Downregulation of microRNA-145a-5p promotes steatosis-to-NASH progression through upregulation of Nr4a2.

BACKGROUND & AIMS: The molecular mechanisms underlying the progression of simple steatosis to non-alcoholic steatohepatitis (NASH) remain incompletely understood, though the potential role of epigenetic regulation by microRNA (miRNAs) is an area of increasing interest. In the present study, we aimed to investigate the role of miRNAs during steatosis-to-NASH progression, as well as underlying mechanisms. METHODS: miR-145a-5p was identified as an important checkpoint in steatosis-to-NASH progression. In vivo loss-of-function and gain-of-function studies were performed to explore the role of miR-145a-5p and Nr4a2 in NASH progression. RNA-sequencing and bioinformatic analysis were used to investigate the targets of miR-145a-5p. RESULTS: Suppression of miR-145a-5p in the liver aggravated lipid accumulation and activated hepatic inflammation, liver injury and fibrosis in steatotic mice, whereas its restoration markedly attenuated diet-induced NASH pathogenesis. Mechanistically, miR-145a-5p was able to downregulate the nuclear receptor Nr4a2 and thus inhibit the expression of NASH-associated genes. Similarly, Nr4a2 overexpression promoted steatosis-to-NASH progression while liver-specific Nr4a2 knockout mice were protected from diet-induced NASH. This role of the miR-145a-5p/Nr4a2 regulatory axis was also confirmed in primary human hepatocytes. Furthermore, the expression of miR-145a-5p was reduced and the expression of Nr4a2 was increased in the livers of patients with NASH, while their expression levels significantly negatively and positively correlated with features of liver pathology, respectively. CONCLUSIONS: Our findings highlight the role of the miR-145a-5p/Nr4a2 regulatory axis in steatosis-to-NASH progression, suggesting that either supplementation of miR-145a-5p or pharmacological inhibition of Nr4a2 in hepatocytes may provide a promising therapeutic approach for the treatment of NASH. IMPACT AND IMPLICATIONS: Non-alcoholic fatty liver disease (NAFLD) is a dynamic spectrum of chronic liver diseases ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). Unfortunately, there are currently no approved drugs for NASH. Our current study identified miR-145a-5p as a novel regulator that inhibits steatosis-to-NASH progression. We found that miR-145a-5p was able to downregulate the nuclear receptor Nr4a2 to suppress the expression of NASH-associated genes. The differential expression of miR-145a-5p and Nr4a2 was further confirmed in patients with NASH, raising the possibility that supplementation of miR-145a-5p or suppression of Nr4a2 in hepatocytes might provide novel strategies for treating NASH.

Comparative analysis of the vaginal microbiome of healthy and polycystic ovary syndrome women: a large cross-sectional study.

RESEARCH QUESTION: What are the different features of the vaginal microbiome (VMB) between patients with polycystic ovary syndrome (PCOS) and healthy women? DESIGN: A cross-sectional study was conducted at a single academic university-affiliated centre. A total of 1446 participants were recruited (PCOS group, n =713, control group, n = 733). Vaginal swabs were analysed using 16S rRNA gene sequencing. The diversity and composition of the microbiome were compared between the PCOS group and the control group. Microbial interaction networks and functional prediction were investigated. RESULTS: The PCOS group had a higher alpha diversity than the control group (Shannon P = 0.03, Simpson P = 0.02), and higher intra-group variability was observed in PCOS group (P < 2.2E-16). At the genus level, the proportion of Lactobacillus decreased (85.1% versus 89.3%, false discovery rate [FDR] = 0.02), whereas the proportion of Gardnerella vaginalis and Ureaplasma increased in the PCOS group (5.1% versus 3.3%, FDR = 0.006; 1.2% versus 0.6%, FDR = 0.002, respectively). Lactobacillus acidophilus, Prevotella buccalis and G. vaginalis were identified as the main differential species. L. acidophilus was positively correlated with serum levels of anti-Müllerian hormone (AMH), and triglyceride (P = 2.01E-05, P = 0.004, respectively). P. buccalis was negatively correlated with serum levels of AMH and testosterone (P = 0.002, P = 0.003, respectively). G. vaginalis was positively correlated with serum levels of AMH, oestradiol and progesterone (P = 0.004, P = 0.005, P = 0.03, respectively). The VMB interaction network indicated that Lactobacillus crispus, Prevotella timonensis, and P. buccalis could be key drivers in the PCOS group. Overall, 55 predicted genes were found to be differentially abundant between PCOS and the control (FDRs < 0.25). CONCLUSIONS: The PCOS group had a higher diversity of vaginal microbiome and showed an enhanced level of heterogeneity. The proportion of Lactobacillus in the PCOS group decreased, whereas the proportions of Gardnerella and Ureaplasma increased. These results warrant further research that can validate the correlation between PCOS and VMB.

