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With the rapid expansion of cities, the construction of 15-minute communities has become an important way to improve the urban living environment and enhance the quality of life of residents. In this study, based on the perspective of a 15-minute community in Chengdu, the current situation of the spatial layout in the 12 main urban districts of 15,941 public service facility points is studied. Additionally, the matching relationship between the supply and demand of five major categories (19 subcategories) of public service facilities and the population is assessed by using the kernel density analysis method, the Gaussian two-step floating catchment area method, the hierarchical analysis method and the bivariate spatial autocorrelation. Finally, suggestions for the optimization of basic service facilities are made in the light of the current development situation in Chengdu. The results show that (1) there is a large spatial heterogeneity in the distribution and accessibility of public service facilities in the study area; (2) there is a mismatch between the supply and demand of public service facilities and the population in Chengdu; and (3) in order to further optimize the allocation of public service facilities, it is necessary to focus first on areas where demand exceeds supply. This study built a framework for assessing the current status of spatial distribution of public service facilities, which measures the 15-minute accessibility of basic public service facilities in a more comprehensive way and bridges the gap of previous single-type studies, which make it difficult to make comprehensive optimization recommendations directly. Meanwhile, the bivariate spatial autocorrelation reveals the areas of mismatch between supply and demand more accurately, and more clearly shows the areas that need to be focused on for optimization by policy makers.

Background Firmicutes have the capacity to remove excess nitrate from the environment via either denitrification, dissimilatory nitrate reduction to ammonium or both. The recent renewed interest in their nitrogen metabolism has revealed many interesting features, the most striking being their wide variety of dissimilatory nitrate reduction pathways. In the present study, nitrous oxide production from Bacillus licheniformis , a ubiquitous Gram-positive, spore-forming species with many industrial applications, is investigated. Results B. licheniformis has long been considered a denitrifier but physiological experiments on three different strains demonstrated that nitrous oxide is not produced from nitrate in stoichiometric amounts, rather ammonium is the most important end-product, produced during fermentation. Significant strain dependency in end-product ratios, attributed to nitrite and ammonium, and medium dependency in nitrous oxide production were also observed. Genome analyses confirmed the lack of a nitrite reductase to nitric oxide, the key enzyme of denitrification. Based on the gene inventory and building on knowledge from other non-denitrifying nitrous oxide emitters, hypothetical pathways for nitrous oxide production, involving NarG, NirB, qNor and Hmp, are proposed. In addition, all publically available genomes of B. licheniformis demonstrated similar gene inventories, with specific duplications of the nar operon, narK and hmp genes as well as NarG phylogeny supporting the evolutionary separation of previously described distinct BALI1 and BALI2 lineages. Conclusions Using physiological and genomic data we have demonstrated that the common soil bacterium B. licheniformis does not denitrify but is capable of fermentative dissimilatory nitrate/nitrite reduction to ammonium (DNRA) with concomitant production of N 2 O. Considering its ubiquitous nature and non-fastidious growth in the lab, B. licheniformis is a suitable candidate for further exploration of the actual mechanism of N 2 O production in DNRA bacteria and its relevance in situ .

The neutrophil-lymphocyte ratio (NLR) and the platelet-lymphocyte ratio (PLR) are markers of systemic inflammation. However, there is little evidence of the value of inflammation in the early diagnosis of gastric cancer (GC). A total of 2,606 patients diagnosed with GC in the past three years and 3,219 healthy controls over the same period were included in this study. Peripheral blood samples were obtained to analyze the NLR, PLR, carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA19-9). The optimal cutoff levels for the NLR and PLR were defined by receiver operating characteristic (ROC) curve analysis (NLR=2.258, PLR=147.368). The value of different biomarkers for diagnosing GC was compared by the area under the curve (AUC). The NLR and PLR showed diagnostic sensitivity in GC (AUC=0.715, AUC=0.707). Using the Bonferroni correction, the NLR and PLR were superior to CEA and CA19-9 in the diagnosis of GC (P<0.0001). The systemic inflammatory markers were significantly higher in the early stage of GC than tumor markers. After grouping patients and healthy controls by gender, we found that the diagnostic significance of combined NLR and PLR for GC was greater in male patients than in female patients (P<0.0001). The diagnostic value of the NLR and PLR in GC is higher than that of the traditional tumor markers CEA and CA19-9. Systemic markers of inflammation are more valuable in male than female patients.

