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Abstract Cloud environment is a virtual, online, and distributed computing environment that provides users with large-scale services. And cloud monitoring plays an integral role in protecting infrastructures in the cloud environment. Cloud monitoring systems need to closely monitor various KPIs of cloud resources, to accurately detect anomalies. However, due to the complexity and highly dynamic nature of the cloud environment, anomaly detection for these KPIs with various patterns and data quality is a huge challenge, especially those massive unlabeled data. Besides, it’s also difficult to improve the accuracy of the existing anomaly detection methods. To solve these problems, we propose a novel Dynamic Graph Transformer based Parallel Framework (DGT-PF) for efficiently detect system anomalies in cloud infrastructures, which utilizes Transformer with anomaly attention mechanism and Graph Neural Network (GNN) to learn the spatio-temporal features of KPIs to improve the accuracy and timeliness of model anomaly detection. Specifically, we propose an effective dynamic relationship embedding strategy to dynamically learn spatio-temporal features and adaptively generate adjacency matrices, and soft cluster each GNN layer through Diffpooling module. In addition, we also use nonlinear neural network model and AR-MLP model in parallel to obtain better detection accuracy and improve detection performance. The experiment shows that the DGT-PF framework have achieved the highest F1-Score on 5 public datasets, with an average improvement of 21.6% compared to 11 anomaly detection models.

ObjectivesPrevious observational epidemiological studies have identified a potential association between inflammatory bowel disease (IBD) and sarcoidosis. Nonetheless, the precise biological mechanisms underlying this association remain unclear. Therefore, we adopted a Mendelian randomization (MR) approach to investigate the causal relationship between IBD with genetic susceptibility to sarcoidosis, as well as to explore the potential mediating role.MethodsThe genetic associations were obtained from publicly available genome-wide association studies (GWASs) of European ancestry. The IBD dataset has 31,665 cases and 33,977 controls, consisting of 13,768 individuals with ulcerative colitis (UC) and 17,897 individuals with Crohn’s disease (CD). The genetic associations of sarcoidosis with 4,854 cases and 446,523 controls. A bidirectional causality between IBD and sarcoidosis was implemented to be determined by a two-sample MR approach. The inverse variance weighted (IVW) method was utilized as the main statistical method, and a series of sensitivity analyses were performed to detect heterogeneity and horizontal pleiotropy. A two-step MR approach was used to investigate whether the mediating pathway from IBD to sarcoidosis was mediated by PBC.ResultsThe forward MR analysis indicated that genetic predisposition to IBD was significantly linked to an increased risk of sarcoidosis (OR = 1.088, 95% CI: 1.023–1.158, pIBD-sar = 7.498e-03). Similar causal associations were observed in CD (OR = 1.082, 95% CI: 1.028–1.138, pCD-sar = 2.397e-03) and UC (OR = 1.079, 95% CI: 1.006–1.158, pUC-sar = 0.034). Reverse MR analysis revealed that genetic susceptibility to sarcoidosis was correlated with an augmented risk of CD (OR = 1.306, 95% CI: 1.110–1.537, psar-CD = 1.290e-03) but not IBD or UC. The mediation analysis via two-step MR showed that the causal influence of IBD and CD on sarcoidosis effects was partly mediated by PBC, and the mediating effect was 0.018 (95% CI: 0.005–0.031, p = 7.596e-03) with a mediated proportion of 21.397% in IBD, and 0.014 (95% CI: 0.004–0.024, p = 7.800e-03) with a mediated proportion of 17.737% in CD.ConclusionsThe MR analysis provided evidence substantiating the causal effect of IBD (CD and UC) on an increased risk of sarcoidosis, with PBC playing a mediating role in IBD and CD. However, sarcoidosis only enhances the risk of developing CD, but not IBD or UC. These findings illuminate the etiology of sarcoidosis and contribute to the management of IBD patients.

