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Abstract Acinetobacter baumannii is a gram-negative bacillus prevalent in nature, capable of thriving under various environmental conditions. As an opportunistic pathogen, it frequently causes nosocomial infections such as urinary tract infections, bacteremia, and pneumonia, contributing to increased morbidity and mortality in clinical settings. Consequently, developing novel vaccines against Acinetobacter baumannii is of utmost importance. In our study, we identified 10 highly conserved antigenic proteins from the NCBI and UniProt databases for epitope mapping. We subsequently screened and selected 8 CTL, HTL, and LBL epitopes, integrating them into three distinct vaccines constructed with adjuvants. Following comprehensive evaluations of immunological and physicochemical parameters, we conducted molecular docking and molecular dynamics simulations to assess the efficacy and stability of these vaccines. Our findings indicate that all three multi-epitope mRNA vaccines designed against Acinetobacter baumannii are promising; however, further animal studies are required to confirm their reliability and effectiveness.

Abstract Identifying spatially variable genes (SVGs) is crucial for understanding the spatiotemporal characteristics of diseases and tissue structures, posing a distinctive challenge in spatial transcriptomics research. We propose HEARTSVG, a distribution-free, test-based method for fast and accurately identifying spatially variable genes in large-scale spatial transcriptomic data. Extensive simulations demonstrate that HEARTSVG outperforms state-of-the-art methods with higher $${F}_{1}$$ F 1 scores (average $${F}_{1}$$ F 1 Score=0.948), improved computational efficiency, scalability, and reduced false positives (FPs). Through analysis of twelve real datasets from various spatial transcriptomic technologies, HEARTSVG identifies a greater number of biologically significant SVGs (average AUC = 0.792) than other comparative methods without prespecifying spatial patterns. Furthermore, by clustering SVGs, we uncover two distinct tumor spatial domains characterized by unique spatial expression patterns, spatial-temporal locations, and biological functions in human colorectal cancer data, unraveling the complexity of tumors.

IntroductionEnterocytozoon bieneusi (E. bieneusi) is a widespread intracellular fungi that poses a significant zoonotic threat due to its infectivity toward both humans and animals.MethodsTo evaluate the zoonotic transmission potential of this fungi, a molecular investigation was undertaken on E. bieneusi in cattle and goats reared across multiple cities in Zhejiang Province, China. A total of 651 fresh samples were collected, consisting of 265 cattle and 386 goats. The presence of E. bieneusi was determined by PCR amplification and sequencing analysis of the internal transcribed spacer (ITS) region of the small subunit ribosomal RNA (SSU rRNA) gene in all collected samples.ResultsThe results revealed that 17.1% (111/859) of the animals were afflicted with E. bieneusi, cattle having a prevalence of 14.0% (37/265) and goats displaying a higher rate of 19.2% (74/386). Seventeen E. bieneusi genotypes were identified, including 10 known, CHG5 (n = 30), CHG3 (n = 21), I (n = 14), J (n = 12), CHG2 (n = 11), COS-II (n = 8), D (n = 4), CHG19 (n = 2), ETMK5 (n = 1), and Henan III (n = 1), and seven novel, ZJG-I to ZJG-VI and ZJN-I (one each) genotypes.DiscussionThese findings indicate widespread infection of E. bieneusi among the surveyed animals, thereby raising concerns about zoonotic genotypes that could pose potential threats to public health. Furthermore, the identification of novel genotypes of E. bieneusi offers valuable insights into the genetic diversity of this pathogen.