Human Papillomavirus Prevalence and Integration Status in Tissue Samples of Bladder Cancer in the Chinese Population.

BACKGROUND: Human papillomavirus (HPV) infection is associated with multiple types of cancer, but the evidence has not yet been fully elucidated in bladder cancer. METHODS: Frozen tissue samples collected from 146 patients aged 32 to 89 years with bladder cancer pathological diagnosis between 2015 and 2019 were analyzed. HPV genotyping and integration status determination were performed by capture-based next generation sequencing. Statistical analysis of HPV type distributions was performed according to stage, grade, sex, and age group of patients. RESULTS: Mean (SD) age of the 146 patients was 66.64 ±â€…10.06 years and 83.56% were men. Overall HPV infection rate was 28.77% (37.50% in women and 27.05% in men), with 11.90% HPV integration events. Among them, 17.12% single and 11.65% coinfections were observed. HPV18 (24.66%) was the most prevalent genotype, followed by HPV33, 16, and 39. All HPV were European lineage (A). HPV16 was more prevalent in women (P = .04). CONCLUSIONS: HPV infection may contribute to the etiology both in men and women with bladder cancer. HPV18, followed by HPV33, 16, and 39 genotypes, potentially represent the predominant oncogenic risk types for bladder carcinogenesis.

Sialidase of Glaesserella parasuis Augments Inflammatory Response via Desialylation and Abrogation of Negative Regulation of Siglec-5.

Siglecs are sialic acid-binding immunoglobulin-like lectins that play an important role in tissue homeostasis, immune response, and pathogen infection. Bacterial sialidases act on natural ligands of Siglecs, interfering with the Siglec-mediated immune response. Glaesserella parasuis is a porcine bacterial pathogen that secretes sialidase. However, little is known about the sialidase of G. parasuis and its impact on immune regulation. Here, we used wild-type G. parasuis, a sialidase-deficient mutant, and complementary strains to investigate the role of sialidase in porcine alveolar macrophage infection. Sialidase induced the release of proinflammatory cytokines, such as interleukin-1α (IL-1α), IL-6, and tumor necrosis factor alpha, from porcine alveolar macrophages. Moreover, sialidase desialylated the surface of porcine alveolar macrophages and altered the expression of Siglecs (the expression of Siglec-5 was reduced). Furthermore, sialidase led to a reduction in endogenous SH2 domain-containing protein tyrosine phosphatase (SHP-2) recruitment to Siglec-5 and simultaneously activated the inflammatory response via the mitogen-activated protein kinase and nuclear factor kappa light chain enhancer of activated B cell signaling pathways. This desialylation occurred before the release of proinflammatory cytokines, suggesting that the sialidase-induced inflammatory response was followed by reduced recruitment of SHP-2 to Siglec-5. Thus, this study is the first to demonstrate the role of sialidase in the inflammatory response of G. parasuis. This role resulted from the abrogation of negative regulation of Siglec-5 on proinflammatory cytokine release. This study helps to understand the molecular mechanism underlying the inflammatory response induced by sialidase secreted by G. parasuis and the acute inflammation caused by G. parasuis.

Attentional bias of subliminal emotional faces in adolescents with obsessive-compulsive disorder.

