Nanopore-based full-length transcriptome sequencing for understanding the underlying molecular mechanisms of rapid and slow progression of diabetes nephropathy.

BACKGROUND: Diabetic nephropathy (DN) has been a major factor in the outbreak of end-stage renal disease for decades. As the underlying mechanisms of DN development remains unclear, there is no ideal methods for the diagnosis and therapy. OBJECTIVE: We aimed to explore the key genes and pathways that affect the rate progression of DN. METHODS: Nanopore-based full-length transcriptome sequencing was performed with serum samples from DN patients with slow progression (DNSP, n = 5) and rapid progression (DNRP, n = 6). RESULTS: Here, transcriptome proclaimed 22,682 novel transcripts and obtained 45,808 simple sequence repeats, 1,815 transcription factors, 5,993 complete open reading frames, and 1,050 novel lncRNA from the novel transcripts. Moreover, a total of 341 differentially expressed transcripts (DETs) and 456 differentially expressed genes (DEGs) between the DNSP and DNRP groups were identified. Functional analyses showed that DETs mainly involved in ferroptosis-related pathways such as oxidative phosphorylation, iron ion binding, and mitophagy. Moreover, Functional analyses revealed that DEGs mainly involved in oxidative phosphorylation, lipid metabolism, ferroptosis, autophagy/mitophagy, apoptosis/necroptosis pathway. CONCLUSION: Collectively, our study provided a full-length transcriptome data source for the future DN research, and facilitate a deeper understanding of the molecular mechanisms underlying the differences in fast and slow progression of DN.

Eddy Current Array for Defect Detection in Finely Grooved Structure Using MSTSA Network.

In this paper, we focus on eddy current array (ECA) technology for defect detection in finely grooved structures of spinning cylinders, which are significantly affected by surface texture interference, lift-off distance, and mechanical dither. Unlike a single eddy current coil, an ECA, which arranges multiple eddy current coils in a specific configuration, offers not only higher accuracy and efficiency for defect detection but also the inherent properties of space and time for signal acquisition. To efficiently detect defects in finely grooved structures, we introduce a spatiotemporal self-attention mechanism to ECA testing, enabling the detection of defects of various sizes. We propose a Multi-scale SpatioTemporal Self-Attention Network for defect detection, called MSTSA-Net. In our framework, Temporal Attention (TA) and Spatial Attention (SA) blocks are incorporated to capture the spatiotemporal features of defects. Depth-wise and point-wise convolutions are utilized to compute channel weights and spatial weights for self-attention, respectively. Multi-scale features of space and time are extracted separately in a pyramid manner and then fused to regress the bounding boxes and confidence levels of defects. Experimental results show that the proposed method significantly outperforms not only traditional image processing methods but also state-of-the-art models, such as YOLOv3-SPP and Faster R-CNN, with fewer parameters and lower FLOPs in terms of Recall and F1 score.

Heterogeneity of SARS-CoV-2 immune responses after the nationwide Omicron wave in China.

It remains unclear how previous infections and vaccinations influenced and shaped heterogeneous immune responses against Omicron and its variants in diverse populations in China. After the national wave of Omicron in early 2023, we evaluated serum levels of neutralizing antibodies (nAbs) against Omicron (B.1.1.529) and its variants (BA.5, BF.7, and CH1.1) in 33 COVID-19 convalescents and 40 uninfected vaccinees, using vesicular stomatitis virus-based pseudovirus neutralizing assay. In addition, we followed 34 Delta convalescent patients to compare their immune responses against Omicron before (late 2021) and after the Omicron wave (early 2023). NAbs at the acute phase of the disease were investigated in 50 Omicron inpatients, including 24 vaccinated and 26 unvaccinated patients. Among them, nasal mucosal IgA levels were measured in 42 subjects. Compared to vaccination, breakthrough infections significantly increased the breadth and magnitude of serum nAbs and mucosal IgA levels against Omicron variants. Exposure to Omicron but not Delta elicited stronger pan-Omicron responses. In Omicron inpatients, nAbs continued to rise as vaccination doses increased. However, in both vaccinees and convalescents, a fourth dose vaccination did not elicit higher nAbs against Omicron. Furthermore, nAbs against Omicron variants lasted longer than nAbs against WT SARS-CoV-2. Breakthrough infections of Omicron variants elicited specific immune responses against Omicron compared to vaccination and Delta infection. Although repeated vaccination revealed limited impacts on serum nAbs, populations at high risk of hospitalization may still benefit from continued vaccination.IMPORTANCEThe study described the specific humoral immunity against Omicron and its variants (BA.5, BF.7, and CH1.1) in diverse populations, including Delta-positive convalescent patients, Omicron-infected patients with a previous or current confirmed Delta infection, Omicron-positive patients, and healthy controls. In addition, we followed Delta convalescents for 1 year to evaluate the effect of a booster vaccine, breakthrough infection, and reinfection. Nasal mucosal IgA levels against SARS-CoV-2 were also examined. The findings of this study demonstrated the varied responses of individuals in different states following the outbreak of Omicron, highlighting the potential advantages of ongoing immunization for groups that are more vulnerable and have a greater likelihood of being hospitalized.

