Then, the encoding and decoding parts of the auto-encoder were used to reconstruct the feature representation learning and the sample feature reconstruction learning, respectively. This ensured that the useful information for the classification was purified and retained. At the same time, the domain discriminator was used to confuse the source and target domain features to enhance the learning ability of the model. Finally, the distribution difference of features at different depths of the auto-encoder was measured to minimize the discrepancy of feature distribution between domains, so as to complete the classification of histopathological images. Compared to the results of the comparative and ablation algorithms from the BreakHis to SNL datasets, the proposed method achieved the best results in terms of F1 score (93.40%), accuracy (95.24%), sensitivity (94.66%), and specificity (95.56%). The experimental results demonstrate that the proposed method achieves a remarkable classification performance.

Summary: Background: Deeper insights into ERBB2-driven cancers are essential to develop new treatment approaches for ERBB2+ breast cancers (BCs). We employed the Collaborative Cross (CC) mouse model to unearth genetic factors underpinning Erbb2-driven mammary tumour development and metastasis. Methods: 732 F1 hybrid female mice between FVB/N MMTV-Erbb2 and 30 CC strains were monitored for mammary tumour phenotypes. GWAS pinpointed SNPs that influence various tumour phenotypes. Multivariate analyses and models were used to construct the polygenic score and to develop a mouse tumour susceptibility gene signature (mTSGS), where the corresponding human ortholog was identified and designated as hTSGS. The importance and clinical value of hTSGS in human BC was evaluated using public datasets, encompassing TCGA, METABRIC, GSE96058, and I-SPY2 cohorts. The predictive power of mTSGS for response to chemotherapy was validated in vivo using genetically diverse MMTV-Erbb2 mice. Findings: Distinct variances in tumour onset, multiplicity, and metastatic patterns were observed in F1-hybrid female mice between FVB/N MMTV-Erbb2 and 30 CC strains. Besides lung metastasis, liver and kidney metastases emerged in specific CC strains. GWAS identified specific SNPs significantly associated with tumour onset, multiplicity, lung metastasis, and liver metastasis. Multivariate analyses flagged SNPs in 20 genes (Stx6, Ramp1, Traf3ip1, Nckap5, Pfkfb2, Trmt1l, Rprd1b, Rer1, Sepsecs, Rhobtb1, Tsen15, Abcc3, Arid5b, Tnr, Dock2, Tti1, Fam81a, Oxr1, Plxna2, and Tbc1d31) independently tied to various tumour characteristics, designated as a mTSGS. hTSGS scores (hTSGSS) based on their transcriptional level showed prognostic values, superseding clinical factors and PAM50 subtype across multiple human BC cohorts, and predicted pathological complete response independent of and superior to MammaPrint score in I-SPY2 study. The power of mTSGS score for predicting chemotherapy response was further validated in an in vivo mouse MMTV-Erbb2 model, showing that, like findings in human patients, mouse tumours with low mTSGS scores were most likely to respond to treatment. Interpretation: Our investigation has unveiled many new genes predisposing individuals to ERBB2-driven cancer. Translational findings indicate that hTSGS holds promise as a biomarker for refining treatment strategies for patients with BC. Funding: The U.S. Department of Defense (DoD) Breast Cancer Research Program (BCRP) (BC190820), United States; MCIN/AEI/10.13039/501100011039 (PID2020-118527RB-I00, PDC2021-121735-I00), the “European Union Next Generation EU/PRTR,” the Regional Government of Castile and León (CSI144P20), European Union.

PurposeThe study aimed to develop a nomogram model for individual prognosis prediction in patients with hormone receptors positive (HR+) mucinous breast carcinoma (MBC) and assess the value of neoadjuvant chemotherapy (NAC) in this context.MethodsA total of 6,850 HR+ MBC patients from the SEER database were identified and randomly (in a 7:3 ratio) divided into training cohorts and internal validation cohorts. 77 patients were enrolled from the Chongqing University Cancer Hospital as the external validation cohort. Independent risk factors affecting overall survival (OS) were selected using univariate and multivariate Cox regression analysis, and nomogram models were constructed and validated. A propensity score matching (PSM) approach was used in the exploration of the value of NAC versus adjuvant chemocherapy (AC) for long-term prognosis in HR+ MBC patients.ResultsMultivariate Cox regression analysis showed 8 independent prognostic factors: age, race, marital status, tumor size, distant metastasis, surgery, radiotherapy, and chemotherapy. The constructed nomogram model based on these 8 factors exhibited good consistency and accuracy. In the training group, internal validation group and external validation group, the high-risk groups demonstrated worse OS (p

BackgroundAlzheimer’s disease (AD) is the predominant cause of dementia on a global scale, significantly impacting the health of the elderly population. The pathogenesis of AD is closely linked to neuroinflammation. The present study employs a bibliometric analysis to examine research pertaining to neuroinflammation and AD within the last decade, with the objective of providing a comprehensive overview of the current research profile, hotspots and trends.MethodsThis research conducted a comprehensive review of publications within the Science Citation Index Expanded of the Web of Science Core Collection Database spanning the years 2014 to 2024. Bibliometric analyses were performed using VOSviewer (version 1.6.19) and CiteSpace (version 6.3.R1) software to visualize data on countries, institutions, authors, journals, keywords, and references.ResultsA total of 3,833 publications on neuroinflammation and AD were included from January 2014 to January 2024. Publications were mainly from the United States and China. Zetterberg, Henrik emerged as the author with the highest publication output, while Edison, Paul was identified as the most cited author. The most productive journal was Journal of Alzheimers Disease, and the most co-cited was Journal of Neuroinflammation. Research hotspot focused on microglia, mouse models, oxidative stress, and amyloid-beta through keyword analysis. Additionally, keywords such as blood–brain barrier and tau protein exhibited prolonged citation bursts from 2022 to 2024.ConclusionThis study provides a comprehensive review of the last 10 years of research on neuroinflammation and AD, including the number and impact of research findings, research hotspots, and future trends. The quantity of publications in this field is increasing, mainly in the United States and China, and there is a need to further strengthen close cooperation with different countries and institutions worldwide. Presently, research hotspots are primarily concentrated on microglia, with a focus on inhibiting their pro-inflammatory responses and promoting their anti-inflammatory functions as a potential direction for future investigations.