Background and objective: Hypertension affects over a billion people worldwide and is often associated with poor prognoses. The neutrophil-to-lymphocyte ratio (NLR) has become a significant marker, showing a connection to adverse outcomes in cardiovascular diseases (CVDs). The objective of this study is to examine the relationship between the NLR and outcomes in patients with hypertension. Methods: The study included hypertensive individuals who were surveyed in the National Health and Nutrition Examination Survey (NHANES) from 2009 to 2018. Mortality status was determined using the data from National Death Index (NDI). To investigate the dose-response relationship, restricted cubic spline (RCS) models were used. This study employed adjusted cox proportional hazards regression models to compute hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) for all-cause and cardiovascular mortality. The predictive accuracy of the NLR for survival outcomes was assessed utilizing time-dependent receiver operating characteristic (ROC) curve analysis. Results: A total of 13,724 participants were included in the final analysis, including 7073 males and 6651 females. The cohort was stratified into higher (>2.0) and lower (≤2.0) NLR groups according to the median value. Over a median follow-up of 64 months, there were 1619 all-cause deaths and 522 cardiovascular deaths among participants. The RCS analysis indicated a non-linear relationship between NLR and the risk of mortality. The adjusted model showed that the group with a higher NLR had a significantly higher risk of all-cause (HR 1.47, 95% CI 1.22–1.77) and cardiovascular mortality (HR 2.08, 95% CI 1.52–2.86). ROC analysis showed that the area under the curves (AUCs) of 0.692, 0.662, 0.644, and 0.625 for predicting all-cause mortality, and 0.712, 0.692, 0.687, and 0.660 for cardiovascular mortality at 1, 3, 5, and 10 years. Conclusion: Elevated NLR is associated with increased risk of cardiovascular and all-cause mortality, and NLR may independently predict outcomes in individuals with hypertension.

A patient presenting with several basal cell carcinomas, pigmented nevi, and developmental defects was diagnosed with nevoid basal cell carcinoma syndrome. Gene panel sequencing and Sanger sequencing were used to identify a novel heterozygous frameshift mutation, c.1312dupA:p.Ser438Lysfs, in exon 9 of PTCH1. I-Tasser and PyMol analyses indicated that the mutated protein patched homolog 1 (PTCH1) lacked 12 transmembrane domains and the intracellular and extracellular rings of ECD2 compared with the wild-type protein, resulting in a remarkably different structure from that of the wild-type protein. This case extends our knowledge of the mutation spectrum of NBCCS.

Physalis philadelphica, a member of the Solanaceae family, commonly known as Physalis, is a one-year-old herbaceous plant with both medicinal and edible properties, as well as ornamental value. At present, only limited research is available on the flower color of P. philadelphica. This study aimed to elucidate the metabolic characteristics underlying the flower color of P. philadelphica and to identify key genes associated with flower color metabolism. We selected two representative varieties of P. philadelphica with significant differences in flower color, namely, “Tieba” (yellow flower) and “Qingjin” (yellow-purple flower), as the experimental materials. The analysis of related pigment components and the determination of relative content by high-performance liquid chromatography were conducted to investigate the flower color-related metabolic pathways of P. philadelphica. Through next-generation sequencing, these pathways were further investigated for the characteristics and differentially expressed genes (DEGs) associated with flower color formation. The results of the research show that: Anthocyanin is the main component of petal coloring of P. philadelphica var. Qingjin, while malvidin pigment, pelargonidin, delphinidin, and cyanidin are the main components of flower color intensity. Carotenoids are the main components of the petal coloring of P. philadelphica var. Tieba and β-carotene is the main component of flower color intensity. Comparing different developmental stages of these two kinds of Physalis pubescens, we identified two key transcription factors (TFs) (eBP and STAT) that were involved in the inhibition of anthocyanin synthesis and regulate the inhibition of pf05G124640 (dihydroflavonol 4-reductase) and pf09G224140 (anthocyanin synthase) in anthocyanin synthesis. One heat shock transcription factor was found to regulate the flavonoid and flavonol synthesis pathway of pf01G020090 (anthocyanin 3-O-glucosyltransferase); two key TFs (NAC and G2-Like), pf10G255070 (isoricin dehydrogenase) and pf09G237080 (abscisic acid 8′-hydroxylase), played important roles in carotene biosynthesis. This study provides new insights for further exploration of the genetic diversity of petal coloring in P. philadelphica and establishes a foundation for subsequent molecular breeding efforts.

