Alzheimer’s disease (AD) has an insidious onset and heterogeneous clinical symptoms. The well-accepted biomarkers for clinical diagnosis of AD includes β-amyloid (Aβ) deposition and pathologic tau ...level within cerebral spinal fluid (CSF) and imaging AD pathology like positive emission tomography (PET) imaging of the amyloid-binding agent Pittsburgh compound B (PET-PiB). However, the high expense and invasive nature of these methods highly limit their wide usage in clinic practice. Therefore, it is imperious to develop less expensive and invasive methods, and plasma biomarkers are the premium targets. In the current study, we utilized a single-blind comparison method, all the probable AD cases met the core clinical NIA-AA criteria, and validated by PET-PiB. We used ultra-sensitive immunomagnetic reduction (IMR) assays to measure plasma Aβ42 and total-tau (t-tau) levels, in combination with different variables including Aβ42 × t-tau value, Montreal Cognitive Scale (MoCA), and mini-mental state examination (MMSE). We used logistic regression to analyze the effect of all these variables in the algorism. Our results showed that (1) plasma Aβ42 and t-tau are efficient biomarkers for AD diagnosis using IMR platform, while Aβ42 × t-tau value is more efficient for discriminating control and AD; (2) in the control group，Aβ42 level and age demonstrated strong negative correlation; Aβ42 × t-tau value and age demonstrated significant negative correlation; (3) in the AD group, t-tau level and MMSE score demonstrated strong negative correlation; (4) using the model that Aβ42, Aβ42 × t-tau, and MoCA as the variable to generate ROC curve, cut-off value = 0.48, sensitivity = 0.973, specificity = 0.982, AUC = 0.986, offered better categorical efficacy, sensitivity, specificity, and AUC. The multi-factor model of plasma Aβ42 and t-tau in combine with MoCA can be a viable model separate health and AD subjects in clinical practice.
Autoantibody production by plasma cells (PCs) plays a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE). The molecular pathways by which B cells become pathogenic PC secreting ...autoantibodies in SLE are incompletely characterized. Histone deactylase 6 (HDAC6) is a unique cytoplasmic HDAC that modifies the interaction of a number of tubulin- associated proteins; inhibition of HDAC6 has been shown to be beneficial in murine models of SLE, but the downstream pathways accounting for the therapeutic benefit have not been clearly delineated. In the current study, we sought to determine whether selective HDAC6 inhibition would abrogate abnormal B cell activation in SLE. We treated NZB/W lupus mice with the selective HDAC6 inhibitor, ACY-738, for 4 weeks beginning at 20 weeks-of age. After only 4 weeks of treatment, manifestation of lupus nephritis (LN) were greatly reduced in these animals. We then used RNAseq to determine the genomic signatures of splenocytes from treated and untreated mice and applied computational cellular and pathway analysis to reveal multiple signaling events associated with B cell activation and differentiation in SLE that were modulated by HDAC6 inhibition. PC development was abrogated and germinal center (GC) formation was greatly reduced. When the HDAC6 inhibitor-treated lupus mouse gene signatures were compared to human lupus patient gene signatures, the results showed numerous immune, and inflammatory pathways increased in active human lupus were significantly decreased in the HDAC6 inhibitor treated animals. Pathway analysis suggested alterations in cellular metabolism might contribute to the normalization of lupus mouse spleen genomic signatures, and this was confirmed by direct measurement of the impact of the HDAC6 inhibitor on metabolic activities of murine spleen cells. Taken together, these studies show HDAC6 inhibition decreases B cell activation signaling pathways and reduces PC differentiation in SLE and suggest that a critical event might be modulation of cellular metabolism.