Introduction The efficacy of multitarget neuroprotective drug DL-3-n-butylphthalide (NBP) in improving cognitive function has been confirmed in patients with vascular cognitive impairment without dementia. However, its efficacy in patients with symptomatic predementia phase of Alzheimer’s disease remains uncertain. This study aims to evaluate the efficacy and safety of NBP in improving cognitive function in patients with mild cognitive impairment (MCI) through a clinical randomised controlled trail.Methods and analysis This study is a 12-month, randomised, double-blind, placebo-controlled, multicentric trial, involving 270 patients with MCI. Subjects are randomly assigned to receive either NBP soft capsule (200 mg, three times per day) or placebo with an allocation ratio of 1:1. The efficacy and safety of NBP are assessed by comparing the results of neuropsychological, neuroimaging and laboratory tests between the two groups. The primary endpoint is the change in Alzheimer’s Disease Assessment Scale-Cognitive Subscale after 12 months. All patients will be monitored for adverse events.Ethics and dissemination This study involving human participants has been reviewed and approved by Ethics Committee of Xuan Wu Hospital (No.2017058). The participants provide their written informed consent to participate in this study. Results will be published in peer-reviewed medical journals and disseminated to healthcare professionals at local and international conferences.Protocol version V 3.0, 3 September 2022.Trial registration number ChiCTR1800018362.

Electroencephalographic Neurofeedback Training (EEG NFT) aims to improve sport performance by teaching athletes to control their mental states, leading to better cognitive, emotional, and physical outcomes. The psychomotor efficiency hypothesis suggests that optimizing brain function could enhance athletic ability, indicating the potential of EEG NFT. However, evidence for EEG-NFT’s ability to alter critical brain activity patterns, such as sensorimotor rhythm and frontal midline theta—key for concentration and relaxation—is not fully established. Current research lacks standardized methods and comprehensive studies. This shortfall is due to inconsistent EEG target selection and insufficient focus on coherence in training. This review aims to provide empirical support for EEG target selection, conduct detailed control analyses, and examine the specificity of electrodes and frequencies to relation to the psychomotor efficiency hypothesis. Following the PRISMA method, 2,869 empirical studies were identified from PubMed, Science Direct, Web of Science, Embase, CNKI, and PsycINFO. Thirteen studies met the inclusion criteria: (i) proficient skill levels; (ii) use of EEG; (iii) neurofeedback training (NFT); (iv) motor performance metrics (reaction time, precision, dexterity, balance); (v) control group for NFT comparison; (vi) peer-reviewed English-language publication; and (vii) randomized controlled trial (RCT) design. Studies indicate that NFT can enhance sports performance, including improvements in shooting accuracy, golf putting, and overall motor skills, as supported by the psychomotor efficiency hypothesis. EEG NFT demonstrates potential in enhancing sports performance by optimizing performers’ mental states and psychomotor efficiency. However, the current body of research is hampered by inconsistent methodologies and a lack of standardized EEG target selection. To strengthen the empirical evidence supporting EEG NFT, future studies need to focus on standardizing target selection, employing rigorous control analyses, and investigating underexplored EEG markers. These steps are vital to bolster the evidence for EEG NFT and enhance its effectiveness in boosting sport performance.

Abstract Introduction We sought to characterize cognitive profiles associated with enlarged perivascular spaces (EPVS) among Chinese older adults. Methods This population‐based study included 1191 dementia‐free participants (age ≥60 years) in the MIND‐China MRI Substudy (2018–2020). We visually evaluated EPVS in basal ganglia (BG) and centrum semiovale (CSO), white matter hyperintensities (WMHs), lacunes, cerebral microbleeds (CMBs), and cortical superficial siderosis. We used a neuropsychological test battery to assess cognitive function. Data were analyzed using general linear models. Results Greater BG‐EPVS load was associated with lower z‐scores in memory, verbal fluency, and global cognition (p 0.05); among apolipoprotein E (APOE) ‐ε4 carriers, greater CSO‐EPVS load was associated with lower verbal fluency z‐score, even when controlling for other CSVD markers (p

Genetic polymorphism of apolipoprotein E (APOE) confers differential susceptibility to Alzheimer's disease (AD), and APOE ɛ4 variants is the most powerful risk factor for this disease. Here, we report the generation of a human induced pluripotent stem cell (iPSC) line carrying the APOE ɛ4/ɛ4 genotype from peripheral blood mononuclear cells (PBMCs) isolated from a male with a family history of AD utilizing non-integrative Sendai virus vector. The iPSC maintains their original genotype, highly express endogenous pluripotency markers, displays a normal karyotype, and retains the ability to differentiate into cells representative of the three germ layers.