Nobiletin restores HFD-induced enteric nerve injury by regulating enteric glial activation and the GDNF/AKT/FOXO3a/P21 pathway.

BACKGROUND: To explore whether nobiletin has a protective effect on high-fat diet (HFD)-induced enteric nerve injury and its underlying mechanism. METHODS: An obesity model was induced by a HFD. Nobiletin (100 mg/kg and 200 mg/kg) and vehicle were administered by gastric gavage for 4 weeks. Lee's index, body weight, OGTT and intestinal propulsion assays were performed before sacrifice. After sampling, lipids were detected using Bodipy 493/503; lipid peroxidation was detected using MDA and SOD kits and the expression of PGP 9.5, Trem2, GFAP, ß-tubulin 3, Bax, Bcl2, Nestin, P75 NTR, SOX10 and EDU was detected using immunofluorescence. The GDNF, p-AKT, AKT, p-FOXO3a, FOXO3a and P21 proteins were detected using western blotting. The relative mRNA expression levels of NOS2 were detected via qPCR. Primary enteric neural stem cells (ENSCs) were cultured. After ENSCs were treated with palmitic acid (PA) and nobiletin, CCK-8 and caspase-3/7 activity assays were performed to evaluate proliferation and apoptosis. RESULTS: HFD consumption caused colon lipid accumulation and peroxidation, induced enteric nerve damage and caused intestinal motor dysfunction. However, nobiletin reduced lipid accumulation and peroxidation in the colon; promoted Trem2, ß-tubulin 3, Nestin, P75NTR, SOX10 and Bcl2 expression; inhibited Bax and GFAP expression; reduced NOS2 mRNA transcription; and regulated the GDNF/AKT/FOXO3a/P21 pathway. Nobiletin also promoted PA-induced impairment of ENSCs. CONCLUSIONS: Nobiletin restored HFD-induced enteric nerve injury, which may be associated with inhibiting enteric nerve apoptosis, promoting enteric nerve survival and regulating the GDNF/AKT/FOXO3a/P21 pathway.

Supervised Group-Based Exercise for Preventing Falls Among Older Adults in the Community: A Systematic Review and Meta-Analysis.

BACKGROUND: Supervised group exercise may have greater health benefits than no exercise or exercise alone. PURPOSE: The purpose of this systematic review and meta-analysis was to investigate the effectiveness of supervised group-based exercise on the risk of falls among community-dwelling older adults compared to no exercise or exercise alone. METHODS: Four databases were searched up to March 1, 2024 for eligible randomized controlled trials. RESULTS: Seventeen randomized controlled trials were eligible for this meta-analysis. Meta-analyses showed that compared with no exercise, supervised group-based exercise had a significant effect on preventing falls, injurious falls, and fall-related fractures. Compared with exercise alone, supervised group-based exercise significantly reduced falls and injurious falls. CONCLUSIONS: Moderate-quality evidence suggests that compared with no exercise or exercise alone, supervised group-based exercise is more effective at preventing falls among community-dwelling older adults.

Replicon-Based Typing About IncG Plasmids and Molecular Characterization of Five IncG Plasmids Carrying Carbapenem Resistance Gene bla KPC-2.

