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miR-124 is a significantly up-regulated miRNA in peripheral blood collected from piglets infected with Salmonella Typhimurium, suggesting that it may play an important role in Salmonella pathogenesis. This study focused on the transcriptomic analysis of peripheral blood mononuclear cells (PBMCs) isolated from miR-124 sponge and Salmonella Typhimurium-treated piglets, and trying to investigate the function of miR-124 in Salmonella infection. The transcriptome profiling analysis revealed that 2778 genes in miR-124 sponge + Salmonella Typhimurium treatment versus control, 2271 genes in Salmonella Typhimurium treatment versus control, and 1301 genes in miR-124 sponge + Salmonella Typhimurium versus Salmonella Typhimurium treatment, were differentially expressed, respectively (FDR 0.05 and fold change 2.0). Pathway analysis indicated that the MAPK signaling pathway, Ribosome pathway, and T-cell receptor signaling pathway were the most significantly enriched pathway in differentially expressed genes between miR-124 sponge + Salmonella Typhimurium and Salmonella Typhimurium along treatment (FDR 0.05). Reporter assays and electrophoretic mobility shift assays showed that miR-124 is a crucial regulatory factor that targets IQ motif containing GTPase-activating protein 2 (IQGAP2). Cell culture experiment indicated that miR-124 attenuated the Salmonella Typhimurium-mediated activation of CDC42 and RAC1 (P 0.05). Cultured PBMCs treated with miR-124 and IQGAP2-siRNA had higher intracellular Salmonella count than control samples, particularly 12 h post-infection (P 0.05). Immunofluorescence analysis revealed that miR-124 treatment reduced the percentage of LAMP-1-positive phagosomes. The miR-124 could be an important regulator for IQGAP2/Rho GTPase pathway in Salmonella Typhimurium-infected PBMCs, and this pathway could be a target for Salmonella that support its infection in PBMCs in piglets.

Background In the general population, metabolic syndrome (MetS) is associated with increased risk of cognitive impairment, including global and specific cognitive domains. These associations are not well studied in patients undergoing hemodialysis and were the focus of the current investigation. Methods In this multicenter cross-sectional study, 5492 adult hemodialysis patients (3351 men; mean age: 54.4 ± 15.2 years) treated in twenty-two dialysis centers of Guizhou, China were included. The Mini-Mental State Examination (MMSE) was utilized to assess mild cognitive impairment (MCI). MetS was diagnosed with abdominal obesity, hypertension, hyperglycemia, and dyslipidemia. Multivariate logistic and linear regression models were used to examine the associations of MetS, its components, and metabolic scores with the risk of MCI. Restricted cubic spline analyses were performed to explore the dose–response associations. Results Hemodialysis patients had a high prevalence of MetS (62.3%) and MCI (34.3%). MetS was positively associated with MCI risk with adjusted ORs of 1.22 [95% confidence interval (CI) 1.08–1.37, P = 0.001]. Compared to no MetS, adjusted ORs for MCI were 2.03 (95% CI 1.04–3.98) for 22.51 (95% CI 1.28–4.90) for 3, 2.35 (95% CI 1.20–4.62) for 4, and 2.94 (95% CI 1.48–5.84) for 5 components. Metabolic syndrome score, cardiometabolic index, and metabolic syndrome severity score were associated with increased risk of MCI. Further analysis showed that MetS was negatively associated with MMSE score, orientation, registration, recall and language (P P for interaction = 0.012) on the MetS-MCI was observed. Conclusion Metabolic syndrome was associated with MCI in hemodialysis patients in a positive dose–response effect.