ABSTRACTHuman metapneumovirus (HMPV) is one of the main pathogens causing severe respiratory infections in children, as a common cause of immunodeficiency-related deaths in children and elderly individuals, the prevalence of HMPV has been showing an increasing trend during the last years. However, no vaccines or effective treatment plans are available currently. In this present, based on candidate proteins highly associated with viral virulence and has promising protective potential, we screened for immunodominant cytotoxic T cells, helper T cells, and Linear B-cell epitopes from the most promising candidate Fusion protein, together with G, SH, M, and M2. All epitopes were predicted to have strong antigenicity by Vaxijen and pose no potential toxicity, allergenicity, or hormonology to human proteins by Toxinpred, Allerpred, and Blast analysis, meanwhile, high conservancy is demanded to cover different subtypes. adjuvants β-defensin II and Pam2Cys was attached with EAAAK linkers to improve vaccine’s efficiency. Then, calculation of physicochemical properties proved the protein vaccine as a product can stably exist in the human body. Besides, we assessed the docking between the vaccine and immune receptors to evaluate its ability to stimulate immune responses, and the dynamic simulation further confirmed that the vaccine can tightly bind with immune receptors, which approved that the construction has the potential to induce strong humoral and cellular immune response. Finally, the vaccine was constructed into a multi-epitope mRNA vaccine, the immune simulations suggest that this is a vaccine candidate for controlling HMPV infection.

Studies have highlighted a possible link between air pollution and cerebral small vessel disease (CSVD) imaging markers. However, the exact association and effects of polygenic risk score (PRS) defined genetic susceptibility remains unclear. This cross-sectional study used data from the UK Biobank. Participants aged 40–69 years were recruited between the year 2006 and 2010. The annual average concentrations of NOX, NO2, PM2.5, PM2.5–10, PM2.5 absorbance, and PM10, were estimated, and joint exposure to multiple air pollutants was reflected in the air pollution index (APEX). Air pollutant exposure was classified into the low (T1), intermediate (T2), and high (T3) tertiles. Three CSVD markers were used: white matter hyper-intensity (WMH), mean diffusivity (MD), and fractional anisotropy (FA). The first principal components of the MD and FA measures in the 48 white matter tracts were analysed. The sample consisted of 44,470 participants from the UK Biobank. The median (T1–T3) concentrations of pollutants were as follows: NO2, 25.5 (22.4–28.7) μg/m3; NOx, 41.3 (36.2–46.7) μg/m3; PM10, 15.9 (15.4–16.4) μg/m3; PM2.5, 9.9 (9.5–10.3) μg/m3; PM2.5 absorbance, 1.1 (1.0–1.2) per metre; and PM2.5–10, 6.1 (5.9–6.3) μg/m3. Compared with the low group, the high group’s APEX, NOX, and PM2.5 levels were associated with increased WMH volumes, and the estimates (95 %CI) were 0.024 (0.003, 0.044), 0.030 (0.010, 0.050), and 0.032 (0.011, 0.053), respectively, after adjusting for potential confounders. APEX, PM10, PM2.5 absorbance, and PM2.5–10 exposure in the high group were associated with increased FA values compared to that in the low group. Sex-specific analyses revealed associations only in females. Regarding the combined associations of air pollutant exposure and PRS-defined genetic susceptibility with CSVD markers, the associations of NO2, NOX, PM2.5, and PM2.5–10 with WMH were more profound in females with low PRS-defined genetic susceptibility, and the associations of PM10, PM2.5, and PM2.5 absorbance with FA were more profound in females with higher PRS-defined genetic susceptibility. Our study demonstrated that air pollutant exposure may be associated with CSVD imaging markers, with females being more susceptible, and that PRS-defined genetic susceptibility may modify the associations of air pollutants.

Abstract Background The relationship between the gut mycobiome and end-stage renal disease (ESRD) remains largely unexplored. Methods In this study, we compared the gut fungal populations of 223 ESRD patients and 69 healthy controls (HCs) based on shotgun metagenomic sequencing data, and analyzed their associations with host serum and fecal metabolites. Results Our findings revealed that ESRD patients had a higher diversity in the gut mycobiome compared to HCs. Dysbiosis of the gut mycobiome in ESRD patients was characterized by a decrease of Saccharomyces cerevisiae and an increase in various opportunistic pathogens, such as Aspergillus fumigatus, Cladophialophora immunda, Exophiala spinifera, Hortaea werneckii, Trichophyton rubrum, and others. Through multi-omics analysis, we observed a substantial contribution of the gut mycobiome to host serum and fecal metabolomes. The opportunistic pathogens enriched in ESRD patients were frequently and positively correlated with the levels of creatinine, homocysteine, and phenylacetylglycine in the serum. The populations of Saccharomyces, including the HC-enriched Saccharomyces cerevisiae, were frequently and negatively correlated with the levels of various toxic metabolites in the feces. Conclusions Our results provided a comprehensive understanding of the associations between the gut mycobiome and the development of ESRD, which had important implications for guiding future therapeutic studies in this field.