Attentional bias to threatening information may play a vital role in the onset and maintenance of obsessive-compulsive disorder (OCD). This study aimed to explore whether adolescents with OCD exhibited attentional bias toward faces that express disgust or fear. Participants were 27 adolescents with a first-time primary diagnosis of OCD and 27 healthy controls. To assess OCD, depression, and anxiety symptoms, all participants completed the Yale-Brown Obsessive Compulsive Scale, the Hamilton Depression Scale, and the Hamilton Anxiety Scale, respectively, followed by the modified dot probe task. Repeated measures ANOVA revealed a main effect of validity type and a significant group × validity type interaction effect. The results of one sample t-tests showed that participants in the OCD group had an attentional bias toward both disgusted and fearful faces. Further analysis indicated that adolescents in the OCD group showed facilitated attention toward the fearful faces and difficulty disengaging from disgusted faces. Adolescents with OCD exhibited facilitated attention toward threat stimuli, and when they allocated attention to threat, they experienced difficulty disengaging from it. Treatment procedures to modify the attentional bias may be effective.

Repetitive element transcripts are elevated in the brain of C9orf72 ALS/FTLD patients.

Significant transcriptome alterations are detected in the brain of patients with amyotrophic lateral sclerosis (ALS), including carriers of the C9orf72 repeat expansion and C9orf72-negative sporadic cases. Recently, the expression of repetitive element transcripts has been associated with toxicity and, while increased repetitive element expression has been observed in several neurodegenerative diseases, little is known about their contribution to ALS. To assess whether aberrant expression of repetitive element sequences are observed in ALS, we analysed RNA sequencing data from C9orf72-positive and sporadic ALS cases, as well as healthy controls. Transcripts from multiple classes and subclasses of repetitive elements (LINEs, endogenous retroviruses, DNA transposons, simple repeats, etc.) were significantly increased in the frontal cortex of C9orf72 ALS patients. A large collection of patient samples, representing both C9orf72 positive and negative ALS, ALS/FTLD, and FTLD cases, was used to validate the levels of several repetitive element transcripts. These analyses confirmed that repetitive element expression was significantly increased in C9orf72-positive compared to C9orf72-negative or control cases. While previous studies suggest an important link between TDP-43 and repetitive element biology, our data indicate that TDP-43 pathology alone is insufficient to account for the observed changes in repetitive elements in ALS/FTLD. Instead, we found that repetitive element expression positively correlated with RNA polymerase II activity in postmortem brain, and pharmacologic modulation of RNA polymerase II activity altered repetitive element expression in vitro. We conclude that increased RNA polymerase II activity in ALS/FTLD may lead to increased repetitive element transcript expression, a novel pathological feature of ALS/FTLD.

Development and application of an antibody detection ELISA for Haemophilus parasuis based on a monomeric autotransporter passenger domain.

BACKGROUND: Haemophilus parasuis is a commensal pathogen in the swine upper respiratory tract and causes Glässer's disease. Surveillance, screening for infection, and vaccination response of H. parasuis is hindered by the lack of a rapid antibody detection method. RESULTS: In the present study, a monomeric autotransporter was identified as a novel antigen for developing an indirect ELISA. The autotransporter passenger domain (Apd) was expressed, purified, and demonstrated to be specific in ELISA and western blotting. Mouse antiserum of recombinant Apd (rApd) recognized native Apd in the 15 serotype reference strains and five non-typeable isolate stains, but showed no reaction with seven other bacterial pathogens. The rApd ELISA was optimized and validated using 67 serum samples with known background, including 27 positive sera from experimentally infected and vaccinated pigs along with 40 negative sera that had been screened with H. parasuis whole cell ELISA from clinically healthy herds. The rApd ELISA provided positive and negative percent agreements of 96.4 and 94.9%, respectively, and an AUC value of 0.961, indicating that the assay produced accurate results. CONCLUSION: Apd was a universal antigen component among 15 serotype and non-typeable strains of H. parasuis and was also specific to this pathogen. The rApd ELISA could detect antibodies elicited by H. parasuis infection and vaccination, thereby exhibiting the potential to be applied for Glässer's disease diagnosis, H. parasuis vaccination evaluation, and large-scale serological surveillance.

Conserved DNA methylation combined with differential frontal cortex and cerebellar expression distinguishes C9orf72-associated and sporadic ALS, and implicates SERPINA1 in disease.