Potato scab, a global soil-borne disease caused by Streptomyces, is pivotal in developing resistant cultivars due to its complex resistance mechanisms. This study investigates the transcriptomic responses in potato to common scab using resistant variety CS10 and susceptible CS11 post S. scabie inoculation (0 d and 10 d, 12 cDNA libraries). Differential expression analysis identified 147 key DEGs (Differentially Expressed Genes) essential in disease recognition, signal transduction, and defense. GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analyses revealed several significant metabolic pathways, such as ADP binding, heme binding, chloroplast thylakoid membrane, photosynthesis, glutathione metabolism, and homologous recombination, among others. Notably, the correlation between chloroplast pathways (GO:0019745) and photosynthesis (map00195) highlights photosynthesis’s role in potato scab response, while the oxygen transport (GO:0031408)-related glutathione metabolism pathway (map00480) emphasizes antioxidant defenses. Furthermore, three potential resistance genes were validated: Ethylene Response Factor ERF010 (LOC102589042), Disease Resistance Protein RPP13 (LOC102605863), and Cytochrome P450 83B1 (LOC102604056), demonstrating the linkage between metabolic pathways and pathogen response. These findings offer insights into potato’s molecular resistance mechanisms against potato scab, supporting the breeding of resistant varieties and comprehensive disease management, thus advancing sustainable agriculture.

Abstract Background Interleukin (IL)-7 signaling through CD127 is impaired in lymphocytes in cancers and chronic infections, resulting in CD8+ T cell exhaustion. The mechanisms underlying CD8+ T cell responses to IL-7 in melanoma remain not completely elucidated. We previously showed reduced IL-7 level in melanoma patients. Thus, the aim of this study was to investigate the effect of IL-7 regulation on CD127 expression and CD8+ T cell responses in melanoma. Methods Healthy controls and primary cutaneous melanoma patients were enrolled. Membrane-bound CD127 (mCD127) expression on CD8+ T cells was determined by flow cytometry. Soluble CD127 (sCD127) protein level was measured by ELISA. Total CD127 and sCD127 mRNA level was measured by real-time PCR. CD8+ T cells were stimulated with recombinant human IL-7, along with signaling pathway inhibitors. CD8+ T cells were co-cultured with melanoma cell line, and the cytotoxicity of CD8+ T cells was assessed by measurement of lactate dehydrogenase expression. Results Plasma sCD127 was lower in melanoma patients compared with controls. The percentage of CD8+ T cells expressing mCD127 was higher, while sCD127 mRNA level was lower in peripheral and tumor-infiltrating CD8+ T cells from melanoma patients. There was no significant difference of total CD127 mRNA expression in CD8+ T cells between groups. IL-7 stimulation enhanced total CD127 and sCD127 mRNA expression and sCD127 release by CD8+ T cells. However, mCD127 mRNA expression on CD8+ T cells was not affected. This process was mainly mediated by phosphatidylinositol 3-kinase (PI3K) pathway. CD8+ T cells from melanoma patients exhibited decreased cytotoxicity. IL-7 stimulation promoted CD8+ T cell cytotoxicity, while inhibition of PI3K dampened IL-7-induced elevation of CD8+ T cell cytotoxicity. Conclusion The current data suggested that insufficient IL-7 secretion might contribute to CD8+ T cell exhaustion and CD127 dysregulation in patients with primary cutaneous melanoma.

Thirty-eight million people worldwide are living with HIV, PWH, a major public health problem. Antiretroviral therapy (ART) revolutionized HIV treatment and significantly increased the lifespan of PWH. However, approximately 15-50% of PWH develop HIV associated neurocognitive disorders (HIV-NCI), a spectrum of cognitive deficits, that negatively impact quality of life. Many PWH also have opioid use disorder (OUD), and studies in animal models of HIV infection as well as in PWH suggest that OUD can contribute to HIV-NCI. The synthetic opioid agonist, buprenorphine, treats OUD but its effects on HIV-NCI are unclear. We reported that human mature inflammatory monocytes express the opioid receptors MOR and KOR, and that buprenorphine reduces important steps in monocyte transmigration. Monocytes also serve as HIV reservoirs despite effective ART, enter the brain, and contribute to HIV brain disease. Using EcoHIV infected mice, an established model of HIV infection and HIV-NCI, we previously showed that pretreatment of mice prior to EcoHIV infection reduces mouse monocyte entry into the brain and prevents NCI. Here we show that buprenorphine treatment of EcoHIV infected mice with already established chronic NCI completely reverses the disease. Disease reversal was associated with a significant reduction in brain inflammatory monocytes and reversal of dendritic injury in the cortex and hippocampus. These results suggest that HIV-NCI persistence may require a continuing influx of inflammatory monocytes into the brain. Thus, we recommend buprenorphine as a potential therapy for mitigation of HIV brain disease in PWH with or without OUD.