Abstract Background Acute lung injury (ALI), manifested as strong pulmonary inflammation and alveolar epithelial damage, is a life-threatening disease with high morbidity and mortality. Small extracellular vesicles (sEVs), secreted by multiple types of cells, are critical cellular communication mediators and can inhibit inflammation by transferring bioactive molecules, such as microRNAs (miRNAs). Thus, we hypothesized that sEVs derived from mesenchymal stromal cells (MSC sEVs) could transfer miRNAs to attenuate inflammation of lung epithelial cells during ALI. Methods C57BL/6 male mice were intratracheally administered LPS (10 mg/kg). Six hours later, the mice were randomly administered with MSC sEVs (40 µg per mouse in 150 µl of saline), which were collected by ultracentrifugation. Control group received saline administration. After 48 h, the mice were sacrificed to evaluate pulmonary microvascular permeability and inflammatory responses. In vitro, A549 cells and primary human small airway epithelial cells (SAECs) were stimulated with LPS with or without MSC sEVs treatment. Results In vitro, MSC sEVs could also inhibit the inflammation induced by LPS in A549 cells and SAECs (reducing TNF-α, IL-1β, IL-6 and MCP-1). Moreover, MSC sEV treatment improved the survival rate, alleviated pulmonary microvascular permeability, and inhibited proinflammatory responses (reducing TNF-α, IL-1β, IL-6 and JE-1) in ALI mice. Notably, miR-223-3p was found to be served as a critical mediator in MSC sEV-induced regulatory effects through inhibition of poly (adenosine diphosphate-ribose) polymerase-1 (PARP-1) in lung epithelial cells. Conclusions Overall, these findings suggest that MSC sEVs may offer a novel promising strategy for ALI.

Abstract Background In pre-post designs, analysis of covariance (ANCOVA) is a standard technique to detect the treatment effect with a continuous variable measured at baseline and follow-up. For measurements subject to a high degree of variability, it may be advisable to repeat the pre-treatment and/or follow-up assessments. In general, repeating the follow-up measurements is more advantageous than repeating the pre-treatment measurements, while the latter can still be valuable and improve efficiency in clinical trials. Methods In this article, we report investigations of using multiple pre-treatment and post-treatment measurements in randomized clinical trials. We consider the sample size formula for ANCOVA under general correlation structures with the pre-treatment mean included as the covariate and the mean follow-up value included as the response. We propose an optimal experimental design of multiple pre-post allocations under a specified constraint, that is, given the total number of pre-post treatment visits. The optimal number of the pre-treatment measurements is derived. For non-linear models, closed-form formulas for sample size/power calculations are generally unavailable, but we conduct Monte Carlo simulation studies instead. Results Theoretical formulas and simulation studies show the benefits of repeating the pre-treatment measurements in pre-post randomized studies. The optimal pre-post allocation derived from the ANCOVA extends well to binary measurements in simulation studies, using logistic regression and generalized estimating equations (GEE). Conclusions Repeating baselines and follow-up assessments is a valuable and efficient technique in pre-post design. The proposed optimal pre-post allocation designs can minimize the sample size, i.e., achieve maximum power.