The increasing frequency of urban flood disasters presents a significant obstacle to urban sustainability. Urban flood management aims to reduce the flood occurrences, currently addressed through urban drainage systems. Previous studies have demonstrated future precipitation extremes will pose larger pressure on urban drainage network, but when and where the pressure will reach a dangerous level have never been assessed in any city of China. This study establishes the initial framework for identifying critical decades and hot spots of urban drainage pressure changes due to future climate change, through a case study conducted in southern China (Haining city). Urban drainage pressure was assessed by a combination of the urban drainage model known as the Storm Water Management Model (SWMM) and pipe statistics. Using climate projections from the latest phase of Coupled Model Intercomparison Project (CMIP6) under four typical SSP-RCP (shared socioeconomic pathway-representative concentration pathway) scenarios, we project the changes in urban drainage pressure by 21st century, and identify the key decades and high risk areas with the occurrence of dangerous pressure levels. The results indicate an overall upward trend in urban drainage pressure for Haining city, with over 97% of the flooding nodes projected to firstly reach the dangerous level by the 2030 s. Comparisons of the patterns under different SSP-RCP scenarios, suggest that a higher forcing pathway would expedite the deterioration of urban drainage pressure, particularly in urban areas with lower DEM and high building intensity. This has broad implications for better informing disaster management and policy-making in similar cities, especially those with inadequate drainage capacities.

Abstract Background Patients with nonischemic dilated cardiomyopathy (NIDCM) are prone to arrhythmias, and the cause of mortality in these patients is either end-organ dysfunction due to pump failure or malignant arrhythmia-related death. However, the identification of patients with NIDCM at risk of malignant ventricular arrhythmias (VAs) is challenging in clinical practice. The aim of this study was to evaluate whether cardiovascular magnetic resonance feature tracking (CMR-FT) could help in the identification of patients with NIDCM at risk of malignant VAs. Methods A total of 263 NIDCM patients who underwent CMR, 24-hour Holter electrocardiography (ECG) and inpatient ECG were retrospectively evaluated. The patients with NIDCM were allocated to two subgroups: NIDCM with VAs and NIDCM without VAs. From CMR-FT, the global peak radial strain (GPRS), global longitudinal strain (GPLS), and global peak circumferential strain (GPCS) were calculated from the left ventricle (LV) model. We investigated the possible predictors of NIDCM combined with VAs by univariate and multivariate logistic regression analyses. Results The percent LGE (15.51 ± 3.30 vs. 9.62 ± 2.18, P 10.37% are independent predictors of NIDCM combined with VAs.

Abstract In the past decades, a band alignment theory has become a basis for designing different high-performance semiconductor devices, such as photocatalysis, photoelectrocatalysis, photoelectrostorage and third-generation photovoltaics. Recently, a faradaic junction model (coupled electron and ion transfer) has been proposed to explain charge transfer phenomena in these semiconductor heterojunctions. However, the classic band alignment theory cannot explain coupled electron and ion transfer processes because it only regulates electron transfer. Therefore, it is very significant to explore a suitable design concept for regulating coupled electron and ion transfer in order to improve the performance of semiconductor heterojunctions. Herein, we propose a potential window alignment theory for regulating ion transfer and remarkably improving the photoelectrocatalytic performance of a MoS2/Cd-Cu2ZnSnS4 heterojunction photocathode. Moreover, we find that a faradaic potential window, rather than the band position of the intermediate layer, is a criterion for identifying interface charge transfer direction. This finding can offer different perspectives for designing high-performance semiconductor heterojunctions with suitable potential windows for solar energy conversion and storage.

Urbanization has led to an increase in impervious areas and, consequently, an increase in the surface runoff volume and runoff rate. This has exacerbated urban flooding and highlighted the importance of modeling urban hydrological processes. The Waterview Community of Hangzhou City (WCHC) was taken as the study area, and three scenarios were developed: the original scenario, the rough description scenario, and the fine description scenario. The urban hydrological processes were simulated through a coupled model incorporating actual measurements and four design precipitation events (1-year, 5-year, 10-year, and 20-year return periods). The results show the following: (1) The refined depiction scenario has the highest accuracy in terms of measured precipitation, with an average error of 0.54 cm. (2) During different precipitation return periods, the refined depiction scenario shows the smallest range of accumulated water, with a more realistic distribution. On average, it differed from the original scenario by 21.45% and from the rough depiction scenario by 32.18%. (3) The simulation results after the refinement of the feature boundaries are more reasonable in terms of the flow rate and flow direction, indicating that the simulation results have better dynamics. The results showed that refined boundary conditions improved the accuracy and dynamics of urban hydrological simulations, especially in terms of their reflection of actual water accumulation under varying precipitation conditions.

Cs0.33WO3 (CWO) is a widely used inorganic material in window films and glass coatings, known for its excellent near-infrared radiation (NIR) blocking property and high visible light transmittance (Tvis). However, the stability of NIR blocking and the optical properties of CWO in the process of application is an urgent and important problem, because significant changes in optical results can impact the related products, such as window films, glass coatings, and so on. In this paper, the particle sizes and optical properties of CWO are tested to study the light stability and their relative relations. The results indicate that CWO particle sizes between 130 nm and 100 nm (D90, the point where 90% of the particles have a diameter smaller than the specified value) exhibit high stability in terms of NIR blocking and visible light transmittance (Tvis). CWO particles with D90 < 100 nm experience a greater reduction in NIR blocking, though this ability significantly recovers upon exposure to sunlight, making these coatings particularly suitable for use in tropical and subtropical climates.