Purpose: To investigate the genetic diversity of IncG plasmids, we have proposed a typing scheme based on replicon repA and performed comparative genomic analysis of five IncG plasmids from China. Methods: p30860-KPC, p116965-KPC, pA1705-KPC, pA1706-KPC and pNY5520-KPC total in five IncG plasmids from clinical isolates of Pseudomonas and Enterobacteriaceae, respectively, were fully sequenced and were compared with the previously collected reference plasmid p10265-KPC. Results: Based on phylogeny, IncG-type plasmids are divided into IncG-I to IncG-VIII, the five plasmids belong to IncG-VIII. A detailed sequence comparison was then presented that the IncG plasmid involved accessory region I (Tn5563a/b/c/d/e), accessory region II (ISpa19), and accessory region III (bla KPC-2-region). Expect for the pNY5520-KPC, the rest of the plasmids had the same backbone structure as the reference one. Within the plasmids, insertion sequences Tn5563d and Tn5563e were identified, a novel unknown insertion region was found in Tn5563b/c/d/e. In addition, Tn6376b and Tn6376c were newly designated in the study. Conclusion: The data presented here including a typing scheme and detailed genetic comparison which provide an insight into the diversification and evolution history of IncG plasmids.

Dysrhythmic saliva microbiota in mobile phone addicts with sleep disorders and restored by acupuncture.

Background: Mobile phone addiction (MPA) greatly affects the biological clock and sleep quality and is emerging as a behavioral disorder. The saliva microbiota has been linked to circadian rhythms, and our previous research revealed dysrhythmic saliva metabolites in MPA subjects with sleep disorders (MPASD). In addition, acupuncture had positive effects. However, the dysbiotic saliva microbiota in MPASD patients and the restorative effects of acupuncture are unclear. Objectives: To probe the circadian dysrhythmic characteristics of the saliva microbiota and acupunctural restoration in MPASD patients. Methods: MPASD patients and healthy volunteers were recruited by the Mobile Phone Addiction Tendency Scale (MPATS) and the Pittsburgh Sleep Quality Index (PSQI). Saliva samples were collected every 4 h for 72 h. After saliva sampling, six MPDSD subjects (group M) were acupuncturally treated (group T), and subsequent saliva sampling was conducted posttreatment. Finally, all the samples were subjected to 16S rRNA gene sequencing and bioinformatic analysis. Results: Significantly increased MPATS and PSQI scores were observed in MPDSD patients (p< 0.01), but these scores decreased (p<0.001) after acupuncture intervention. Compared with those in healthy controls, the diversity and structure of the saliva microbiota in MPASD patients were markedly disrupted. Six genera with circadian rhythms were detected in all groups, including Sulfurovum, Peptostreptococcus, Porphyromonas and Prevotella. There were five genera with circadian rhythmicity in healthy people, of which the rhythmicities of the genera Rothia and Lautropia disappeared in MPASD patients but effectively resumed after acupuncture intervention. Conclusions: This work revealed dysrhythmic salivary microbes in MPASD patients, and acupuncture, as a potential intervention, could be effective in mitigating this ever-rising behavioral epidemic.

Anti-inflammatory effects of Olive (olea europaea L.) fruit extract in LPS-stimulated RAW264.7 cells via MAPK and NF-κB signal pathways.

BACKGROUND: Olive is an evergreen tree of Oleaceae Olea with numerous bioactive components. While the anti-inflammatory properties of olive oil and the derivatives are well-documented, there remains a dearth of in-depth researches on the immunosuppressive effects of olive fruit water extract. This study aimed to elucidate the dose-effect relationship and underlying molecular mechanisms of olive fruit extract in mediating anti-inflammatory responses. METHODS AND RESULTS: The impacts of olive fruit extract on the release of nitric oxide (NO), tumor necrosis factor (TNF-α), interleukins-6 (IL-6) and reactive oxygen species (ROS) were assessed in RAW264.7 cells induced by lipopolysaccharide (LPS). For deeper understanding, the expression of genes encoding inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-α and IL-6 was quantitatively tested. Additionally, the expression patterns of MAPK and NF-κB pathways were further observed to analyze the action mechanisms. Results suggested that olive fruit extract (200, 500, 1000 µg/mL) markedly exhibited a dose-dependent reduction in the generation of NO, TNF-α, IL-6 and ROS, as well as the expression of correlative genes studied. The activation of ERK, JNK, p38, IκB-α and p65 were all suppressed when p65 nuclear translocation was further restricted by olive fruit extract in NF-κB and MAPK signal pathways. CONCLUSIONS: Olive fruit extract targeted imposing restrictions on the signal transduction of key proteins in NF-κB and MAPK pathways, and thereby lowered the level of inflammatory mediators, which put an enormous hindrance to inflammatory development. Accordingly, it is reasonable to consider olive fruit as a potent ingredient in immunomodulatory products.