We previously found C9orf72-associated (c9ALS) and sporadic amyotrophic lateral sclerosis (sALS) brain transcriptomes comprise thousands of defects, among which, some are likely key contributors to ALS pathogenesis. We have now generated complementary methylome data and combine these two data sets to perform a comprehensive "multi-omic" analysis to clarify the molecular mechanisms initiating RNA misregulation in ALS. We found that c9ALS and sALS patients have generally distinct but overlapping methylome profiles, and that the c9ALS- and sALS-affected genes and pathways have similar biological functions, indicating conserved pathobiology in disease. Our results strongly implicate SERPINA1 in both C9orf72 repeat expansion carriers and non-carriers, where expression levels are greatly increased in both patient groups across the frontal cortex and cerebellum. SERPINA1 expression is particularly pronounced in C9orf72 repeat expansion carriers for both brain regions, where SERPINA1 levels are strictly down regulated across most human tissues, including the brain, except liver and blood, and are not measurable in E18 mouse brain. The altered biological networks we identified contain critical molecular players known to contribute to ALS pathology, which also interact with SERPINA1. Our comprehensive combined methylation and transcription study identifies new genes and highlights that direct genetic and epigenetic changes contribute to c9ALS and sALS pathogenesis.

Erratum: Neurofilament light chain and vaccination status associate with clinical outcomes in severe COVID-19.

[This corrects the article DOI: 10.1016/j.isci.2022.105272.].

Whole-genome DNA methylation and gene expression profiling in the livers of mice with nonalcoholic steatohepatitis.

AIMS: Non-alcoholic fatty liver disease (NAFLD) has emerged as one of the major causes of liver-related morbidity and mortality. It ranges simple steatosis to non-alcoholic steatohepatitis (NASH). Previous studies have shown that epigenetic factors, such as DNA methylation, can contribute to the development and progression of simple steatosis. However, the profiling of whole-genome DNA methylation remains poorly characterized in NASH. MAIN METHODS: In this study, we established a mouse model of diet-induced NASH, by maintaining male mice on a high-fructose-high-cholesterol diet (HFHC), to generate hepatic steatosis, inflammation and injury. We profiled hepatic gene expression by RNA-Sequencing and locus-specific 5-methylcytosine level, using Whole Genome Bisulfite Sequencing (WGBS). KEY FINDINGS: We identified >1000 differentially methylated regions in NASH versus control group, indicating that NASH diet could modulate the liver methylome. Furthermore, integrated analysis of methylome and transcriptome identified certain key methylated genes and pathways, which may be involved in steroid metabolism and inflammation response. The liver methylation levels of key genes especially Tgfb, Msn, Iqgap1, Cyba, Fcgr1 decreased, and their consequent increased expression may lead to NASH development. SIGNIFICANCE: We found that HFHC diet-induced NASH could induces genome-wide differential DNA methylation changes. Thus, we proposed that DNA methylation profiles of genomes may be a useful signature of gene transcription and may play an important role in the development of NASH. We also screened and validated the changes of key genes, which may provide new perspectives for the mechanistic study of NASH in future.

Progress in overactive bladder: novel avenues from psychology to clinical opinions.

Rationale: Overactive bladder (OAB) is a common, distressing condition that worsens with age and impacts quality of life significantly. As a results of its clinical symptoms, patients suffer from serious physical and mental health issues, have a poor quality of life, and participate in a serious economic burden. The key social-psychological factors include living habits, eating habits, and personality characteristics on this disease, even though the pathogenesis of OAB is complex. However, there is few cognitions and research on OAB in the field of psychology. Methods/Search Strategy: Between 2000 and 2022, two electronic databases were systematically searched in accordance with Cochrane library guidelines (PubMed/Medline, Web of Science). An analysis of the remaining articles with relevant information was conducted using a data extraction sheet. An itemized flow diagram was adopted and used to report systematic reviews and meta-analysis. A systematic review of studies published from 2000 to 2022 in English language were conducted and included in the review. The intended audience: Urological surgeon and psychologists majoring in urinary diseases. Implication: As a result of this information, we are able to develop a better understanding of the role of psychological factors in the development of OAB and suggest potential therapeutic directions for OAB patients. This may benefit the recovery of OAB patients.