Abstract Allogeneic Vγ9Vδ2 (Vδ2) T cells have emerged as attractive candidates for developing cancer therapy due to their established safety in allogeneic contexts and inherent tumor-fighting capabilities. Nonetheless, the limited clinical success of Vδ2 T cell-based treatments may be attributed to donor variability, short-lived persistence, and tumor immune evasion. To address these constraints, we engineer Vδ2 T cells with enhanced attributes. By employing CD16 as a donor selection biomarker, we harness Vδ2 T cells characterized by heightened cytotoxicity and potent antibody-dependent cell-mediated cytotoxicity (ADCC) functionality. RNA sequencing analysis supports the augmented effector potential of Vδ2 T cells derived from CD16 high (CD16Hi) donors. Substantial enhancements are further achieved through CAR and IL-15 engineering methodologies. Preclinical investigations in two ovarian cancer models substantiate the effectiveness and safety of engineered CD16Hi Vδ2 T cells. These cells target tumors through multiple mechanisms, exhibit sustained in vivo persistence, and do not elicit graft-versus-host disease. These findings underscore the promise of engineered CD16Hi Vδ2 T cells as a viable therapeutic option for cancer treatment.

Abstract Reversing ventricular remodeling represents a promising treatment for the post-myocardial infarction (MI) heart failure (HF). Here, we report a novel small molecule HHQ16, an optimized derivative of astragaloside IV, which effectively reversed infarction-induced myocardial remodeling and improved cardiac function by directly acting on the cardiomyocyte to reverse hypertrophy. The effect of HHQ16 was associated with a strong inhibition of a newly discovered Egr2-affiliated transcript lnc9456 in the heart. While minimally expressed in normal mouse heart, lnc9456 was dramatically upregulated in the heart subjected to left anterior descending coronary artery ligation (LADL) and in cardiomyocytes subjected to hypertrophic stimulation. The critical role of lnc9456 in cardiomyocyte hypertrophy was confirmed by specific overexpression and knockout in vitro. A physical interaction between lnc9456 and G3BP2 increased NF-κB nuclear translocation, triggering hypertrophy-related cascades. HHQ16 physically bound to lnc9456 with a high-affinity and induced its degradation. Cardiomyocyte-specific lnc9456 overexpression induced, but knockout prevented LADL-induced, cardiac hypertrophy and dysfunction. HHQ16 reversed the effect of lnc9456 overexpression while lost its protective role when lnc9456 was deleted, further confirming lnc9456 as the bona fide target of HHQ16. We further identified the human ortholog of lnc9456, also an Egr2-affiliated transcript, lnc4012. Similarly, lnc4012 was significantly upregulated in hypertrophied failing hearts of patients with dilated cardiomyopathy. HHQ16 also specifically bound to lnc4012 and caused its degradation and antagonized its hypertrophic effects. Targeted degradation of pathological increased lnc4012/lnc9456 by small molecules might serve as a novel promising strategy to regress infarction-induced cardiac hypertrophy and HF.

IntroductionSelf-efficacy (SE), defined as an individual's belief in their ability to complete a task, is linked to top-down attentional control, influencing motor performance in sports. Although the behavioral effects of SE are well-documented, there is a lack of research on the mechanisms through which SE affects sports performance. Our research aims to elucidate the neurophysiological mechanisms that underlie the impact of self-efficacy on sports performance. Specifically, we intend to explore the effects of low and high SE on frontal midline theta (Fmθ) activity, associated with sustained top-down attention, and on motor performance.MethodsWe recruited thirty-four professional golfers to perform 60 putts, during which their electroencephalographic activity was monitored. SE levels were assessed using a visual analog scale from 0 to 10 before each putt, with scores categorized into higher or lower SE based on each golfer's individual average score.ResultsPaired t-tests indicated that trials with higher SE scores had a higher putting success rate than those with lower SE scores (53.3% vs. 46.7%). Furthermore, trials associated with higher SE scores exhibited lower Fmθ activity compared to those with lower SE scores (4.49 vs. 5.18).DiscussionOur results suggest that higher SE is associated with reduced top-down attentional control, leading to improved putting performance. These findings support Bandura's theory of SE, which suggests that the effects of efficacy beliefs are mediated by cognitive, motivational, emotional, and decision-making processes. This study sheds light on the intermediate processes of SE by examining its impact on the anticipation of outcomes, sports performance, and attentional control prior to putting.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease refractory to all targeted and immune therapies. However, our understanding of PDAC microenvironment especially the metastatic microenvironment is very limited partly due to the inaccessibility to metastatic tumor tissues. Here, we present the single-cell transcriptomic landscape of synchronously resected PDAC primary tumors and matched liver metastases. We perform comparative analysis on both cellular composition and functional phenotype between primary and metastatic tumors. Tumor cells exhibit distinct transcriptomic profile in liver metastasis with clearly defined evolutionary routes from cancer cells in primary tumor. We also identify specific subtypes of stromal and immune cells critical to the formation of the pro-tumor microenvironment in metastatic lesions, including RGS5+ cancer-associated fibroblasts, CCL18+ lipid-associated macrophages, S100A8+ neutrophils and FOXP3+ regulatory T cells. Cellular interactome analysis further reveals that the lack of tumor-immune cell interaction in metastatic tissues contributes to the formation of the immunosuppressive microenvironment. Our study provides a comprehensive characterization of the transcriptional landscape of PDAC liver metastasis.

Enhancing legal compliance towards corporate anti-corruption has become a tendency to assure corporate operation sustainable. Corruption that jeopardizes construction supervision, project management, operation maintenance remains a governance challenge in public construction and procurement. The research purpose is to explore the impact factors for anti-corruption legal compliance towards top 5 engineering consulting companies in the Taiwan construction industry. A comprehensive literature review brings 8 hypotheses based on the Structural Equation Modeling (SEM) involving 28 stems for a 5-scale Likert questionnaire. The pilot survey with 22 effective returns demonstrates the validation for the questionnaire. The comprehensive survey collects 314 valid returns from top engineering consulting firms and proves that 5 out of 8 hypotheses stand. The findings conclude the legal compliance framework and top 5 impact factors: commitment, ethical management policy, organization and responsibility, prevention programs, and legal compliance policy. The contributions lie on (1) the identification and ranking for the impact factors, and (2) establishment of legal compliance framework toward corporate legal compliance and anti-corruption for top engineering consulting firms in the Taiwan construction industry. The legal compliance framework is correspondingly built to present how engineering consulting companies carry out anti-corruption legal compliance to assure corporate operation sustainable.