Since the recent application of metagenomic next-generation sequencing (mNGS) techniques to clinics, Torquetenoviruses (TTV) have received much attention due to their high positive rates. However, there is an insufficient understanding in clinical settings of the pathogen, especially in immunocompromised patients. This study explores the clinical characteristics of TTV infection in immunocompromised patients using mNGS. We enrolled a total of 120 TTV-infected patients in the study, including 81 immunocompromised and 39 immunocompetent individuals. The prevalence, diagnosis, treatment, and co-pathogens were compared between the two groups. The microbial diversity and presence of co-pathogens in patients infected with Torquetenovirus (TTV) were elucidated through comprehensive analysis. T-tests compared the normally distributed continuous data. The immunocompromised patients exhibited significantly elevated TTV loads, and a notable proportion of these patients also presented with hematopoietic disorders. Importantly, our investigation revealed that current treatments showed no efficacy against TTV infection.Furthermore, the presence of copathogens such as Staphylococcus , Bacillus , Mycobacterium , and Acinetobacter was observed in TTV-infected individuals. Immunocompromised patients exhibited a significantly higher abundance of Staphylococcus and Shewanella compared to immunocompetent patients ( p  < 0.05). Cautious use of antiviral therapy is recommended for patients with TTV mono-infection. However, greater attention should be given to co-pathogens, such as Staphylococcus spp. and Shewanella spp . This cohort study provides valuable insights into the clinical significance of TTV infection, particularly in immunocompromised patients. We found that TTV is frequently detected in this population, often with higher viral loads and an increased burden of co-pathogens. These findings suggest that TTV may serve primarily as a marker of immune dysfunction rather than as a sole pathogen. Incorporating TTV monitoring into mNGS-based diagnostics could help identify high-risk patients, support early intervention, and guide tailored management strategies in immunocompromised settings.

Background Lung adenocarcinoma with micropapillary and solid predominant subtypes was reported to be associated with poor prognosis; however, whether minor components (non-predominant) of micropapillary and solid subtypes predict poor prognosis remains unknown. In this study, we investigated the predictive and prognostic value of lymph node metastasis of minor micropapillary and solid components. Methods Specimens of resected tumors of 1244 patients were reclassified to determine the predominant subtype and minor components (>5 %, but not predominant). Of these specimens, 105 contained a micropapillary component and 210 contained a solid component. The correlation between each subtype and lymph node metastasis was analyzed, and survival analyses were used to determine the association between each subtype and patient survival. Results Adenocarcinomas harboring micropapillary and/or solid components held higher rates of metastatic lymph node stations (25.2 % vs. 15.6 %, p = 0.002; and 24.0 % vs. 14.9 %, p < 0.001, respectively) and lymph nodes (17.3 % vs. 10.1 %, p = 0.004; and 15.5 % vs. 9.7 %, p = 0.001, respectively). Patients with micropapillary and solid components in their tumors showed a shorter median recurrence-free survival (15.8 vs. 62.8 months, p < 0.001; and 20.8 months vs. not reached, p < 0.001) and overall survival (47.0 months vs. not reached, p < 0.001; and 69.0 months vs. not reached, p < 0.001). Conclusions Minor components of micropapillary and/or solid subtypes of lung adenocarcinoma are correlated with lymph node metastasis and poor prognosis. Thus, it is beneficial to focus not only on predominant subtypes but also minor components to predict prognoses and make therapeutic strategies more comprehensively.