Nonalcoholic Fatty Liver Disease and Adverse Pregnancy Outcomes in Women With Normal Prepregnant Weight.

CONTEXT: Existing studies focusing on the effects of nonalcoholic fatty liver disease (NAFLD) combined with normal prepregnant weight on pregnancy outcomes are limited. OBJECTIVE: This study aimed to explore the relationship between maternal NAFLD and adverse pregnancy outcomes in different body mass index (BMI) groups. METHODS: Using an antenatal care and delivery database, we retrospectively analyzed women who delivered in Minhang Hospital affiliated to Fudan University, Shanghai, China from January 1, 2013, to June 30, 2020. NAFLD was confirmed by ultrasound in early pregnancy. A logistic regression model with adjustment for confounders was used to examine potential associations between NAFLD and pregnancy outcomes. RESULTS: A total of 14 708 pregnant women (mean prepregnant BMI 21.0 [SD, 2.8] kg/m2) were included in our final study, of whom 554 (3.8%) had NAFLD. After fully adjusting for potential confounders, NAFLD significantly increased the risk of gestational diabetes mellitus (adjusted odds ratio 2.477; 95% CI, 1.885-3.254), gestational hypertension (3.054; 2.191-4.257), preeclampsia/eclampsia (3.994; 2.591-6.005), cesarean section (1.569; 1.315-1.872), preterm births (1.831; 1.229-2.727), and macrosomia (1.691; 1.300-2.198). It is notable that 83.9% (12 338) of women were of normal weight at the start of pregnancy (prepregnant 18.5 ≤ BMI < 24 kg/m2), and they still had higher odds of adverse pregnancy outcomes. CONCLUSION: Women with NAFLD and a normal weight have a higher risk for adverse pregnancy outcomes. Pregnant women with NAFLD, regardless of obesity status, should be offered a more qualified surveillance to optimize pregnancy outcomes.

Association between white blood cell count and adverse pregnancy outcomes: a retrospective cohort study from a tertiary hospital in China.

OBJECTIVES: This study aimed to clarify the relationship between white blood cell (WBC) and adverse pregnancy outcomes. DESIGN: A total of 25 270 pregnant women underwent peripheral blood white blood cell count tests in the first, second and third trimesters. Adverse pregnancy outcomes were gestational hypertension, pre-eclampsia, gestational diabetes mellitus, preterm birth, low birth weight, caesarean delivery, macrosomia and fetal distress. Due to acute infectious disease or other diseases, 1127 were excluded. SETTING: Minhang Hospital, China. PARTICIPANTS: A total of 24 143 pregnant women were included in this study. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the adverse pregnancy outcomes. RESULTS: For the 24 143 participants, we calculated adjusted ORs for adverse pregnancy outcomes associated with an increased WBC count. For gestational hypertension, the ORs were 1.18 (95% CI, 1.05 to 1.24) in the first trimester and 1.10 (1.06 to 1.13) in the second trimester; for pre-eclampsia, ORs were 1.14 (95% CI, 1.47 to 1.64) in the first trimester and 1.10 (1.05 to 1.16) in the second trimester; for gestational diabetes mellitus, ORs were 1.06 (95% CI, 1.00 to 1.13) in the first trimester and 1.10 (1.04 to 1.16) in the second trimester; for preterm birth, ORs were 1.12 (95% CI, 1.06 to 1.18) in the first trimester, 1.10 (1.06 to 1.13) in the second trimester and 1.12 (1.09 to 1.15) in the third trimester; for low birth weight, ORs were 1.09 (95% CI, 1.02 to 1.17) in the first trimester, 1.03 (0.99 to 1.08) in the second trimester and 1.12 (1.08 to 1.16) in the third trimester. Significant associations were not observed obviously for caesarean delivery, macrosomia and fetal distress. CONCLUSIONS: Our results indicate strong, continuous associations of maternal WBC count with increased risks of adverse pregnancy outcomes.

Early-Life Skin Microbial Biomarkers for Eczema Phenotypes in Chinese Toddlers.