BackgroundSkin cutaneous melanoma (SKCM) is a highly malignant skin tumor. DIRAS2 is considered to be a tumor suppressor gene; however, its function in SKCM has not been explored.MethodsThe Gene Expression Profiling Interactive Analysis (GEPIA) was implemented to investigate the expression of DIRAS2 in SKCM, and plot the survival curve to determine the effect of DIRAS2 on the survival rates of SKCM patients. Then, the correlation between DIRAS2 and tumor immune infiltration was also discussed, and the expression of DIRAS2 and immune infiltration level in SKCM immune cells was determined using TIMER. The top 100 genes most associated with DIRAS2 expression were used for functional enrichment analysis. In order to confirm the anti-cancer effects of DIRAS2 in SKCM in the data analysis, in vitro assays as well as in vivo studies of DIRAS2 on SKCM tumor cell proliferation, migration, invasion, and metastasis were conducted. Western blot and immunofluorescence assay were employed to study the relationship between DIRAS2 and Wnt/β-catenin signaling pathway in SKCM.ResultsDIRAS2 expression was shown to be significantly correlated with tumor grade using univariate logistic regression analysis. DIRAS2 was found to be an independent prognostic factor for SKCM in multivariate analysis. Of note, DIRAS2 expression levels were positively correlated with the infiltration levels of B cells, CD4+ T cells, and CD8+ T cells in SKCM. The infiltration of B cells, CD4+ T cells, and CD8+ T cells was positively correlated with the cumulative survival rate of SKCM patients. In vitro experiments suggested that proliferation, migration, invasion, and metastasis of SKCM tumor cells were distinctly enhanced after DIRAS2 knockdown. Furthermore, DIRAS2 depletion promoted melanoma growth and metastasis in vivo. As for the mechanism, silencing DIRAS2 can activate the signal transduction of the Wnt/β-catenin signaling pathway.ConclusionDIRAS2 functions as a tumor suppressor gene in cases of SKCM by inhibiting the Wnt/β-catenin signaling. It is also associated with immune infiltration in SKCM.

Background: The estimation of postmortem interval (PMI) is one of the most important topics in forensic medicine research. We speculate that with an increased PMI, the computed tomography (CT) values of different tissues may show regular changes. Purpose: To use postmortem computed tomography (PMCT) to measure the myocardial CT value (unit: Hounsfield Unit, HU) of the heart to explore its pattern in postmortem change, and to discuss whether it can serve as a new parameter for PMI estimation. Methods: A total of 10 healthy adult New Zealand rabbits were selected and then put into a 20°C incubator after being sacrificed. Within 0–156 h after death, CT scans were performed every 12 h to detect changes in the myocardial CT value of the heart over time. Regression analysis was used to determine the relationship between the myocardial CT value of the heart and PMI. At the same time, HE and Masson were used to stain the cardiac tissue sections detected by PMCT at 0h, 48h and 156h, respectively. Results: During 0–156 h, the overall myocardial CT value showed a trend of first rising and then decreasing with the increase of PMI. The fitting regression equation was y = −2873.193 + 143.866x − 1.728x2 (x: myocardial CT value, unit: Hu; y: PMI, unit: h, R2 = 0.466, P < 0.05). During 48–156 h, the overall myocardial CT value decreased gradually with the increase of PMI. The fitting regression equation was y = −93.038 + 18.700x − 0.321x2 (x: myocardial CT value, unit: Hu; y: PMI, unit: h, R2 = 0.963, P < 0.001). The results of the morphological changes of the myocardial tissue structure after death showed that the myocardial cell structure was relatively complete at 0−48 hours after death; and the myocardial cell structure disappeared at 156 hours after death. Conclusions: Our results revealed evident postmortem changes in the myocardial CT value of the heart. Accordingly, measuring the myocardial CT value through PMCT shows promise for being used as a parameter for PMI estimation in forensic medicine and is worthy of further studies. The morphological changes of the myocardial tissue structure after death provide morphological basis for postmortem changes of tissue density, and further prove the reasons for the changes of CT value.