Abstract We propose BIGKnock (BIobank-scale Gene-based association test via Knockoffs), a computationally efficient gene-based testing approach for biobank-scale data, that leverages long-range chromatin interaction data, and performs conditional genome-wide testing via knockoffs. BIGKnock can prioritize causal genes over proxy associations at a locus. We apply BIGKnock to the UK Biobank data with 405,296 participants for multiple binary and quantitative traits, and show that relative to conventional gene-based tests, BIGKnock produces smaller sets of significant genes that contain the causal gene(s) with high probability. We further illustrate its ability to pinpoint potential causal genes at $$\sim 80\%$$ ∼ 80 % of the associated loci.

Abstract Background The prevalence of carbapenem-resistant Klebsiella pneumoniae bloodstream infection (CRKP-BSI) is increasing worldwide. CRKP-BSI is associated with high rates of morbidity and mortality due to limited antibiotic choices. Here, we aim to identify the prevalence and risk factors for infection and mortality of CRKP BSI. Methods This was a retrospective study of the past data from January 1st, 2012 to December 31st, 2019 of adult patients with KP-BSI in Xiangya Hospital, China. Results Among the 706 incidences included in this study, 27.4% of them (212/753) being CR-KP strains. The occurrence of CRKP-BSI was increased from 20.69 to 37.40% from 2012 to 2019. Hematologic malignancies and ICU acquired infection were identified to be substantial risk factors of carbapenem resistance. The overall 28-day mortality rates of CRKP-BSI patients was significantly higher than that of CSKP-BSI (P

The authors present GhostKnockoff, a method for genome-wide association studies which can be applied to enhance existing and future studies to identify functional variants with weaker statistical effects that might be missed by conventional association tests.

Abstract Background Underwater endoscopic mucosal resection (UMER) is a new method of endoscopic resection to completely remove the lesion without submucosal injection. But few attempts have been carried out for rectal neuroendocrine tumors (rectal NETs). Methods We retrospectively investigated data on the tumor characteristics and outcomes of patients with ≤ 10 mm rectal NETs who underwent UEMR or endoscopic submucosal dissection (ESD) from January 2019 to June 2021 in our institute. Results The endoscopic resection rate was 100% in both UEMR and ESD groups. The histological complete resection rate of the UEMR group (95.5%) was lower than that of the ESD group (96.4%) with no significant difference. The average operation time, hospitalization time and operation cost of UEMR group were less than those of ESD group (P

BackgroundNocardia genus, a complex group of species classified to be aerobic actinomycete, can lead to severe concurrent infection as well as disseminated infection, typically in immunocompromised patients. With the expansion of the susceptible population, the incidence of Nocardia has been gradually growing, accompanied by increased resistance of the pathogen to existing therapeutics. However, there is no effective vaccine against this pathogen yet. In this study, a multi-epitope vaccine was designed against the Nocardia infection using reverse vaccinology combined with immunoinformatics approaches.MethodsFirst, the proteomes of 6 Nocardia subspecies Nocardia subspecies (Nocardia farcinica, Nocardia cyriacigeorgica, Nocardia abscessus, Nocardia otitidiscaviarum, Nocardia brasiliensis and Nocardia nova) were download NCBI (National Center for Biotechnology Information) database on May 1st, 2022 for the target proteins selection. The essential, virulent-associated or resistant-associated, surface-exposed, antigenic, non-toxic, and non-homologous with the human proteome proteins were selected for epitope identification. The shortlisted T-cell and B-cell epitopes were fused with appropriate adjuvants and linkers to construct vaccines. The physicochemical properties of the designed vaccine were predicted using multiple online servers. The Molecular docking and molecular dynamics (MD) simulation were performed to understand the binding pattern and binding stability between the vaccine candidate and Toll-like receptors (TLRs). The immunogenicity of the designed vaccines was evaluated via immune simulation.Results3 proteins that are essential, virulent-associated or resistant-associated, surface-exposed, antigenic, non-toxic, and non-homologous with the human proteome were selected from 218 complete proteome sequences of the 6 Nocardia subspecies epitope identification. After screening, only 4 cytotoxic T lymphocyte (CTL) epitopes, 6 helper T lymphocyte (HTL) epitopes, and 8 B cell epitopes that were antigenic, non-allergenic, and non-toxic were included in the final vaccine construct. The results of molecular docking and MD simulation showed that the vaccine candidate has a strong affinity for TLR2 and TLR4 of the host and the vaccine-TLR complexes were dynamically stable in the natural environment. The results of the immune simulation indicated that the designed vaccine had the potential to induce strong protective immune responses in the host. The codon optimization and cloned analysis showed that the vaccine was available for mass production.ConclusionThe designed vaccine has the potential to stimulate long-lasting immunity in the host, but further studies are required to validate its safety and efficacy.