Enhanced Mechanical Strength and Sustained Drug Release in Carrier-Free Silver-Coordinated Anthraquinone Natural Antibacterial Anti-Inflammatory Hydrogel for Infectious Wound Healing.

The persistent challenge of healing infectious wounds and the rise of bacterial resistance represent significant hurdles in contemporary medicine. In this study, based on the natural small molecule drug Rhein self-assembly to form hydrogels and coordinate assembly with silver ions (Ag+), a sustained-release carrier-free hydrogel with compact structure is constructed to promote the repair of bacterial-infected wounds. As a broad-spectrum antimicrobial agent, Ag+ can avoid the problem of bacterial resistance caused by the abuse of traditional antibiotics. In addition, due to the slow-release properties of Rhein hydrogel, continuous effective concentration of Ag+ at the wound site can be ensured. The assembly of Ag+ and Rhein makes the hydrogel system with enhanced mechanical stability. More importantly, it is found that Rhein effectively promotes skin tissue regeneration and wound healing by reprogramming M1 macrophages into M2 macrophages. Further mechanism studies show that Rhein realizes its powerful anti-inflammatory activity through NRF2/HO-1 activation and NF-κB inhibition. Thus, the hydrogel system combines the excellent antibacterial properties of Ag+ with the excellent anti-inflammatory and tissue regeneration ability of Rhein, providing a new strategy for wound management with dual roles.

Genetic Characteristics of Novel IncpSE5381-aadB Plasmids, Integrative and Mobilizable Elements, and Integrative and Conjugative Elements in Pseudomonas aeruginosa.

Purpose: Pseudomonas aeruginosa is a common causative bacteria in nosocomial infections. This study aims to describe the structure and evolutionary characteristics of mobile genetic elements (MGEs) carrying antibiotic resistance genes (ARGs) from P. aeruginosa and to conduct bioinformatics and comparative genomic analysis to provide a deeper understanding of the genetic characteristics and diversity of MGEs in P. aeruginosa. Methods: Fifteen clinical isolates of P. aeruginosa from China were collected and sequenced in this study, and 15 novel MGEs were identified. Together with four MGEs from GenBank, a total of 19 MGEs were used to perform detailed modular structure dissection and sequence comparison. Then, the biological experiments were carried out to verify the biological characteristics of these isolates and MEGs. Results: The novel MGEs identified in this study displayed diversification in modular structures, which showed complex mosaic natures. The seven types of 19 MGEs included in this study were divided into three groups: i) novel MGEs (firstly identified in this study): four IncpSE5381-aadB plasmids and three Tn7495-related integrative and mobilizable elements (IMEs); ii) newly defined MGEs (firstly designated in this study, but with previously determined sequences): four Tn7665-related IMEs; iii) novel transposons with reference prototypes identified in this study: two Tn6417-related integrative and conjugative elements (ICEs), two IS-based transposition units, two Tn501-related unit transposons, two Tn1403-related unit transposons. At least 36 ARGs involved in resistance to 11 different classes of antimicrobials and heavy metals were identified. Additionally, three novel blaOXA variants were identified. Antimicrobial susceptibility testing showed that these variants were resistant to some ß-lactamase antibiotics and blaOXA-1204 was additionally resistant to cephalosporins. Conclusion: The continuous evolution of ARG-carrying MGEs during transmission, leading to the emergence of novel MGEs or ARGs, which facilitates the spread of antibiotic resistance in P. aeruginosa and enhances the diversity of transmission modes of bacterial resistance.