Baculovirus-mediated gene transfer has been developed as a vaccine design strategy against a number of diseases without apparent viral replication. However, it has been hampered by ...complement-dependent inactivation, thus hindering the in vivo application of baculovirus. A variety of approaches have been exploited to bypass the complement system in the serum. In this study, we constructed and screened a series of baculovirus vectors displaying complement interfering factors, of which a baculovirus vector displaying swine IgG1 Fc (pFc) showed the highest complement antagonism (75.6%). Flow cytometry analysis of transduced cells demonstrated that the baculovirus display of pFc had a significant increase in transduction efficiency and transgene expression of reporter genes. On this basis, a VSV-G-pseudotyped with swine IgG1 Fc surface displayed baculovirus vector was developed to express the classical swine fever virus (CSFV) E2 gene. The translational enhancers Syn21 and P10UTR were incorporated to improve the antigen expression. The E2 gene was efficiently expressed in both insect and mammalian cells. Pigs immunized with this recombinant baculovirus developed high levels of E2-specific antibody, CSFV-specific neutralizing antibody and IFN-γ-secreting cellular immune responses. These results demonstrate that the strategy of surface-displaying swine IgG1 Fc has a great potential to improve the efficiency of baculovirus-vectored vaccine for CSFV and other swine pathogens.
Background
Diabetic kidney disease (DKD) patients are facing an extremely high risk of cardiovascular disease (CVD), which is a major cause of death for DKD patients. We aimed to build a deep ...learning model to predict CVD risk among DKD patients and perform risk stratifying, which could help them perform early intervention and improve personal health management.
Methods
A retrospective cohort study was conducted to assess the risk of the occurrence of composite cardiovascular disease, which includes coronary heart disease, cerebrovascular diseases, congestive heart failure, and peripheral artery disease, in DKD patients. A least absolute shrinkage and selection operator (LASSO) regression was used to perform the variable selection. A deep learning-based survival model called DeepSurv, based on a feed-forward neural network was developed to predict CVD risk among DKD patients. We compared the model performance with the conventional Cox proportional hazards (CPH) model and the Random survival forest (RSF) model using the concordance index (C-index), the area under the curve (AUC), and integrated Brier scores (IBS).
Results
We recruited 890 patients diagnosed with DKD in this retrospective study. During a median follow-up of 10.4 months, there are 289 patients who sustained a subsequent CVD. Seven variables, including age, high density lipoprotein (HDL), hemoglobin (Hb), systolic blood pressure (SBP), smoking status, 24 h urinary protein excretion, and total cholesterol (TC), chosen by LASSO regression were used to develop the predictive model. The DeepSurv model showed the best performance, achieved a C-index of 0.767(95% confidence intervals CI: 0.717–0.817), AUC of 0.780(95%CI: 0.721–0.839), and IBS of 0.067 in the validation set. Then we used the cut-off value determined by ROC (receiver operating characteristic) curve to divide the patients into different risk groups. Moreover, the DeepSurv model was also applied to develop an online calculation tool for patients to conduct risk monitoring.
Conclusion
A deep-learning-based predictive model using seven clinical variables can effectively predict CVD risk among DKD patients and perform risk stratification. An online calculator allows its easy implementation.
Listeria monocytogenes (L. monocytogenes) is a foodborne pathogen that causes listeriosis in humans and other animals. Surface proteins with the LPXTG motif have important roles in the virulence of ...L. monocytogenes. Lmo0159 is one such protein, but little is known about its role in L. monocytogenes virulence, motility, and biofilm formation. Here, we constructed and characterized a deletion mutant of lmo0159 (∆lmo0159). We analyzed not only the capacity of biofilm formation, motility, attachment, and intracellular growth in different cell types but also LD50; bacterial load in mice’s liver, spleen, and brain; expression of virulence genes; and survival time of mice after challenge. The results showed that the cross-linking density of the biofilm of ∆lmo0159 strain was lower than that of WT by microscopic examination. The expression of biofilm-formation and virulence genes also decreased in the biofilm state. Subsequently, the growth and motility of ∆lmo0159 in the culture medium were enhanced. Conversely, the growth and motility of L. monocytogenes were attenuated by ∆lmo0159 at both the cellular and mouse levels. At the cellular level, ∆lmo0159 reduced plaque size; accelerated scratch healing; and attenuated the efficiency of adhesion, invasion, and intracellular proliferation in swine intestinal epithelial cells (SIEC), RAW264.7, mouse-brain microvascular endothelial cells (mBMEC), and human-brain microvascular endothelial cells (hCMEC/D3). The expression of virulence genes was also inhibited. At the mouse level, the LD50 of the ∆lmo0159 strain was 100.97 times higher than that of the WT strain. The bacterial load of the ∆lmo0159 strain in the liver and spleen was lower than that of the WT strain. In a mouse model of intraperitoneal infection, the deletion of the lmo0159 gene significantly prolonged the survival time of the mice, suggesting that the lmo0159 deletion mutant also exhibited reduced virulence. Thus, our study identified lmo0159 as a novel virulence factor among L. monocytogenes LPXTG proteins.
Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease in which the body's immune system mistakenly attacks healthy cells. Although the exact cause of SLE has not been ...identified, it is clear that both genetics and environmental factors trigger the disease. Identical twins have a 24% chance of getting lupus disease if the other one is affected. Internal factors such as female gender and sex hormones, the major histocompatibility complex (MHC) locus and other genetic polymorphisms have been shown to affect SLE, as well as external, environmental influences such as sunlight exposure, smoking, vitamin D deficiency, and certain infections. Several studies have reported and proposed multiple associations between the alteration of the epigenome and the pathogenesis of autoimmune disease. Epigenetic factors contributing to SLE include microRNAs, DNA methylation status, and the acetylation/deacetylation of histone proteins. Additionally, the acetylation of non-histone proteins can also influence cellular function. A better understanding of non-genomic factors that regulate SLE will provide insight into the mechanisms that initiate and facilitate disease and also contribute to the development of novel therapeutics that can specifically target pathogenic molecular pathways.
The disease burden of hepatitis C virus (HCV) infection in HIV-positive and HIV-negative men who have sex with men (MSM) is changing. We aim to provide an updated comprehensive estimate of HCV ...prevalence and incidence among the HIV-positive and HIV-negative MSM population at the country, regional, and global levels and their changing trends over time.
PubMed, Embase, PsycINFO, CINAHL, and conference databases were searched and eligible records on the prevalence and incidence of HCV antibodies were selected and pooled
a random-effects model. Meta-regression was performed to demonstrate the association between the pooled rates and study year.
A total of 230 articles reporting 245 records from 51 countries with 445,883 participants and 704,249 follow-up person-years were included. The pooled prevalence of HCV in MSM was 5.9% (95% CI: 5.1-6.8), with substantial differences between countries and regions. Low- and lower-middle-income countries (12.3 and 7.0%) manifested a larger disease burden than high- and upper-middle-income countries (5.8 and 3.8%). HCV prevalence in HIV-positive MSM was substantially higher than in HIV-negative MSM (8.1 vs. 2.8%,
< 0.001). The pooled incidence of HCV was 8.6 (95% CI: 7.2-10.0) per 1,000 person-years, with an increasing trend over time, according to meta-regression (
< 0.05).
Global HCV prevalence in MSM varies by region and HIV status. Behavior counseling and regular HCV monitoring are needed in HIV-positive subgroups and high-risk regions. Given the upward trend of HCV incidence and sexual risk behaviors, there is also a continued need to reinforce risk-reduction intervention.
PROSPERO, identifier CRD42020211028; https://www.crd.york.ac.uk/prospero/.