Abstract Introduction: The focus on social determinants of health (SDOH) and their impact on health outcomes is evident in U.S. federal actions by Centers for Medicare & Medicaid Services and Office of National Coordinator for Health Information Technology. The disproportionate impact of COVID-19 on minorities and communities of color heightened awareness of health inequities and the need for more robust SDOH data collection. Four Clinical and Translational Science Award (CTSA) hubs comprising the Texas Regional CTSA Consortium (TRCC) undertook an inventory to understand what contextual-level SDOH datasets are offered centrally and which individual-level SDOH are collected in structured fields in each electronic health record (EHR) system potentially for all patients. Methods: Hub teams identified American Community Survey (ACS) datasets available via their enterprise data warehouses for research. Each hub’s EHR analyst team identified structured fields available in their EHR for SDOH using a collection instrument based on a 2021 PCORnet survey and conducted an SDOH field completion rate analysis. Results: One hub offered ACS datasets centrally. All hubs collected eleven SDOH elements in structured EHR fields. Two collected Homeless and Veteran statuses. Completeness at four hubs was 80%–98%: Ethnicity, Race; < 10%: Education, Financial Strain, Food Insecurity, Housing Security/Stability, Interpersonal Violence, Social Isolation, Stress, Transportation. Conclusion: Completeness levels for SDOH data in EHR at TRCC hubs varied and were low for most measures. Multiple system-level discussions may be necessary to increase standardized SDOH EHR-based data collection and harmonization to drive effective value-based care, health disparities research, translational interventions, and evidence-based policy.

IntroductionAchieving optimal visuomotor performance in precision sports relies on maintaining an optimal psychological state during motor preparation. To uncover the optimal psychological state, extensive EEG studies have established a link between the Mu rhythm (8–13 Hz at Cz) and cognitive resource allocation during visuomotor tasks (i.e., golf or shooting). In addition, the new approach in EEG neurofeedback training (NFT), called the function-specific instruction (FSI) approach, for sports involves providing function-directed verbal instructions to assist individuals to control specific EEG parameters and align them with targeted brain activity features. While this approach was initially hypothesized to aid individuals in attaining a particular mental state during NFT, the impact of EEG-NFT involving Mu rhythm on visuomotor performance, especially when contrasting the traditional instruction (TI) approach with the FSI approach, underscores the necessity for additional exploration. Hence, the objective of this study is to investigate the impact of the FSI approach on modulating Mu rhythm through EEG-NFT in the context of visuomotor performance.MethodsThirty novice participants were recruited and divided into three groups: function-specific instruction (FSI, four females, six males; mean age = 27.00 ± 7.13), traditional instruction (TI, five females, five males; mean age = 27.00 ± 3.88), and sham control (SC, five females, five males; mean age = 27.80 ± 5.34). These groups engaged in a single-session EEG-NFT and performed golf putting tasks both before and after the EEG-NFT.ResultsThe results showed that within the FSI group, single-session NFT with augmented Mu power led to a significant decrease in putting performance (p = 0.013). Furthermore, we noted a marginal significance indicating a slight increase in Mu power and a reduction in the subjective sensation of action control following EEG-NFT (p = 0.119). While there was a positive correlation between Mu power and mean radial error in golf putting performance (p = 0.043), it is important to interpret this relationship cautiously in the context of reduced accuracy in golf putting.DiscussionThe findings emphasize the necessity for extended investigation to attain a more profound comprehension of the nuanced significance of Mu power in visuomotor performance. The study highlights the potential effectiveness of the FSI approach in EEG-NFT and in enhancing visuomotor performance, but it also emphasizes the potential impact of skill level and attentional control, particularly in complex visuomotor tasks.

Abstract Driver identification using in‐vehicle data is receiving considerable attention in the field of intelligent transportation owing to the advances in deep learning (DL). In order to improve accuracy and robustness of identification, this paper proposes an ensemble deep learning framework that integrates a modified one‐dimensional convolutional neural network (M 1‐D CNN) and bidirectional long short‐term memory (BLSTM) to improve the performance and robustness of driver identification using information extracted from vehicular CAN‐bus signals. The M 1‐D CNN architecture is developed by adopting inception blocks, residual connection, and global average pooling to obtain optimal deep‐feature representations of local time series. The BLSTM is used to learn the bidirectional long‐term temporal dependencies. Results of extensive experiments using real driving data show that the proposed ensemble DL model can improve the accuracy and robustness of driver identification. Furthermore, four data augmentation methods, namely up‐sampling, adding noise, data reversal, and random drifting, are used to expand the original training data to improve the performance of the ensemble method. Especially, few‐shot learning is performed using the four data augmentation methods, and it shows excellent potential for driver identification with limited data.