Adenocarcinoma in situ and minimally invasive adenocarcinoma are the pre-invasive forms of lung adenocarcinoma. The genomic and immune profiles of these lesions are poorly understood. Here we report exome and transcriptome sequencing of 98 lung adenocarcinoma precursor lesions and 99 invasive adenocarcinomas. We have identified EGFR , RBM10 , BRAF , ERBB2 , TP53 , KRAS , MAP2K1 and MET as significantly mutated genes in the pre/minimally invasive group. Classes of genome alterations that increase in frequency during the progression to malignancy are revealed. These include mutations in TP53 , arm-level copy number alterations, and HLA loss of heterozygosity. Immune infiltration is correlated with copy number alterations of chromosome arm 6p, suggesting a link between arm-level events and the tumor immune environment. The genomic and immune landscape of pre-invasive lung adenocarcinoma is poorly understood. Here, the authors perform exome and transcriptome sequencing on precursor legions and invasive lung adenocarcinomas, identifying recurrently mutated genes in pre/minimally invasive cases, and arm level alteration events linked to immune infiltration.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly become a global public health threat. The efficacy of several repurposed drugs has been evaluated in clinical trials. Among these drugs, a second-generation antiandrogen agent, enzalutamide, was proposed because it reduces the expression of transmembrane serine protease 2 (TMPRSS2), a key component mediating SARS-CoV-2-driven entry, in prostate cancer cells. However, definitive evidence for the therapeutic efficacy of enzalutamide in COVID-19 is lacking. Here, we evaluated the antiviral efficacy of enzalutamide in prostate cancer cells, lung cancer cells, human lung organoids and Ad-ACE2-transduced mice. Tmprss2 knockout significantly inhibited SARS-CoV-2 infection in vivo. Enzalutamide effectively inhibited SARS-CoV-2 infection in human prostate cells, however, such antiviral efficacy was lacking in human lung cells and organoids. Accordingly, enzalutamide showed no antiviral activity due to the AR-independent TMPRSS2 expression in mouse and human lung epithelial cells. Moreover, we observed distinct AR binding patterns between prostate cells and lung cells and a lack of direct binding of AR to TMPRSS2 regulatory locus in human lung cells. Thus, our findings do not support the postulated protective role of enzalutamide in treating COVID-19 through reducing TMPRSS2 expression in lung cells. Enzalutamide, an approved drug for prostate cancer, acts on TMPRSS2 expression, a key mediator for SARS-CoV-2 infection. Here, the authors characterize the anti-SARS-CoV-2 effects of Enzalutamide in prostate cancer cells, lung cancer cells, human lung organoids and in hACE2-transduced Tmprss2 knockout mice and show lack antiviral action in human lung cells and human lung organoids, likely due to the AR-independent TMPRSS2 expression in mouse and human lung epithelial cells.

Carpal tunnel syndrome (CTS) is a common condition in pregnancy, yet reliable tools for identifying women at high risk-particularly those with gestational diabetes mellitus (GDM)-remain lacking. Although GDM shares metabolic features with type 2 diabetes, a recognised CTS risk factor, whether GDM itself causally increases CTS risk and through which molecular pathways has not been established. We used linkage disequilibrium score regression and two-sample Mendelian randomization across FinnGen and UK Biobank to evaluate the genetic correlation and causal effect of GDM on CTS. To identify molecular mediators, we integrated CTS GWAS with whole-blood cis-eQTLs and plasma protein QTLs using summary-data MR and Bayesian colocalization. We then characterised trait specificity through phenome-wide MR and quantified mediation effects through two-step MR. Bulk RNA-seq of CTS tissue, single-cell RNA-seq of placental cell from women with and without GDM, murine histology and immunofluorescence, and molecular docking were used to delineate downstream mechanisms and therapeutic potential. GDM and CTS showed significant genetic correlation (rg = 0.219). Genetic liability to GDM causally increased CTS risk across discovery, replication, and female-only models, independent of other metabolic or pregnancy-related traits. Multi-omics integration identified CCS as the only gene supported at both eQTL and pQTL levels and revealed its strongest and most specific causal association with CTS. Mediation MR demonstrated that circulating CCS accounts for a substantial proportion of the GDM-CTS effect. Transcriptomic, single-cell, and animal analyses confirmed a CCS-high, inflamed, and collagen-rich microenvironment in CTS, whereas docking analyses indicated that CCS-centred pathways are pharmacologically tractable. GDM exerts a causal effect on CTS, largely mediated through CCS-driven oxidative, immune, and fibrotic pathways. CCS emerges as a promising biomarker for risk stratification and a potential therapeutic target. These findings provide a mechanistic foundation for early CTS surveillance and personalised management in women with GDM, addressing an important unmet clinical need in perinatal care.