The effect of cognitive impairment based on Mini-Mental State Examination (MMSE) on suicidal tendency in patients with schizophrenia: A large cross-sectional study.

BACKGROUND: The effect of cognitive function on suicidal tendency in patients with schizophrenia is still inconclusive. This study aimed to explore the effect of cognitive impairment on suicidal tendency in schizophrenia patients and the risk factors of suicidal tendency in schizophrenia patients with cognitive impairment. METHODS: A total of 988 subjects were recruited for this study and finally 517 patients were included in the statistical analysis. Sociodemographic information was collected for each subject. Mini-Mental State Examination (MMSE) was used to assess patients' cognitive functioning. In addition, the Positive and Negative Syndrome Scale (PANSS) positive subscale, Insomnia Severity Index (ISI), and Beck Scale for Suicide Ideation (BSI) were used to assess psychotic symptoms, severity of insomnia, and intensity of suicidal ideation, respectively. RESULTS: Schizophrenia patients with cognitive dysfunction were significantly less likely to develop suicidal tendencies than those without cognitive dysfunction (P < 0.05, OR = 0.58, 95%CI: 0.39-0.81). In patients with cognitive impairment, those with suicidal tendency had substantially higher scores on BSI, ISI, EC, PD, IRI, F1, and PANSS positive subscale, and took more types of antipsychotic drugs than those without suicidal tendency (all P < 0.05), and the results of binary logistic regression analysis showed that, PANSS positive subscale score (B = 0.06, p = 0.04, OR = 1.07, 95%CI: 1.00-1.13) was a risk factor for suicidal tendencies. CONCLUSIONS: Our findings suggest that schizophrenia patients with cognitive dysfunction are significantly less likely to develop suicidal tendencies. Moreover, positive symptom is a risk factor for suicidal tendencies in schizophrenia patients with cognitive dysfunction.

Integrating Phenotypic Information of Obstructive Sleep Apnea and Deep Representation of Sleep-Event Sequences for Cardiovascular Risk Prediction.

Background: Advances in mobile, wearable and machine learning (ML) technologies for gathering and analyzing long-term health data have opened up new possibilities for predicting and preventing cardiovascular diseases (CVDs). Meanwhile, the association between obstructive sleep apnea (OSA) and CV risk has been well-recognized. This study seeks to explore effective strategies of incorporating OSA phenotypic information and overnight physiological information for precise CV risk prediction in the general population. Methods: 1,874 participants without a history of CVDs from the MESA dataset were included for the 5-year CV risk prediction. Four OSA phenotypes were first identified by the K-mean clustering based on static polysomnographic (PSG) features. Then several phenotype-agnostic and phenotype-specific ML models, along with deep learning (DL) models that integrate deep representations of overnight sleep-event feature sequences, were built for CV risk prediction. Finally, feature importance analysis was conducted by calculating SHapley Additive exPlanations (SHAP) values for all features across the four phenotypes to provide model interpretability. Results: All ML models showed improved performance after incorporating the OSA phenotypic information. The DL model trained with the proposed phenotype-contrastive training strategy performed the best, achieving an area under the Receiver Operating Characteristic (ROC) curve of 0.877. Moreover, PSG and FOOD FREQUENCY features were recognized as significant CV risk factors across all phenotypes, with each phenotype emphasizing unique features. Conclusion: Models that are aware of OSA phenotypes are preferred, and lifestyle factors should be a greater focus for precise CV prevention and risk management in the general population.

Whole transcriptome mapping reveals the lncRNA regulatory network of TFP5 treatment in diabetic nephropathy.