Faithful chromosome segregation of 8 duplicated haploid genomes into 8 daughter gametes is essential for male gametogenesis and mosquito transmission of Plasmodium. Plasmodium undergoes endomitosis in this multinucleated cell division, which is highly reliant on proper spindle-kinetochore attachment. However, the mechanisms underlying the spindle-kinetochore attachment remain elusive. End-binding proteins (EBs) are conserved microtubule (MT) plus-end binding proteins and play an important role in regulating MT plus-end dynamics. Here, we report that the Plasmodium EB1 is an orthologue distinct from the canonical eukaryotic EB1. Both in vitro and in vivo assays reveal that the Plasmodium EB1 losses MT plus-end tracking but possesses MT-lattice affinity. This MT-binding feature of Plasmodium EB1 is contributed by both CH domain and linker region. EB1-deficient parasites produce male gametocytes that develop to the anucleated male gametes, leading to defective mosquito transmission. EB1 is localized at the nucleoplasm of male gametocytes. During the gametogenesis, EB1 decorates the full-length of spindle MTs and regulates spindle structure. The kinetochores attach to spindle MTs laterally throughout endomitosis and this attachment is EB1-dependent. Consequently, impaired spindle-kinetochore attachment is observed in EB1-deficient parasites. These results indicate that a parasite-specific EB1 with MT-lattice binding affinity fulfills the spindle-kinetochore lateral attachment in male gametogenesis.

Background Brucellosis is a chronic zoonotic disease, and Ningxia is one of the high prevalence regions in China. To mitigate the spread of brucellosis, the government of Ningxia has implemented a comprehensive prevention and control plan (2022-2024). It is meaningful to quantitatively evaluate the accessibility of this strategy. Methods Based on the transmission characteristics of brucellosis in Ningxia, we propose a dynamical model of sheep-human-environment, which coupling with the stage structure of sheep and indirect environmental transmission. We first calculate the basic reproduction number $$R_0$$ R 0 and use the model to fit the data of human brucellosis. Then, three widely applied control strategies of brucellosis in Ningxia, that is, slaughtering of sicked sheep, health education to high risk practitioners, and immunization of adult sheep, are evaluated. Results The basic reproduction number is calculated as $$R_{0}=1.47$$ R 0 = 1.47 , indicating that human brucellosis will persist. The model has a good alignment with the human brucellosis data. The quantitative accessibility evaluation results show that current brucellosis control strategy may not reach the goal on time. “Ningxia Brucellosis Prevention and Control Special Three-Year Action Implementation Plan (2022-2024)” will be achieved in 2024 when increasing slaughtering rate $$\gamma$$ γ by 30$$\%$$ % , increasing health education to reduce $$\beta _{h}$$ β h to 50$$\%$$ % , and an increase of immunization rate of adult sheep $$\theta$$ θ by 40$$\%$$ % . Conclusion The results demonstrate that the comprehensive control measures are the most effective for brucellosis control, and it is necessary to further strengthen the multi-sectoral joint mechanism and adopt integrated measures to prevention and control brucellosis. These results can provide a reliable quantitative basis for further optimizing the prevention and control strategy of brucellosis in Ningxia.

Background To develop a fully automatic framework for the diagnosis of cause for left ventricular hypertrophy (LVH) via cardiac cine images. Methods A total of 302 LVH patients with cine MRI images were recruited as the primary cohort. Another 53 LVH patients prospectively collected or from multi-centers were used as the external test dataset. Different models based on the cardiac regions (Model 1), segmented ventricle (Model 2) and ventricle mask (Model 3) were constructed. The diagnostic performance was accessed by the confusion matrix with respect to overall accuracy. The capability of the predictive models for binary classification of cardiac amyloidosis (CA), hypertrophic cardiomyopathy (HCM) or hypertensive heart disease (HHD) were also evaluated. Additionally, the diagnostic performance of best Model was compared with that of 7 radiologists/cardiologists. Results Model 3 showed the best performance with an overall classification accuracy up to 77.4% in the external test datasets. On the subtasks for identifying CA, HCM or HHD only, Model 3 also achieved the best performance with AUCs yielding 0.895–0.980, 0.879–0.984 and 0.848–0.983 in the validation, internal test and external test datasets, respectively. The deep learning model showed non-inferior diagnostic capability to the cardiovascular imaging expert and outperformed other radiologists/cardiologists. Conclusion The combined model based on the mask of left ventricular segmented from multi-sequences cine MR images shows favorable and robust performance in diagnosing the cause of left ventricular hypertrophy, which could be served as a noninvasive tool and help clinical decision.