Eczema is a common inflammatory skin disorder during infancy. Evidence has shown that skin-microbiome fluctuations may precede eczema development, but their predictive value for eczema phenotypes remains unknown. We aimed to investigate the early-life evolution of the skin microbiome and its temporal associations with different pairs of eczema phenotypes (transient versus persistent, atopic versus non-atopic) in Chinese children. We followed 119 term Chinese infants from birth to 24 months old within a Hong Kong birth cohort. The skin microbes at the left antecubital fossa were serially sampled by flocked swabs at 1, 6, and 12 months for bacterial 16S rRNA gene sequencing. The atopic sensitization at 12 months was strongly associated with eczema persisting to 24 months (odds ratio 4.95, 95% confidence interval 1.29-19.01). Compared with those with non-atopic eczema, the children with atopic eczema had reduced alpha diversity at 12 months (p < 0.001) and transiently higher abundance of the genus Janibacter at 6 months (p < 0.001). Our findings suggest that atopic sensitization at 12 months may predict persistent eczema by 24 months, and atopic eczema at 12 months is associated with unique skin microbiome profiles at 6 and 12 months. Non-invasive skin-microbiome profiling may have predictive value for atopic eczema.

TDP-43-regulated cryptic RNAs accumulate in Alzheimer's disease brains.

BACKGROUND: Inclusions of TAR DNA-binding protein 43 kDa (TDP-43) has been designated limbic-predominant, age-related TDP-43 encephalopathy (LATE), with or without co-occurrence of Alzheimer's disease (AD). Approximately, 30-70% AD cases present TDP-43 proteinopathy (AD-TDP), and a greater disease severity compared to AD patients without TDP-43 pathology. However, it remains unclear to what extent TDP-43 dysfunction is involved in AD pathogenesis. METHODS: To investigate whether TDP-43 dysfunction is a prominent feature in AD-TDP cases, we evaluated whether non-conserved cryptic exons, which serve as a marker of TDP-43 dysfunction in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP), accumulate in AD-TDP brains. We assessed a cohort of 192 post-mortem brains from three different brain regions: amygdala, hippocampus, and frontal cortex. Following RNA and protein extraction, qRT-PCR and immunoassays were performed to quantify the accumulation of cryptic RNA targets and phosphorylated TDP-43 pathology, respectively. RESULTS: We detected the accumulation of misspliced cryptic or skiptic RNAs of STMN2, KCNQ2, UNC13A, CAMK2B, and SYT7 in the amygdala and hippocampus of AD-TDP cases. The topographic distribution of cryptic RNA accumulation mimicked that of phosphorylated TDP-43, regardless of TDP-43 subtype classification. Further, cryptic RNAs efficiently discriminated AD-TDP cases from controls. CONCLUSIONS: Overall, our results indicate that cryptic RNAs may represent an intriguing new therapeutic and diagnostic target in AD, and that methods aimed at detecting and measuring these species in patient biofluids could be used as a reliable tool to assess TDP-43 pathology in AD. Our work also raises the possibility that TDP-43 dysfunction and related changes in cryptic splicing could represent a common molecular mechanism shared between AD-TDP and FTLD-TDP.

CRISPR interference to evaluate modifiers of C9ORF72-mediated toxicity in FTD.

Treatments for neurodegenerative disease, including Frontotemporal dementia (FTD) and Amyotrophic lateral sclerosis (ALS), remain rather limited, underscoring the need for greater mechanistic insight and disease-relevant models. Our ability to develop novel disease models of genetic risk factors, disease modifiers, and other FTD/ALS-relevant targets is impeded by the significant amount of time and capital required to develop conventional knockout and transgenic mice. To overcome these limitations, we have generated a novel CRISPRi interference (CRISPRi) knockin mouse. CRISPRi uses a catalytically dead form of Cas9, fused to a transcriptional repressor to knockdown protein expression, following the introduction of single guide RNA against the gene of interest. To validate the utility of this model we have selected the TAR DNA binding protein (TDP-43) splicing target, stathmin-2 (STMN2). STMN2 RNA is downregulated in FTD/ALS due to loss of TDP-43 activity and STMN2 loss is suggested to play a role in ALS pathogenesis. The involvement of STMN2 loss of function in FTD has yet to be determined. We find that STMN2 protein levels in familial FTD cases are significantly reduced compared to controls, supporting that STMN2 depletion may be involved in the pathogenesis of FTD. Here, we provide proof-of-concept that we can simultaneously knock down Stmn2 and express the expanded repeat in the Chromosome 9 open reading frame 72 (C9ORF72) gene, successfully replicating features of C9-associated pathology. Of interest, depletion of Stmn2 had no effect on expression or deposition of dipeptide repeat proteins (DPRs), but significantly decreased the number of phosphorylated Tdp-43 (pTdp-43) inclusions. We submit that our novel CRISPRi mouse provides a versatile and rapid method to silence gene expression in vivo and propose this model will be useful to understand gene function in isolation or in the context of other neurodegenerative disease models.