BackgroudOxygen metabolism is an important factor affecting the development of tumors, but its roles and clinical value in Colorectal cancer are not clear. We developed an oxygen metabolism (OM) based prognostic risk model for colorectal cancer and explored the role of OM genes in cancer.MethodsGene expression and clinical data obtained from The Cancer Genome Atlas, Clinical Proteomic Tumor Analysis Consortium databases were consider as discovery and validation cohort, respectively. The prognostic model based on differently expressed OM genes between tumor and GTEx normal colorectal tissues were constructed in discovery cohort and validated in validation cohort. The Cox proportional hazards analysis was used to test clinical independent. Upstream and downstream regulatory relationships and interaction molecules are used to clarify the roles of prognostic OM genes in colorectal cancer.ResultsA total of 72 common differently expressed OM genes were detected in the discovery and validation set. A five-OM gene prognostic model including LRT2, ATP6V0E2, ODC1, SEL1L3 and VDR was established and validated. Risk score determined by the model was an independent prognostic according to routine clinical factors. Besides, the role of prognostic OM genes involves transcriptional regulation of MYC and STAT3, and downstream cell stress and inflammatory response pathways.ConclusionsWe developed a five-OM gene prognostic model and study the unique roles of oxygen metabolism in of colorectal cancer

Abstract Background Some clinical researchers have reported that patients with cCR (clinical complete response) status after neoadjuvant chemoradiotherapy (nCRT) could adopt the watch-and-wait (W&W) strategy. Compared with total mesorectal excision (TME) surgery, the W&W strategy could achieve a similar overall survival. Could the W&W strategy replace TME surgery as the main treatment option for the cCR patients? By using the meta-analysis method, we evaluated the safety and efficacy of the W&W strategy and TME surgery for rectal cancer exhibiting cCR after nCRT. Methods We evaluated two treatment strategies for rectal cancer with cCR after nCRT up to July 2021 by searching the Cochrane Library, PubMed, Wanfang, and China National Knowledge Infrastructure (CNKI) databases. Clinical data for primary outcomes (local recurrence, cancer-related death and distant metastasis), and secondary outcomes (disease-free survival (DFS) and overall survival (OS)) were collected to evaluate the efficacy and safety in the two groups. Results We included nine studies with 818 patients in the meta-analysis, and there were five moderate-quality studies and four high-quality studies. A total of 339 patients were in the W&W group and 479 patients were in the TME group. The local recurrence rate in the W&W group was greater than that in the TME group in the fixed-effects model (OR 8.54, 95% CI 3.52 to 20.71, P < 0.001). The results of other outcomes were similar in the two groups. Conclusion The local recurrence rate of the W&W group was greater than that in the TME group, but other results were similar in the two groups. With the help of physical examination and salvage therapy, the W&W strategy could achieve similar treatment effects with the TME approach. Trial registration Protocol registration number: CRD42021244032 .

Ferroptosis has recently been associated with immunological changes in sepsis. However, the clinical significance of ferroptosis-associated genes (FAGs) remains unknown. In this paper, a FAG-based prognostic model was constructed for sepsis patients using an integrated machine learning approach. The prognosis model was composed of 14 FAGs that classify the patients as high or low risk. Based on immunological study, it was found that the immune status differed between the high-risk and low-risk clusters. Cox regression analysis revealed that FAGs were independent risk factors for the overall survival of sepsis patients. ROC curves and nomograms revealed that the FAG-based model was robust for prognosis prediction. Lastly, NEDD4L was identified from the 14 FAGs as a potential hub gene for sepsis prediction.