BACKGROUND: TFP5 is a Cdk5 inhibitor peptide, which could restore insulin production. However, the role of TFP5 in diabetic nephropathy (DN) is still unclear. OBJECTIVE: This study aims to characterize the transcriptome profiles of mRNA and lncRNA in TFP5-treated DN mice to mine key lncRNAs associated with TFP5 efficacy. METHODS: We evaluated the role of TFP5 in DN pathology and performed RNA sequencing in C57BL/6J control mice, C57BL/6J db/db model mice, and TFP5 treatment C57BL/6J db/db model mice. The differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) were analyzed. WGCNA was used to screen hub-gene of TFP5 in treatment of DN. RESULTS: Our results showed that TFP5 therapy ameliorated renal tubular injury in DN mice. In addition, compared with the control group, the expression profile of lncRNAs in the model group was significantly disordered, while TFP5 alleviated the abnormal expression of lncRNAs. A total of 67 DElncRNAs shared among the three groups, 39 DElncRNAs showed a trend of increasing in the DN group and decreasing after TFP treatment, while the remaining 28 showed the opposite trend. DElncRNAs were enriched in glycosphingolipid biosynthesis signaling pathways, NF-κB signaling pathways, and complement activation signaling pathways. There were 1028 up-regulated and 1117 down-regulated DEmRNAs in the model group compared to control group, and 123 up-regulated and 153 down-regulated DEmRNAs in the TFP5 group compared to the model group. The DEmRNAs were involved in PPAR and MAPK signaling pathway. We confirmed that MSTRG.28304.1 is a key DElncRNA for TFP5 treatment of DN. TFP5 ameliorated DN maybe by inhibiting MSTRG.28304.1 through regulating the insulin resistance and PPAR signaling pathway. The qRT-PCR results confirmed the reliability of the sequencing data through verifying the expression of ENSMUST00000211209, MSTRG.31814.5, MSTRG.28304.1, and MSTRG.45642.14. CONCLUSION: Overall, the present study provides novel insights into molecular mechanisms of TFP5 treatment in DN.

Spatial effect of biomass energy consumption on carbon emissions reduction: the role of globalization.

As globalization proceeds, increasing biomass energy consumption is an important pathway to replace fossil fuels for tackling climate change by reducing emissions. This study explores the spatial spillover effect in biomass energy carbon reduction, which is frequently ignored when investigating environmental factors. It uncovers whether globalization and its dimensions can strengthen the spatial effect of biomass energy carbon reduction. Besides, we reveal whether biomass energy consumption can promote CO2 emissions reduction while ensuring economic progress. Results show that (1) owing to the spillover effect, biomass energy consumption plays a significant role in direct and indirect enhancing carbon emissions reduction, with their feedback effects of - 0.003 or 3.3% of the direct effect. (2) Increasing overall, social and political globalization enhances biomass energy consumption's carbon reduction effect. (3) In countries with higher economic development, overall, economic and political globalization has a better promotion in the spatial effect of biomass energy carbon reduction. (4) Developing biomass energy can support the environment quality while enhancing economic growth.

Nomogram combining pre-operative clinical characteristics and spectral CT parameters for predicting the WHO/ISUP pathological grading in clear cell renal cell carcinoma.

PURPOSE: To develop a novel clinical-spectral-computed tomography (CT) nomogram incorporating clinical characteristics and spectral CT parameters for the preoperative prediction of the WHO/ISUP pathological grade in clear cell renal cell carcinoma (ccRCC). METHODS: Seventy-three ccRCC patients who underwent spectral CT were included in this retrospective analysis from December 2020 to June 2023. The subjects were pathologically divided into low- and high-grade groups (WHO/ISUP 1/2, n = 52 and WHO/ISUP 3/4, n = 21, respectively). Information on clinical characteristics, conventional CT imaging features, and spectral CT parameters was collected. Multivariate logistic regression analyses were conducted to create a nomogram combing clinical data and image data for preoperatively predicting the pathological grade of ccRCC, and the area under the curve (AUC) was utilized to assess the predictive performance of the model. RESULTS: Multivariate logistic regression analyses revealed that age, systemic immune-inflammation index (SII), and the slope of the spectrum curve in the cortex phase (CP-K) were independent predictors for predicting high-grade ccRCC. The clinical-spectral-CT model exhibited high evaluation efficacy, with an AUC of 0.933 (95% confidence interval [CI]: 0.878-0.998; sensitivity: 0.810; specificity: 0.923). The calibration curve revealed that the predicted probability of the clinical-spectral-CT nomogram could better fit the actual probability, with high calibration. The Hosmer-Lemeshow test showed that the model had a good fitness (χ2 = 5.574, p = 0.695). CONCLUSION: The clinical-spectral-CT nomogram has the potential to predict WHO/ISUP grading of ccRCC preoperatively.