The Predictive Effect of Negative Psychological Emotions of Anxiety and Depression on the Poor Prognosis of CHD Patients with Stent Implantation and the Improvement of Clinical Intervention Measures.

OBJECTIVE: To explore the predictive effect of negative emotions such as anxiety and depression on the poor prognosis of coronary heart disease (CHD) patients with stent implantation and to seek the improvement of clinical intervention measures. METHODS: A total of 303 patients with CHD and PCI were recruited from February 2019 to April 2021. The risk factors of CHD such as anxiety and depression, age, sex, smoking and drinking, BMI, hypertension, diabetes, dyslipidemia, and family history of CHD were collected. Meanwhile, clinical data such as laboratory examination, angiography, diseased vessels, and stent types were collected. The patients were followed up for 1 year, and the medical records, hospitalization records, or death records were checked by telephone interview once a month. Major adverse cardiovascular events (MACE) such as emergency and causes, readmission times and causes, new nonfatal myocardial infarction, stent restenosis, heart failure, arrhythmia, and death were recorded. The incidence of anxiety and depression in patients after PCI was counted, and Cox regression was applied to analyze the influence and prediction of anxiety and depression on MACE in patients with CHD stent implantation and improve clinical intervention measures. RESULTS: Compared with those without MACE, anxiety (56.25% vs 30.63%), depression (62.5% vs 22.88%, P < 0.01), anxiety combined with depression (46.88% vs 15.50%, P < 0.01), and hypertension history (71.8% vs 39.11%, P < 0.01) were more common in patients with MACE. Uncorrected Cox proportional hazard regression found that people with anxiety had a higher risk of developing MACE than those without anxiety (HR 3.181, P < 0.01). Multiple Cox proportional hazard regression analysis of anxiety showed that anxiety was an independent predictor of cumulative MACE (P < 0.01). The risk of developing MACE in patients with anxiety was 3.742 times higher than that in patients without anxiety (P < 0.01). Uncorrected Cox hazard regression analysis showed that people with depression had a higher risk of developing MACE than those without depression (HR 5.434, P < 0.01). Furthermore, the results also uncovered that depression was an independent predictor of cumulative MACE (P < 0.01). The risk of MACE in patients with depression was 3.087 times higher than that in patients without depression (P < 0.01). Cox hazard regression showed that the risk of MACE in patients with anxiety and depression was significantly higher than that in patients without anxiety and depression (HR 4.642, P < 0.01). After screening, it was found that anxiety with depression could predict the occurrence of MACE (P < 0.01). The risk of MACE in patients with anxiety and depression was 3.702 times higher than that in patients without anxiety and depression (P < 0.01). Cox regression analysis showed that the risk of MACE with only anxiety and depression was 2.793 times higher than that without anxiety and depression (95% CI 0.914 8.526), with no statistical significance (P > 0.05), and the risk of MACE with depression without anxiety was significantly higher than that without anxiety and depression (P < 0.01). The risk of MACE in patients with anxiety and depression was 7.303 times higher than that in patients without anxiety and depression (P < 0.01). CONCLUSION: Negative emotions such as anxiety and depression can increase the risk of poor prognosis of patients with CHD. Therefore, in clinical work, in addition to routine treatment and nursing during hospitalization, it is recommended to screen patients with depression in CHD patients. Medical staff should use simple and effective assessment tools in time and take active measures to improve the depression of patients. This trial is registered with ChiCTR2200055645.

Temporal Dynamics of the Nasopharyngeal Microbiome and its Relationship with Childhood Asthma Exacerbation.