MicroRNA-21 (miR-21) is a well-known oncomiR and plays key roles in regulating various biological processes related to pulmonary diseases, especially lung carcinoma. The regulatory roles and downstream targets of miR-21 remain far from well understood. We aimed to identify miR-21-gene regulatory network in lung tissue.Transcriptome and proteome analyses were performed on lung tissues from miR-21 knockout (KO) mice and their wildtype (WT) littermates. Differentially expressed genes (DEGs) and proteins (DEPs) between miR-21KO and WT were analyzed, and correlation analysis was performed between transcriptional and translational level. DEPs were used for prediction of miR-21 target genes and construction of co-expression network.Comparing with WT mice, 820 DEGs and 623 DEPs were identified in lung tissues of miR-21KO mice. Upregulated DEGs and DEPs were both significantly enriched in pathways of metabolism of xenobiotics by cytochrome P450, drug metabolism, and chemical carcinogenesis. Of the 31 molecules commonly identified in DEGs and DEPs, 9 upregulated genes were tumor suppressor genes while 8 downregulated genes were oncogenes, and 12 genes showed closely positive correlation between mRNA and protein expression. Real-time PCR validation results were consistent with the omics data. Among the upregulated DEPs in miR-21KO mice, 21 genes were predicted as miR-21 targets. The miR-21 regulatory network was constructed by target genes and their highly co-expressed proteins, which identified the miR-21 target Itih4 as a hub gene.MiR-21-gene regulatory network was constructed in mouse lung tissue. MiR-21KO resulted in extensive upregulation of tumor suppressor genes and downregulation of oncogenes.

Background This Bayesian network analysis was performed to assess the effects of different intravenous sedatives on outcomes in adult critically ill patients. Methods We searched for and gathered data from MEDLINE, Cochrane Central Register of Controlled Trials, Elsevier and Web of Science databases. Bayesian network analysis was performed to evaluate the effect of different intravenous sedatives on outcome in adult critically ill patients. Random errors were evaluated by trial sequential analysis (TSA). Results Twenty-seven studies including 8,599 critically ill adult patients were enrolled in the analysis. Comparisons among lorazepam, midazolam, propofol, dexmedetomidine, haloperidol and placebo or usual care were presented in a network plot. No significant differences were found for longest mortality in critically ill patients. However, when compared with midazolam, dexmedetomidine had a shorter ICU length of stay and a lower incidence of delirium. Meanwhile, midazolam had a longer ICU length of stay when compared with placebo, propofol and usual care. Subgroup analyses were performed respectively in sepsis, invasive ventilated patients and postoperative patients, as well as patients with higher severity of disease. Lower mortality was found in dexmedetomidine group when compared with placebo in postoperative patients. No differences were found for mortality, ICU length of stay and incidence of delirium in other subgroups. When compared with other sedatives, dexmedetomidine shortened ICU length of stay significantly in ventilated patients. TSA indicated lack of firm evidence for a beneficial effect. Conclusions No differences were found for longest mortality of different sedatives in adult critically ill patients. However, when compared with midazolam, dexmedetomidine had a shorter ICU length of stay and a lower incidence of delirium. TSA indicated lack of firm evidence for the results. More powered, randomized, controlled trials are needed to determine the effects.