Neutralizing monoclonal antibodies protect against human adenovirus type 55 infection in transgenic mice and tree shrews.

Re-emerging human adenovirus type 55 (HAdV55) has become a significant threat to public health due to its widespread circulation and the association with severe pneumonia, but an effective anti-HAdV55 agent remains unavailable. Herein, we report the generation of macaque-derived, human-like monoclonal antibodies (mAbs) protecting against HAdV55 infection with high potency. Using fluorophore-labelled HAdV55 virions as probes, we isolated specific memory B cells from rhesus macaques (Macaca mulatta) that were immunized twice with an experimental vaccine based on E1-, E3-deleted, replication-incompetent HAdV55. We cloned a total of 19 neutralizing mAbs, nine of which showed half-maximal inhibitory concentrations below 1.0 ng/ml. These mAbs recognized the hyper-variable-region (HVR) 1, 2, or 7 of viral hexon protein, or the fibre knob. In transgenic mice expressing human desmoglein-2, the major cellular receptor for HAdV55, a single intraperitoneal injection with hexon-targeting mAbs efficiently prevented HAdV55 infection, and mAb 29C12 showed protection at a dose as low as 0.004 mg/kg. Fibre-targeting mAb 28E8, however, showed protection only at a dose up to 12.5 mg/kg. In tree shrews that are permissive for HAdV55 infection and disease, mAb 29C12 effectively prevented HAdV55-caused pneumonia. Further analysis revealed that fibre-targeting mAbs blocked the attachment of HAdV55 to host cells, whereas hexon-targeting mAbs, regardless of their targeting HVRs, mainly functioned at post-attachment stage via inhibiting viral endosomal escape. Our results indicate that hexon-targeting mAbs have great anti-HAdV55 activities and warrant pre-clinical and clinical evaluation.

Investigation of T cell-related hub genes in diabetic nephropathy by bioinformatics analysis and experiment validation.

Diabetic nephropathy(DN) remains a significant risk factor for cardiovascular and all-cause mortality, and end-stage renal disease (ESRD) associated with it is growing in prevalence.However, there is absolutely no curative strategy for DN. We subjected db/db and control mouse kidneys to transcriptional sequencing analysis to obtain transcriptome expression profile data in the diabetic nephropathy.We next performed differential analysis of db/db and control mice kidney sequencing data to obtain differentially expressed genes. The differential expressed genes were intersected with the oxidative stress and inflammatory response related genes derived from the MGI/MsiDB gene set to yield oxidative stress inflammatory response related differential 122 genes (OIRDEGs). To further clarify the biological functions of DEGs, we conducted GOKEGG analysis and obtained the top 20 genes by five computational algorithms of the cytohubba plugin via cytoscape, respectively. The genes obtained by the five algorithms were intersected and the intersection genes were considered as key genes,including Cd40lg, Il2rb, Lck, Il2rg, Zap70, Serpinb1a. Also,we used GSEA and immune infiltration analysis to clarify the biological signaling pathways and immune cell infiltration that are substantial in the diabetic nephropathy.Correlation studies of key genes with immune cell infiltration revealed that they were correlated with the majority types of T cells while only with two types of B cells.Then, we predicted miRNA and TF for the key genes and constructed the interaction network. Finally, the expression differences of key genes were examined by validation dataset and RT-PCR experiment.In conclusion,we have identified key genes associated with T cell immune response in a diabetic nephropathy model, which bear significance in the etiopathogenesis of immunological injury in diabetic nephropathy and provide an innovative proposal for the recognition and management of DN.

Altered levels of cytokine, T- and B-lymphocytes, and PD-1 expression rates in drug-naïve schizophrenia patients with acute phase.