METRNL is a recently identified secreted protein with emerging functions. This study is to find major cellular source of circulating METRNL and to determine METRNL novel function. Here, we show METRNL is abundant in human and mouse vascular endothelium and released by endothelial cells using endoplasmic reticulum-Golgi apparatus pathway. By creating endothelial cell-specific Metrnl knockout mice, combined with bone marrow transplantation to produce bone marrow-specific deletion of Metrnl, we demonstrate that most of circulating METRNL (approximately 75%) originates from the endothelial cells. Both endothelial and circulating METRNL decrease in atherosclerosis mice and patients. By generating endothelial cell-specific Metrnl knockout in apolipoprotein E-deficient mice, combined with bone marrow-specific deletion of Metrnl in apolipoprotein E-deficient mice, we further demonstrate that endothelial METRNL deficiency accelerates atherosclerosis. Mechanically, endothelial METRNL deficiency causes vascular endothelial dysfunction including vasodilation impairment via reducing eNOS phosphorylation at Ser1177 and inflammation activation via enhancing NFκB pathway, which promotes the susceptibility of atherosclerosis. Exogenous METRNL rescues METRNL deficiency induced endothelial dysfunction. These findings reveal that METRNL is a new endothelial substance not only determining the circulating METRNL level but also regulating endothelial function for vascular health and disease. METRNL is a therapeutic target against endothelial dysfunction and atherosclerosis.

he first imported case of monkeypox in Taiwan was diagnosed in an Asian man with HIV-1 infection and asymptomatic COVID-19, returning from Germany. Atypical presentations included asynchronous skin lesions, anogenital lesions and prominent inguinal lymphadenopathy. Whole genomic sequence alignment indicate that the Taiwan strain clustered together with human monkeypox virus West African clade B.1, currently circulating in Europe. Prompt diagnosis and infection control measures are crucial to mitigate the spread of monkeypox.

The β-amyloid precursor protein (APP) is a crucial pathogenic gene linked to Alzheimer's disease (AD). A human induced pluripotent stem cell (iPSC) line was generated from peripheral blood mononuclear cells (PBMCs) isolated from a female with APP gene mutation utilizing non-integrative Sendai virus. The iPSC line exhibits high expression of pluripotency markers, retains the APP mutation, displays a normal karyotype, and has the ability to differentiate into normal teratoma tissue. This iPSC line represents a valuable cell model for investigating the pathological mechanisms and therapeutic strategies of AD.

Abstract Background Liver ischemia reperfusion injury (LIRI) is not only a common injury during liver transplantation and major hepatic surgery, but also one of the primary factors that affect the outcome of postoperative diseases. However, there are still no reliable ways to tackle the problem. Our study aimed to find some characteristic genes associated with immune infiltration that affect LIRI, which can provide some insights for future research in the future. Therefore, it is essential for the treatment of LIRI, the elucidation of the mechanisms of LIRI, and exploring the potential biomarkers. Efficient microarray and bioinformatics analyses can promote the understanding of the molecular mechanisms of disease occurrence and development. Method Data from GSE151648 were downloaded from GEO data sets, and we performed a comprehensive analysis of the differential expression, biological functions and interactions of LIRI-associated genes. Then we performed Gene ontology (GO) analysis and Kyotoencydlopedia of genes and genomes (KEGG) enrichment analysis of DEGs. At last, we performed a protein-protein interaction network to screen out hub genes. Results A total of 161 differentially expressed genes (DEGs) were identified. GO analysis results revealed that the changes in the modules were mostly enriched in the neutrophil degranulation, neutrophil activation involved in immune response, and neutrophil mediated immunity. KEGG enrichment analysis of DEGs demonstrated that LIRI mainly involved the cytokine-cytokine receptor interaction. Our data indicated that macrophages and neutrophils are closely related to LIRI. 9 hub genes were screened out in the protein-protein interaction network. Conclusions In summary, our data indicated that neutrophil degranulation, neutrophil activation involved in immune response, neutrophil mediated immunity and cytokine-cytokine receptor interaction may play a key role in LIRI, HRH1, LRP2, P2RY6, PKD1L1, SLC8A3 and TNFRSF8, which were identified as potential biomarkers in the occurrence and development of LIRI. However, further studies are needed to validate these findings and explore the molecular mechanism of these biomarkers in LIRI.

Abstract Objective Expression of glial fibrillary acidic protein (GFAP), a marker of reactive astrocytosis, colocalizes with neuropathology in the brain. Blood levels of GFAP have been associated with cognitive decline and dementia status. However, further examinations at a population‐based level are necessary to broaden generalizability to community settings. Methods Circulating GFAP levels were assayed using a Simoa HD‐1 analyzer in 4338 adults without prevalent dementia from four longitudinal community‐based cohort studies. The associations between GFAP levels with general cognition, total brain volume, and hippocampal volume were evaluated with separate linear regression models in each cohort with adjustment for age, sex, education, race, diabetes, systolic blood pressure, antihypertensive medication, body mass index, apolipoprotein E ε4 status, site, and time between GFAP blood draw and the outcome. Associations with incident all‐cause and Alzheimer's disease dementia were evaluated with adjusted Cox proportional hazard models. Meta‐analysis was performed on the estimates derived from each cohort using random‐effects models. Results Meta‐analyses indicated that higher circulating GFAP associated with lower general cognition (ß = −0.09, [95% confidence interval [CI]: −0.15 to −0.03], p = 0.005), but not with total brain or hippocampal volume (p > 0.05). However, each standard deviation unit increase in log‐transformed GFAP levels was significantly associated with a 2.5‐fold higher risk of incident all‐cause dementia (Hazard Ratio [HR]: 2.47 (95% CI: 1.52–4.01)) and Alzheimer's disease dementia (HR: 2.54 [95% CI: 1.42–4.53]) over up to 15‐years of follow‐up. Interpretation Results support the potential role of circulating GFAP levels for aiding dementia risk prediction and improving clinical trial stratification in community settings.