This study aims to investigate the dosage pattern, efficacy, and safety of sacubitril/valsartan (Sac/Val) in Chinese heart failure with reduced ejection fraction (HFrEF) patients regarding real-world settings. Patients from 27 centers with a confirmed diagnosis of HFrEF and initiated Sac/Val treatment were enrolled. The primary objective was to evaluate the dosage pattern and change of heart failure status. In a final cohort of 983 patients, outpatient Sac/Val treatment demonstrated a similar beneficial effect in NT-proBNP and cardiac function. After initiating the treatment, overall and sub-population showed similar safety and efficacy. Patients who received a higher dose of Sac/Val (> 200 mg/d) demonstrated better improvement in LV function and reduction of NT-proBNP regardless of adjustment. Among Chinese HFrEF patients, Sac/Val showed a comparable reduction in NT-proBNP and improvement in cardiac function. Data further support guideline recommendations of Sac/Val in Chinese population. Optimal up-titration might provide further benefits. Further long-term and prognostic studies are needed. Graphical abstract

The association between muscle mass and cognitive impairment (CI) is conflicting. We aimed to evaluate and compare the associations of muscle strength, muscle mass and CI risk in maintenance hemodialysis (MHD) patients.We conducted a multicenter, cross-sectional study. Cognitive function was assessed with the Mini-Mental State Examination (MMSE) score. Muscle strength was assessed by hand grip strength (HGS), muscle mass was assessed by lean tissue mass (LTM). Education status was divided into two groups: lower education status (senior middle school and below) and higher education status (high school and above). Multivariable logistic regression models and subgroup analyses were performed. Receiver-operating characteristic (ROC) analyses were conducted to compare their predictive power in discriminating CI.2827 adult MHD patients were included in our final analysis. Patients in the lowest quartile of HGS was 2.82-fold as likely to have CI as compared to those in the highest quartile, while participants in the lowest quartile of LTM group were 1.52-fold as likely to have CI, when compared with the highest quartile group of LTM after adjusting for age, gender and education level. The association persisted in all subgroups except for women and well-educated participants. There was a significant interaction between HGS and education status on CI and age played an interactive role in the association between LTM and incident CI (P for interaction 0.05). The AUC value of the HGS was significantly higher than that of LTM (0.69 VS 0.63, P 0.001).Muscle strength performed better than muscle mass in identifying individuals at high risk of CI, particularly in male and less educated Chinese MHD patients.Level V, cross-sectional study.

Maximizing a submodular function has a wide range of applications in machine learning and data mining. One such application is data summarization whose goal is to select a small set of representative and diverse data items from a large dataset. However, data items might have sensitive attributes such as race or gender, in this setting, it is important to design \emph{fairness-aware} algorithms to mitigate potential algorithmic bias that may cause over- or under- representation of particular groups. Motivated by that, we propose and study the classic non-monotone submodular maximization problem subject to novel group fairness constraints. Our goal is to select a set of items that maximizes a non-monotone submodular function, while ensuring that the number of selected items from each group is proportionate to its size, to the extent specified by the decision maker. We develop the first constant-factor approximation algorithms for this problem. We also extend the basic model to incorporate an additional global size constraint on the total number of selected items., Comment: This article has been accepted for publication in the Journal on Combinatorial Optimization

A 24-year-old man with central nervous system (CNS) involvement of T-cell lineage acute lymphoblastic leukemia received sibling allogeneic stem cell transplantation (allo-SCT). He developed isolated CNS relapse early post-SCT, while high-dose systemic chemotherapy, intrathecal (IT) triple infusion and IT donor lymphocytes infusion (DLI) all demonstrated effectiveness. We performed IT umbilical cord blood-derived CAR-NK (target CD7) cells infusion, which was not previously reported. After infusion, detection of cytokines revealed that interferon-γ, interleukin-6 and interleukin-8 increased in CSF. He developed high fever, headache, nausea, vomiting and a spinal cord transection with incontinence in a short time, whereas the ptosis and blurred vision improved completely. The bone marrow remained encouragingly complete remission and complete donor chimerism over 9 months after IT CAR-NK cells infusion. In conclusion, IT CAR-NK cells infusion is a potentially feasible and effective option for patients with CNS relapse, with limited neurological toxicity.