Background: Th subsets particularly T helper 17 and regulatory T cells play a critical role in immune balance in colonic mucosa of Inflammatory Bowel Disease. Recent studies have indicated miR-155 is overexpressed in the colonic mucosa in IBD patients. Thus, whether and how miR-155 influences Th17/Treg cell balance in IBD patients is worthy of researching. Methods: We divided mice into four groups: the mice oral administration of 3.0 % DSS in fresh drinking water for 7 days except normal group. In this period, starting from the fifth day, the miR-155 and NC antagomir group were carried out by intraperitoneal injection of miR-155 antagomirs and corresponding negative controls. In vitro, we isolated naïve CD4+T cells and divided into two groups: the cells were transfected with mmu-miR-155-5p inhibitor or corresponding negative controls and then induced differentiation. Results: We found miR-155 antagomir can reach colon tissues in DSS-induced colitis and indeed ameliorated DSS-induced experimental colitis. Subsequently, we proved the levels of Th17 cells in spleens and Mesenteric lymph nodes and its associated IL-6, IL-17A and RORγt in colonic tissues were dramatically decreased and TGF-β1 raised in DSS + miR-155 antagomir group. However, miR-155 antagomir significantly increased the expression of Tregs. In vitro, we found miR-155 inhibitor could improve the Tregs but decrease Th17 cells. Finally, we dig out that Jarid2 was apparently improved by miR-155 antagomir, Wnt/β-catenin and its associated T cell factor-4 (TCF-4) and Cyclin D1 expression were positively correlated with Jarid2. Conclusion: Silencing of miR-155 attenuates DSS-induced colitis by regulating Th17/Treg cell balance and Jarid2/Wnt/β-catenin participated in the process.

Chronic urticaria (CU) is defined as the continuous or intermittent presence of urticaria for a period exceeding 6 weeks and sometimes occurring with angioedema. Between 66 and 93% of patients with CU have chronic spontaneous urticaria (CSU), the precise pathogenesis of which is largely unknown. The aim of this study was to determine the relationship between gut microbiota and serum metabolites and the possible pathogenesis underlying CSU. We collected feces and blood samples from CSU patients and healthy controls and the relationship between gut microbiota and serum metabolites was assessed using 16S rRNA gene sequencing and untargeted metabolomic analyses. The CSU group exhibited decreased alpha diversity of the microbial population compared to the control group. The abundance of unidentified Enterobacteriaceae was increased, while the abundance of Bacteroides, Faecalibacterium, Bifidobacterium, and unidentified Ruminococcaceae was significantly reduced in CSU patients. The serum metabolome analysis revealed altered levels of docosahexaenoic acid, arachidonic acid, glutamate, and succinic acid, suggesting changes in unsaturated fatty acids and the butanoate metabolism pathway. The combined serum metabolomics and gut microbiome datasets were correlated; specifically, docosahexaenoic acid, and arachidonic acid were positively correlated with Bacteroides. We speculate that alterations in gut microbes and metabolites may contribute to exacerbated inflammatory responses and dysregulated immune function with or without regulatory T cell dependence in the pathogenesis of CSU.

ABSTRACT HIV causes neurodegeneration and dementia in AIDS patients, but its function in milder cognitive impairments in virologically suppressed patients on antiretroviral therapy is unknown. Such patients are immunocompetent, have low peripheral and brain HIV burdens, and show minimal brain neuropathology. Using the model of HIV-related memory impairment in EcoHIV-infected conventional mice, we investigated the neurobiological and cognitive consequences of efficient EcoHIV expression in the mouse brain after intracerebral infection. HIV integrated and persisted in an expressed state in brain tissue, was detectable in brain monocytic cells, and caused neuroinflammatory responses and lasting spatial, working, and associative memory impairment. Systemic antiretroviral treatment prevented direct brain infection and memory dysfunction indicating the requirement for HIV expression in the brain for disease. Similarly inoculated murine leukemia virus used as a control replicated in mouse brain but not in monocytic cells and was cognitively benign, linking the disease to HIV-specific functions. Memory impairment correlated in real time with hippocampal dysfunction shown by defective long-term potentiation in hippocampal slices ex vivo and with diffuse synaptodendritic injury in the hippocampus reflected in significant reduction in microtubule-associated protein 2 and synapsin II staining. In contrast, there was no evidence of overt neuronal loss in this region as determined by neuron-specific nuclear protein quantification, TUNEL assay, and histological observations. Our results reveal a novel capacity of HIV to induce neuronal dysfunction and memory impairment independent of neurotoxicity, distinct from the neurotoxicity of HIV infection in dementia. IMPORTANCE HIV neuropathogenesis has been attributed in large measure to neurotoxicity of viral proteins and inflammatory factors produced by infected monocytic cells in the brain. We show here that HIV expression in mouse brain causes lasting memory impairment by a mechanism involving injury to hippocampal synaptodendritic arbors and neuronal function but not overt neuronal loss in the region. Our results mirror the observation of minimal neurodegeneration in cognitively impaired HIV patients on antiretroviral therapy and demonstrate that HIV is nonneurotoxic in certain brain abnormalities that it causes. If neurons comprising the cognition-related networks survive HIV insult, at least for some time, there is a window of opportunity for disease treatment.