BackgroundAbnormal thyroid function is a metabolic disorder and can lead to several complications, including cardiovascular diseases. In this study, we aimed to examine the relationship between clinical traits and outcomes and the thyroid hormone level of euthyroid individuals with valvular heart disease (VHD).MethodThe thyroid function was evaluated in 526 euthyroid VHD patients and 155 healthy control people. As well as clinical indicators were collected and analyzed.ResultsNo difference in TSH levels (p>0.05) was recorded; however, fT3, TT3, and TT4 levels were lower in the euthyroid VHD patients than in healthy control(4.3 vs 4.63; 1.37 vs 1.48; 97.7 vs 102.09, respectively, all p

BackgroundHuman hypopharygeal squamous cell carcinoma (HSCC) is a common head and neck cancer with a poor prognosis in advanced stages. The occurrence and development of tumor is the result of mutual influence and co-evolution between tumor cells and tumor microenvironment (TME). Tumor immune microenvironment (TIME) refers to the immune microenvironment surrounding tumor cells. Studying TIME in HSCC could provide new targets and therapeutic strategies for HSCC.MethodsWe performed single-cell RNA sequencing (scRNA-seq) and analysis of hypopharyngeal carcinoma, paracancerous, and lymphoid tissues from five HSCC patients. Subdivide of B cells, T cells, macrophages cells, and monocytes and their distribution in three kinds of tissues as well as marker genes were analyzed. Different genes of IGHG1 plasma cells and SPP1+ macrophages between HSCC tissues, adjacent normal tissues and lymphatic tissues were analyzed. Additionally, we studied proliferating lymphocytes, T cells exhaustion, and T cell receptor (TCR) repertoire in three kinds of tissues.ResultsTranscriptome profiles of 132,869 single cells were obtained and grouped into seven cell clusters, including epithelial cells, lymphocytes, mononuclear phagocytics system (MPs), fibroblasts, endothelial cells (ECs), plasmacytoid dendritic cells (pDCs), and mast cells. Tumor metastasis occurred in three lymphoid tissues. Four distinct populations were identified from lymphocytes, including B cells, plasma cells, T cells and proliferating lymphocytes. We found IGHA1 and IGHG1 specific plasma cells significantly overexpressed in HSCC tissues compared with normal hypopharygeal tissues and lymphatic tissues. Five distinct populations from MPs were identified, including macrophages, monocytes, mature dendritic cells (DCs), Type 1 conventional dendritic cells (cDC1) and Type 2 conventional dendritic cells (cDC2). SPP1+ macrophages were significantly overexpressed in HSCC tissues and lymphatic tissues compared with normal hypopharygeal tissues, which are thought to be M2-type macrophages. Exhaustion of CD8+ Teff cells occurred in HSCC tissues. At last, we verified that IgA and IgG1 protein expression levels were significantly up-regulated in HSCC tissues compared to adjacent normal tissues.ConclusionOverall, this study revealed TIME in HSCC and lymphatic metastasis, and provided potential therapeutic targets for HSCC.

IntroductionClear cell renal cell carcinoma (ccRCC) is the most prevalent type of urological carcinoma. Although targeted therapy and immunotherapy are usually employed, they often result in primary and acquired resistance. There is currently a lack of dependable biomarkers that can accurately anticipate the prognosis of ccRCC. Recent research has indicated the critical role of neutrophil extracellular traps (NETs) in the development, metastasis, and immune evasion of cancer. The aim of this study was to explore the value of NETs in the development and prognosis of ccRCC.MethodsClinical features and genetic expression information of ccRCC patients were acquired from The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC) and E-MTAB-1980 database. NETs-related gene set were obtained from previous studies. A NETs-related gene signature was constructed based on TCGA data and validated using ICGC and E-MTAB-1980 databases. Furthermore, the immune microenvironment and responsiveness to anticancer medications in ccRCC patients with varying levels of NETs risks were investigated.ResultsA total of 31 NET-related genes were differently expressed between normal kidney and ccRCC tissues. 17 out of 31 were significantly associated with overall survival. After LASSO Cox regression analysis, nine NETs-related genes were enrolled to construct the NETs prognosis signature, and all the ccRCC patients from TCGA were divided into low and high risk group. This signature demonstrated excellent performance in predicting the overall survival of TCGA patients as well as the validation ICGC and E-MTAB-1980 patients. Additionally, the NETs signature was significantly correlated with immune infiltration and drug sensitivity.ConclusionsThe NETs signature established by the current study has prognostic significance in ccRCC, and may serve as a useful biomarker for patient stratification and treatment decisions. Further validation and clinical studies are required to fully translate these findings into clinical practice.

Abstract Triple‐negative breast cancer (TNBC) has the worst prognosis among all breast cancer subtypes due to lack of specific target sites and effective treatments. Herein, a transformable prodrug (DOX‐P18) based on neuropeptide Y analogue with tumor microenvironment responsiveness is developed for TNBC treatment. The prodrug DOX‐P18 can achieve reversible morphological transformation between monomers and nanoparticles through the manipulation of protonation degree in different environments. It can self‐assemble into nanoparticles to enhance the circulation stability and drug delivery efficiency in the physiological environment while transforming from nanoparticles to monomers and being endocytosed into the breast cancer cells in the acidic tumor microenvironment. Further, the DOX‐P18 can precisely be enriched in the mitochondria, and efficiently activated by matrix metalloproteinases. Then, the cytotoxic fragment (DOX‐P3) can subsequently be diffused into the nucleus, generating a sustained cell toxicity effect. In the meanwhile, the hydrolysate residue P15 can assemble into nanofibers to construct nest‐like barriers for the metastasis inhibition of cancer cells. After intravenous injection, the transformable prodrug DOX‐P18 demonstrated superior tumor growth and metastasis suppression with much better biocompatibility and improved biodistribution compared to free DOX. As a novel tumor microenvironment‐responsive transformable prodrug with diversified biological functions, DOX‐P18 shows great potential in smart chemotherapeutics discovery for TBNC.