Background Carbapenem-resistant Pseudomonas aeruginosa (CRPA) has emerged as a critical threat in bloodstream infections (BSIs), with rising global prevalence and elevated mortality rates. Traditional surveillance methods often lacks resolution for resistance-virulence-transmission interplay, highlighting the importance of high-resolution genomics. Whole-genome sequencing (WGS) has enabled unprecedented resolution in dissecting CRPA’s genetic landscape, revealing links between resistance, virulence, and outcomes. Results This study employed WGS to characterize 61 P. aeruginosa isolates from BSIs, with a focus on 18 CRPA strains. Clinical data linked central venous catheterization to CRPA BSI development (OR = 6.6, p  = 0.002) and identified carbapenem exposure, mechanical ventilation, and low hemoglobin as independent mortality risk factors. WGS identified 33.3% ( n  = 6, 6/18) of the strains harbored β-lactamase genes, and 44.4%( n  = 8, 8/18) of the strains carried truncated OprD protein due to frameshift mutations or point mutations inducing translational truncation. Efflux pump overexpression (61.1% with ≥ 2-fold upregulation) further contributed to this resistance phenotype. MLST identified 49 distinct STs (including 2 novel types) and a pattern of endemic diversification. O11 is strongly linked to carbapenem resistance (CRPA: p  = 0.02; MDRPA: p  = 0.004), correlating with oprD mutations ( p  = 0.008) and exoU +/ exoS -, indicating enhanced nosocomial adaptability. Conclusions A very high genetic diversity was noted amongst P. aeruginosa strains isolated from BSIs cases. The mechanism of carbapenem resistance is mainly attributed to oprD mutations and efflux pumps activation, with carbapenemases emerging as an additional mechanism of concern. These resistance mechanisms with high-risk clinical factors collectively indicate that strict policies are essential for in CRPA BSIs management.

PIK3CA gene encoding a catalytic subunit of the phosphatidylinositol-3-kinase (PI3K) is mutated and/or amplified in various neoplasia, including lung cancer. Here we investigated PIK3CA gene alterations, the expression of core components of PI3K pathway, and evaluated their clinical importance in non-small cell lung cancer (NSCLC). Oncogenic mutations/rearrangements in PIK3CA, EGFR, KRAS, HER2, BRAF, AKT1 and ALK genes were detected in tumors from 1117 patients with NSCLC. PIK3CA gene copy number was examined by fluorescent in situ hybridization and the expression of PI3K p110 subunit alpha (PI3K p110α), p-Akt, mTOR, PTEN was determined by immunohistochemistry in PIK3CA mutant cases and 108 patients without PIK3CA mutation. PIK3CA mutation was found in 3.9% of squamous cell carcinoma and 2.7% of adenocarcinoma. Among 34 PIK3CA mutant cases, 17 tumors harbored concurrent EGFR mutations and 4 had KRAS mutations. PIK3CA mutation was significantly associated with high expression of PI3K p110α (p<0.0001), p-Akt (p = 0.024) and mTOR (p = 0.001), but not correlated with PIK3CA amplification (p = 0.463). Patients with single PIK3CA mutation had shorter overall survival than those with PIK3CA-EGFR/KRAS co-mutation or wildtype PIK3CA (p = 0.004). A significantly worse survival was also found in patients with PIK3CA mutations than those without PIK3CA mutations in the EGFR/KRAS wildtype subgroup (p = 0.043). PIK3CA mutations frequently coexist with EGFR/KRAS mutations. The poor prognosis of patients with single PIK3CA mutation in NSCLC and the prognostic value of PIK3CA mutation in EGFR/KRAS wildtype subgroup suggest the distinct mutation status of PIK3CA gene should be determined for individual therapeutic strategies in NSCLC.