Free amino acids are an important indicator of the freshness of yellow tea. This study investigated a novel procedure for predicting the free amino acid (FAA) concentration of yellow tea. It was developed based on the combined spectral and textural features from hyperspectral images. For the purposes of exploration and comparison, hyperspectral images of yellow tea (150 samples) were captured and analyzed. The raw spectra were preprocessed with Savitzky-Golay (SG) smoothing. To reduce the dimension of spectral data, five feature wavelengths were extracted using the successive projections algorithm (SPA). Five textural features (angular second moment, entropy, contrast, correlation, and homogeneity) were extracted as textural variables from the characteristic grayscale images of the five characteristic wavelengths using the gray-level co-occurrence matrix (GLCM). The FAA content prediction model with different variables was established by a genetic algorithm-support vector regression (GA-SVR) algorithm. The results showed that better prediction results were obtained by combining the feature wavelengths and textural variables. Compared with other data, this prediction result was still very satisfactory in the GA-SVR model, indicating that data fusion was an effective way to enhance hyperspectral imaging ability for the determination of free amino acid values in yellow tea.

Cold stress is one of the most important abiotic stresses in rice. C2H2 zinc finger proteins play important roles in response to abiotic stresses in plants. In the present study, we isolated and functionally characterized a new C2H2 zinc finger protein transcription factor OsCTZFP8 in rice. OsCTZFP8 encodes a C2H2 zinc finger protein, which contains a typical zinc finger motif, as well as a potential nuclear localization signal (NLS) and a leucine-rich region (L-box). Expression of OsCTZFP8 was differentially induced by several abiotic stresses and was strongly induced by cold stress. Subcellular localization assay and yeast one-hybrid analysis revealed that OsCTZFP8 was a nuclear protein and has transactivation activity. To characterize the function of OsCTZFP8 in rice, the full-length cDNA of OsCTZFP8 was isolated and transgenic rice with overexpression of OsCTZFP8 driven by the maize ubiquitin promoter was generated using Agrobacterium-mediated transformation. Among 46 independent transgenic lines, 6 single-copy homozygous overexpressing lines were selected by Southern blot analysis and Basta resistance segregation assay in both T1 and T2 generations. Transgenic rice overexpressing OsCTZFP8 exhibited cold tolerant phenotypes with significantly higher pollen fertilities and seed setting rates than nontransgenic control plants. In addition, yield per plant of OsCTZFP8-expressing lines was significantly (p

SUMMARY Heterosexual transmission accounts for the majority of new human immunodeficiency virus (HIV) cases worldwide. The current approach to investigate HIV heterosexual transmission in animals involves application of virus stock to the vaginal surface, a method that does not reproduce the physiological conditions of vaginal intercourse that influence the rate of transmission. We have previously described efficient infection of conventional mice using EcoHIV/NL4-3 and EcoHIV/NDK, chimeric HIV molecular clones constructed to express all HIV structural and regulatory genes except envelope, which is replaced by a rodent-tropic envelope gene. Here we investigated whether EcoHIV/NDK-infected male mice transmit virus to females during coitus, and the sensitivity of this transmission to HIV pre-exposure prophylaxis and the estrus state. Our general approach was to allow mating between EcoHIV/NDK-infected male mice and uninfected females for 1–7 nights. At 1–6 weeks after mating, mice were euthanized and virus burdens were measured by quantitative PCR (qPCR) amplification of HIV RNA or DNA in peritoneal macrophages, inguinal lymph node cells, spleen cells or vas deferens, or by ELISA for antibodies to HIV Gag. We found that 70–100% of female mice mated to EcoHIV/NDK-infected males acquired infection. Pericoital treatment of females with either 2′,3′-dideoxcytidine (ddC) or tenofovir largely prevented their EcoHIV/NDK infection by mating (P

A series of N,N’-disubstituted-2-nitroethene-1,1-diamine and N,N’-disubstituted- N’’-cyanoguanidine derivatives were prepared and evaluated for in vivo analgesic activity. The blood brain barrier (BBB) VolSurf model was used to predict the BBB permeation profiles of our synthesized compounds. Some compounds show both remarkable analgesic activity and good BBB permeation profiles, and these compounds might be developed for treatment of opioid tolerance and dependence.