The efficiency of immunotherapy for triple-negative breast cancer (TNBC) is relatively low due to the difficulty in accurately detecting immune checkpoints. The detection of TNBC-related programmed cell death ligand-1 (PD-L1) expression is important to guide immunotherapy and improve treatment efficiency. Surface-enhanced Raman spectroscopy (SERS) and magnetic resonance (MR) imaging exhibit great potential for early TNBC diagnosis. SERS, an optical imaging mode, has the advantages of high detection sensitivity, good spatial resolution, and “fingerprint” spectral characteristics; however, the shallow detection penetration of SERS bioprobes limits its application in vivo. MR has the advantages of allowing deep penetration with no radiation; however, its spatial resolution needs to be improved. SERS and MR have complementary imaging features for tumor marker detection. In this study, gold nanorod and ultrasmall iron oxide nanoparticle composites were developed as dual-modal bioprobes for SERS-MRI to detect PD-L1 expression. Anti-PD-L1 (aPD-L1) was utilized to improve the targeting ability and specificity of PD-L1 expression detection. TNBC cells expressing PD-L1 were accurately detected via the SERS imaging mode in vitro, which can image at the single-cell level. In addition, bioprobe accumulation in PD-L1 expression-related tumor-bearing mice was simply and dynamically monitored and analyzed in vivo using MR and SERS. To the best of our knowledge, this is the first time a SERS-MRI dual-modal bioprobe combined with a PD-L1 antibody has been successfully used to detect PD-L1 expression in TNBC. This work paves the way for the design of high-performance bioprobe-based contrast agents for the clinical immunotherapy of TNBC.

Abstract Objective Ischemic stroke is a leading cause of human mortality and long‐term disability worldwide. As one of the main forms of regulator of calcineurin 1 (RCAN1), the contribution of RCAN1.4 in diverse biological and pathological conditions has been implicated. But the role of RCAN1.4 in ischemic stroke progression remains elusive. This study is to explore the expression changes and roles of RCAN1.4 in ischemic stroke as well as the underlying mechanisms for these changes and effects of RCAN1.4 in ischemic stroke. Methods Middle cerebral artery occlusion model in C57BL/6J mice and oxygen–glucose deprivation (OGD) model in primary astrocytes were performed to induce the cerebral ischemic stroke. The expression pattern of RCAN1.4 was assessed using real‐time quantitative PCR and western blotting in vivo and in vitro. Mechanistically, the underlying mechanism for the elevation of RCAN1.4 in the upstream was investigated. Lentiviruses were administrated, and the effect of RCAN1.4 in postischemic inflammation was clearly clarified. Results Here we uncovered that RCAN1.4 was dramatically increased in mouse ischemic brains and OGD‐induced primary astrocytes. HIF1α, activated upon OGD, significantly upregulated RCAN1.4 gene expression through specifically binding to the RCAN1.4 promoter region and activating its promoter activity. The functional hypoxia‐responsive element (HRE) was located between −254 and −245 bp in the RCAN1.4 promoter region. Moreover, elevated RCAN1.4 alleviated the release of pro‐inflammatory cytokines TNFα, IL1β, IL6 and reduced expression of iNOS, COX2 in primary astrocytes upon OGD, whereas RCAN1.4 silencing has the opposite effect. Of note, RCAN1.4 overexpression inhibited OGD‐induced NF‐κB activation in primary astrocytes, leading to decreased degradation of IκBα and reduced nuclear translocation of NF‐κB/p65. Interpretation Our results reveal a novel mechanism underscoring the upregulation of RCAN1.4 by HIF1α and the protective effect of RCAN1.4 against postischemic inflammation, suggesting its significance as a promising therapeutic target for ischemic stroke treatment.

Abstract Background As the COVID-19 pandemic evolves, more information is needed on its long-term impacts on health-related quality of life (HRQoL) and social determinants of health (SDoH). The aim of the study was to assess HRQoL and SDoH among a predominantly Latino population of COVID-19 survivors and to compare effects in Latinos versus non-Latinos. Methods This cross-sectional study consisted of a survey (in English and Spanish) of COVID-19 survivors from December 2020 to July 2021. The study assessed sociodemographic data, clinical characteristics, and SDoH, consisting of 10 COVID-19—related concerns. The PROMIS-29 + 2 (PROPr) measure, which captures 8 HRQoL domains and a preference-based health utility, was used to assess HRQoL. Bivariate analyses included chi-square tests and t-tests. Generalized linear models were conducted for multivariable analyses. Results Of 230 respondents (6.3% response rate), the mean [SD] age was 43.1 [14.3] years; 83.0% were Latino; the mean [SD] time since diagnosis was 8.1 [3.2] months; and 12.6% had a history of hospitalization with COVID-19. HRQoL scores were slightly worse than population norms on all domains, especially anxiety; the mean [SD] PROPr health utility was 0.36 [0.25]. Domain scores were similar by ethnicity except for cognitive function—abilities, where scores were lower in Latinos. Multivariable analyses revealed that: (1) financial concerns were associated with worse health utility, as well as worse scores on all 8 PROMIS domains; (2) interpersonal conflict was associated with worse health utility and worse scores on 6 of the 8 PROMIS domains (anxiety, depression, fatigue, sleep disturbance, social function, and pain interference); and (3) Latino ethnicity was only associated with 1 PROMIS domain (cognitive function—abilities) after controlling for covariates. Conclusion COVID-19 infection is associated with HRQoL decrements long after the acute infection, and financial concerns and interpersonal conflict are particularly associated with worse HRQoL.