Abstract Background The diagnosis of Barrett’s esophagus (BE) is disturbed by numerous factors, including correct gastroesophageal junction judgment, the initial location of the Z-line and the biopsy result above it. The acetic acid (AA) could help to diagnose BE better than high resolution imaging technology or magnifying endoscopy, by providing enhanced contrast of different epithelium. We have noticed AA could produce multiple white circular lines, forming circular stripes (CS), at lower esophagus, which hasn’t been reported by others. This study aimed to investigate whether the CS is a special marker in BE patients. Methods A total of 47 BE patients and 63 healthy people were enrolled from March 2016 to October 2016, and 2% AA staining had been operated routinely at lower esophagus under high resolution gastroscopy. We observed whether there were CS after AA staining and the images were compared between the two groups. Results CS were confirmed in 42 patients (89.36%) in the BE group and 5 (7.94) in the control group ((χ2 = 72.931, P

Great efforts have been made to explore the potential treatment for cancers, and the most common therapies include surgery, chemotherapy and radiotherapy. As an alternative medication, earthworms have drawn increased attention considering its abundance in resource, easy access and minor side effects compared to traditional therapies. However, few studies had focused on the antitumor effect of earthworm-derived components. The purpose of this study is to investigate whether earthworm extract has an effect on tumor cell apoptosis and growth. Earthworm extract (EE) was purified through multiple steps of centrifugation and chromatography. Mice were inoculated with ascitic fluid derived from mice inoculated with S180 sarcoma tumor cells and fed orally with different amounts of EE for 25 days. Tumor samples were analyzed for size and cell apoptosis. And we found that the weight and sizes of tumor decreased gradually as the amount of EE administered increased. More apoptotic cells and lowered level of lactate dehydrogenase (LDH), a biomarker of tumor invasiveness, was detected in EE-treated group than the untreated group. Our results suggested that EE could dramatically promote tumor apoptosis and reduce tumor size in vivo, suggesting a novel alternative therapy for cancer patients.

One patient with Dieulafoy’s lesion (DL) of the rectum who had a history of anal receptive intercourse is described and the relevant literature reviewed. DL is rare in clinical practice and is extremely rare in the rectum. It often affects patients with no history of cirrhosis or gastrointestinal disease and occurs with abrupt or recurrent gastrointestinal bleeding. Visible vessels can usually be found by endoscopy and coinstantaneous treatments are essential while surgical interventions can occur when necessary. The diagnosis of DL is mainly based on clinical manifestations and endoscopic features, and endoscopic treatment is the first option for hemostasis.

Compatibility is a decisive and necessary factor which impacts the successfulness and correctness of establishing connections among services. Reliable service parameter predictions on compatibility may not only provide assurance on fulfilling workflow, but also reduce the risk of unexpected wasting on time and expenses. Recent research on service's parameter prediction focus on two aspects: Collaborative Filtering and Matrix Factorization. Both of them faces challenges from data-sparse problem, lack of solid mathematical support, and weakness on tracking dynamic services. In this paper, we propose Link-ability, a parameter to reveal the compatibility of a service. Firstly, we propose an architecture called Topology-Retrievable Service Oriented Architecture (TSOA), which is capable of collecting successful invocation records from service requesters and generate the whole topology of the service pool in a specific period of time. Secondly, we bring up the Link-ability Generation Algorithm (LGA) and Markovian mathematical strategies to generate Link-ability value. The algorithm is supported by solid mathematical proof and capable of solving data-sparse problems. Both TSOA and LGA are upgraded to adapt the circumstances of services exiting the service pool (we define it as a Drop-out). Lastly, we design and conduct two series of experiment to strengthen the reliability and correctness of Link-ability. The result shows that Link-ability considers comprehensive information of the whole topology and bring 54.18% reduction in average error rate against Drop-out scenarios. [ABSTRACT FROM AUTHOR]