Objectives: All patients with congenital heart disease (CHD) receive postoperative management in ICUs. Infection prevention and control (IPC) has a significant impact on prognosis. This study provides a preliminary understanding of the fundamental aspects of IPC in ICUs following CHD surgery in China. Methods: From September to October 2023, we initiated a survey on healthcare-associated infection (HAI) management in hospitals that perform CHD surgeries independently. The questionnaires were jointly completed by the ICU physicians and IPC personnel. Duplicate or unqualified questionnaires were excluded from the study. The contents of our questionnaires covered hospital and ICU capacity, performance of the infection control department, HAI surveillance, implementation of IPC measures, and antimicrobial stewardship (AMS). Qualified questionnaires were compared according to the volume of annual CHD surgeries performed in different ICUs. Group 1 was defined as volume more than 300 cases and group 2 was defined as volume less than or equal to 300 cases. Results: Sixty-two of the 118 questionnaires were completed, with a response rate of 53%. The CHD surgical volume in 2022 of the 62 hospitals was 36342, accounting for 52%of the annual CHD surgical volume (69 672) across the country. The postoperative infection rates obtained from the 15 ICUs varied from 1.3 to 15%, with a median rate of 4.5%. A total of 16 ICUs provided data on drug-resistant bacteria, Klebsiella pneumoniae exhibiting the highest frequency. More than 95% of ICUs have established complete HAI management systems. Information-based HAI surveillance was conducted in 89% of ICUs. Approximately 67% of ICUs stopped prophylactic antibiotics within 48 hours after surgery. In complex cases, carbapenems were administered empirically in 89% of ICUs. Group 1 had an advantage over group 2 in preventing multi-drug-resistant organisms (all instruments should be used alone 100% vs. 86%, P=0.047; cleaning and disinfection of environmental surfaces, 100% vs. 81%, P=0.035; antibiotic consumption control 85%vs. 61%, P=0.044) and in preventing surgical site infections (perioperative blood glucose monitoring, 88% vs. 67%, P=0.048). However, Group 1 did not perform well in preventing catheter-related bloodstream infection (delayed catheter removal due to convenience of laboratory tests, 31% vs. 6%, P=0.021) and catheter-associated urinary tract infection (delayed catheter removal due to muscle relaxant administration, 88% vs. 58%, P=0.022). Conclusions: A relatively complete HAI management system has been established throughout the country in ICUs for CHD patients. Information-based surveillance of HAI needs to be promoted, and actions should be taken to facilitate the implementation of IPC measures and AMS bundles. Training and feedback are critical for implementing IPC measures. [ABSTRACT FROM AUTHOR]

Thirty-eight million people worldwide are living with HIV, PWH, a major public health problem. Antiretroviral therapy (ART) revolutionized HIV treatment and significantly increased the lifespan of PWH. However, approximately 15-50% of PWH develop HIV associated neurocognitive disorders (HIV-NCI), a spectrum of cognitive deficits, that negatively impact quality of life. Many PWH also have opioid use disorder (OUD), and studies in animal models of HIV infection as well as in PWH suggest that OUD can contribute to HIV-NCI. The synthetic opioid agonist, buprenorphine, treats OUD but its effects on HIV-NCI are unclear. We reported that human mature inflammatory monocytes express the opioid receptors MOR and KOR, and that buprenorphine reduces important steps in monocyte transmigration. Monocytes also serve as HIV reservoirs despite effective ART, enter the brain, and contribute to HIV brain disease. Using EcoHIV infected mice, an established model of HIV infection and HIV-NCI, we previously showed that pretreatment of mice prior to EcoHIV infection reduces mouse monocyte entry into the brain and prevents NCI. Here we show that buprenorphine treatment of EcoHIV infected mice with already established chronic NCI completely reverses the disease. Disease reversal was associated with a significant reduction in brain inflammatory monocytes and reversal of dendritic injury in the cortex and hippocampus. These results suggest that HIV-NCI persistence may require a continuing influx of inflammatory monocytes into the brain. Thus, we recommend buprenorphine as a potential therapy for mitigation of HIV brain disease in PWH with or without OUD. [ABSTRACT FROM AUTHOR]