Many studies have investigated the changes of immune cells and proinflammatory cytokines in patients with acute schizophrenia, but few studies have investigated the functional phenotypes of immune cells and the expression rate of programmed cell death protein 1 (PD-1)/ programmed cell death-Ligand 1 (PD-L1). The aim of this study was to investigate the extent of immune cells activation, PD-1/PD-L1 expressions, and altered cytokine levels in drug-naïve schizophrenia patients with acute-phase. 23 drug-naïve schizophrenia patients in acute-phase and 23 healthy individuals were enrolled in this study as experimental and control groups, separately. Socio-demographic information including gender, age, duration of illness, and smoking status was collected for each subject. Beckman DXFLEX triple laser thirteen-color flow cytometer and self-contained software CytoFLEX flow cytometric analysis software were used to detect the expressions of PD-1/PD-L1 on CD4+/CD8+ T lymphocytes, B lymphocytes, monocytes and NK cells. BD Bioscience was used to examine the levels of cytokines including interferon (IFN)-γ, tumor necrosis factor (TNF)-α, Interleukin (IL)-2, IL-4, IL-6, and IL-10. Drug-naïve schizophrenia patients in acute-phase had higher levels of peripheral blood CD4+ T lymphocytes and B lymphocytes, higher PD-1 expression in B lymphocytes, and lower levels of CD8+ T lymphocytes. In addition, IL-6 levels of peripheral blood were higher in schizophrenia patients (all P < 0.05). Significant immune stress was present in schizophrenia patients with acute-phase.

Uncovering the hidden threat: The widespread presence of chromosome-borne accessory genetic elements and novel antibiotic resistance genetic environments in Aeromonas.

The emergence of antibiotic-resistant Aeromonas strains in clinical settings has presented an escalating burden on human and public health. The dissemination of antibiotic resistance in Aeromonas is predominantly facilitated by chromosome-borne accessory genetic elements, although the existing literature on this subject remains limited. Hence, the primary objective of this study is to comprehensively investigate the genomic characteristics of chromosome-borne accessory genetic elements in Aeromonas. Moreover, the study aims to uncover novel genetic environments associated with antibiotic resistance on these elements. Aeromonas were screened from nonduplicated strains collected from two tertiary hospitals in China. Complete sequencing and population genetics analysis were performed. BLAST analysis was employed to identify related elements. All newly identified elements were subjected to detailed sequence annotation, dissection, and comparison. We identified and newly designated 19 chromosomal elements, including 18 integrative and mobilizable elements (IMEs) that could be classified into four categories: Tn6737-related, Tn6836-related, Tn6840-related, and Tn6844a-related IMEs. Each class exhibited a distinct pattern in the types of resistance genes carried by the IMEs. Several novel antibiotic resistance genetic environments were uncovered in these elements. Notably, we report the first identification of the blaOXA-10 gene and blaVEB-1 gene in clinical A. veronii genome, the first presence of a tetA(E)-tetR(E) resistance gene environment within the backbone region in IMEs, and a new mcr-3.15 resistance gene environment. The implications of these findings are substantial, as they provide new insights into the evolution, structure, and dissemination of chromosomal-borne accessory elements.

Cdk5 activation promotes Cos-7 cells transition towards neuronal-like cells.

Objectives: Cyclin-dependent kinase 5 (Cdk5) activity is specifically active in neurogenesis, and Cdk5 and neocortical neurons migration related biomarker are expressed in Cos-7 cells. However, the function of Cdk5 on the transformation of immortalized Cos-7 cells into neuronal-like cells is not clear. Methods: Cdk5 kinase activity was measured by [γ-32P] ATP and p81 phosphocellulose pads based method. The expression of neuron liker markers was evaluated by immunofluorescence, real-time PCR, Western blot, and Elisa. Results: P35 overexpression upregulated Cdk5 kinase activity in Cos-7 cells. p35 mediated Cdk5 expression promoted the generation of nerite-like outgrowth. Compared with the empty vector, p35-induced Cdk5 activation resulted in time-dependent increase in neuron-like marker, including Tau, NF-H, NF-H&M, and TuJ1. Tau-5 and NF-M exhibited increased expression at 48 h while TuJ1 was only detectable after 96 h in p35 expressed Cos-7 cells. Additionally, the neural cell biomarkers exhibited well colocation with p35 proteins. Next-generation RNA sequence showed that p35 overexpression significantly upregulated the level of nerve growth factor (NGF). Gene set enrichment analysis showed significant enrichment of multiple neuron development pathways and increased NGF expression after p35 overexpression. Conclusion: p35-mediated Cdk5 activation promotes the transformation of immortalized Cos-7 cells into neuronal-like cells by upregulating NGF level.