The upper reaches of the Yangtze River are a very important ecological barrier in China, but the ecological benefits of large-scale Cupressus funebris Endl.plantations are low. This study ...investigated 12 plantations of different compositions and densities, including two densities of Cinnamomum septentrionale Hand.-Mazz. (Cs), Alnus cremastogyne Burk. (Ac), and Toona sinensis (A. Juss.) Roem. (Ts), and mixed plantations of Cs + Ac (CA), Ts + Cs (TC), Ts + Ac (TA), and Ac + Ts + Cs (ATC) and the cutting-blank (CB), and, at the same time, the unreconstructed pure C. funebris (Cf) forest was set as the control. We aimed to explore the influence mechanism of upper tree composition and density on shrub diversity, as well as the relationship between shrub diversity and niche. Our research results are as follows: (1) Among all the patterns, the TA, CA, and TC patterns are the most conducive to improving the diversity of shrubs. The composition and density of different trees have a great influence on the diversity of shrubs. (2) Niche is closely related to the diversity of shrubs. In the patterns of low niche overlap between dominant shrubs, the diversity of shrubs is greater. These results contribute to a deeper understanding of the relationship between the diversity of overstory and shrubs, and reveals the relationship between niche and diversity.
Hepatitis B virus (HBV) infection remains a significant public health problem. The purpose of this study was to investigate the seroepidemiology of HBV in people living in the insular regions, and to ...provide the most recent baseline data for planning and monitoring of health.
A cross-sectional, community-based survey was conducted without age restriction, on two isolated islands, Zhoushan and Yuhuan, China. The study sample was selected by random multistage cluster sampling. Serological samples and demographic information were collected from 15878 participants.
The prevalences of anti-HBV core antibody (anti-HBc), hepatitis B virus surface antigen (HBsAg), and anti-HBV surface antibody (anti-HBs) were 33.1, 10.4, and 56.1%, respectively. We found statistically significant differences of HBV markers in men versus women (P<0.01). The prevalence of HBV infection increased with age. There were significant differences in the rates of HBsAg and anti-HBc positivity between the two islands (P<0.01). Alanine aminotransferase (ALT) levels were elevated (>38 IU/L) in 15.6% and 7.2% of the HBsAg-positive and negative groups, respectively. Elevated ALT levels were significantly higher in males (12.0%) compared with females (5.8%) (P<0.01). The α-fetoprotein (AFP) positivity rate was 0.6% in HBsAg-positive participants over the age of 30.
Due to the geographic location, we found that the HBV prevalence and potential for the development of hepatocellular carcinoma remained high in insular regions of southeast China, and are far above the national figures. Although a vaccination program has been in effect over the last 20 years, several additional measures should be adopted by the government to limit the spread of hepatitis B. These include the management of high risk persons and the floating population living on the islands, expansion of the immune population, and increased health education for fisherman.
African swine fever (ASF) is an acute and severe disease transmitted among domestic pigs and wild boars. This disease is notorious for its high mortality rate and has caused great losses to the ...world's pig industry in the past few years. After infection, pigs can develop symptoms such as high fever, inflammation, and acute hemorrhage, finally leading to death. African swine fever virus (ASFV) is the causal agent of ASF; it is a large DNA virus with 150-200 genes. Elucidating the functions of each gene could provide insightful information for developing prevention and control methods. Herein, to investigate the function of I267L, porcine alveolar macrophages (PAMs) infected with an I267L-deleted ASFV strain (named ∆I267L) and wild-type ASFV for 18 h and 36 h were taken for transcriptome sequencing (RNA-seq). The most distinct different gene that appeared at both 18 hpi (hours post-infection) and 36 hpi was F3; it is the key link between inflammation and coagulation cascades. KEGG analysis (Kyoto encyclopedia of genes and genomes analysis) revealed the complement and coagulation cascades were also significantly affected at 18 hpi. Genes associated with the immune response were also highly enriched with the deletion of I267L. RNA-seq results were validated through RT-qPCR. Further experiments confirmed that ASFV infection could suppress the induction of F3 through TNF-α, while I267L deletion partially impaired this suppression. These results suggest that I267L is a pathogenicity-associated gene that modulates the hemorrhages of ASF by suppressing F3 expression. This study provides new insights into the molecular mechanisms of ASFV pathogenicity and potential targets for ASFV prevention and control.
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