Despite distinct nasopharyngeal microbiome (NPM) profiles between asthmatics and healthy subjects, little is known about the NPM dynamics and its relation to childhood asthma exacerbation (AE). We investigated NPM changes by longitudinally collecting 135 flocked nasopharyngeal swabs (FNPSs) from 33 school-age asthmatic children at six time points (2 to 4-week intervals) from September to December 2017 in Hong Kong. Subjects were categorized into AE and stable asthma (AS) groups according to whether they experienced any exacerbation during follow-up. One-off FNPSs from nine nonasthmatic children were included as controls. Microbiota profiles were analyzed using 16S rRNA gene sequencing. All 144 NPMs were classified into six microbiome profile groups (MPGs), each dominated by Moraxella, Corynebacterium 1, Dolosigranulum, Staphylococcus, Streptococcus, or Anoxybacillus. The microbial diversity and compositions of NPM in exacerbation samples were different from both baseline samples and those from healthy controls. Moraxella and Dolosigranulum-dominated NPM exhibited high temporal stability revealed by MPG transition analysis. NPM diversity decreased whereas microbial composition remained similar over time. The relative abundances of Moraxella increased while Corynebacterium 1, Anoxybacillus, and Pseudomonas decreased longitudinally. However, these temporal patterns did not differ between AE and AS groups, suggesting that short-term dynamic patterns were not sufficient to predict AE occurrence. Asthmatic NPM underwent Moraxella expansion during AE and presented a high microbiome resilience (recovery potential) after AE resolution. Microbial pathways involved in methane, ketone bodies, and vitamin B3 metabolisms were enhanced during AE and primarily contributed by Moraxella. IMPORTANCE Evidence on the dynamic changes of NPM in asthmatic patients remains limited. Here, we present that asthmatic NPMs deviating from a healthy status still showed resilience after disturbance. Our data imply from a longitudinal perspective that Moraxella increase is closely related to AE occurrence. The finding of functional dysbiosis (imbalance) during AE offers a plausible explanation for the known association between nasopharyngeal Moraxella expansion and increased AE risk. This work serves as a basis for future long-term prospective studies leveraging multiomics approaches to elucidate the temporal association between NPM and pediatric AE.

Evidence of cerebellar TDP-43 loss of function in FTLD-TDP.

Frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) is a neurodegenerative disease primarily affecting the frontal and/or temporal cortices. However, a growing body of evidence suggests that the cerebellum contributes to biochemical, cognitive, and behavioral changes in FTLD-TDP. To evaluate cerebellar TDP-43 expression and function in FTLD-TDP, we analyzed TDP-43 protein levels and the splicing of a TDP-43 target, STMN2, in the cerebellum of 95 FTLD-TDP cases and 25 non-neurological disease controls. Soluble TDP-43 was decreased in the cerebellum of FTLD-TDP cases but a concomitant increase in insoluble TDP-43 was not seen. Truncated STMN2 transcripts, an indicator of TDP-43 dysfunction, were elevated in the cerebellum of FTLD-TDP cases and inversely associated with TDP-43 levels. Additionally, lower cerebellar TDP-43 associated with a younger age at disease onset. We provide evidence of TDP-43 loss of function in the cerebellum in FTLD-TDP, supporting further investigation into this understudied brain region.

Neurofilament light chain and vaccination status associate with clinical outcomes in severe COVID-19.

Blood neurofilament light chain (NFL) is proposed to serve as an estimate of disease severity in hospitalized patients with coronavirus disease 2019 (COVID-19). We show that NFL concentrations in plasma collected from 880 patients with COVID-19 within 5 days of hospital admission were elevated compared to controls. Higher plasma NFL associated with worse clinical outcomes including the need for mechanical ventilation, intensive care, prolonged hospitalization, and greater functional disability at discharge. No difference in the studied clinical outcomes between black/African American and white patients was found. Finally, vaccination associated with less disability at time of hospital discharge. In aggregate, our findings support the utility of measuring NFL shortly after hospital admission to estimate disease severity and show that race does not influence clinical outcomes caused by COVID-19 assuming equivalent access to care, and that vaccination may lessen the degree of COVID-19-caused disability.