Brain high-throughput multi-omics data reveal molecular heterogeneity in Alzheimer's disease.

Unbiased data-driven omic approaches are revealing the molecular heterogeneity of Alzheimer disease. Here, we used machine learning approaches to integrate high-throughput transcriptomic, proteomic, metabolomic, and lipidomic profiles with clinical and neuropathological data from multiple human AD cohorts. We discovered 4 unique multimodal molecular profiles, one of them showing signs of poor cognitive function, a faster pace of disease progression, shorter survival with the disease, severe neurodegeneration and astrogliosis, and reduced levels of metabolomic profiles. We found this molecular profile to be present in multiple affected cortical regions associated with higher Braak tau scores and significant dysregulation of synapse-related genes, endocytosis, phagosome, and mTOR signaling pathways altered in AD early and late stages. AD cross-omics data integration with transcriptomic data from an SNCA mouse model revealed an overlapping signature. Furthermore, we leveraged single-nuclei RNA-seq data to identify distinct cell-types that most likely mediate molecular profiles. Lastly, we identified that the multimodal clusters uncovered cerebrospinal fluid biomarkers poised to monitor AD progression and possibly cognition. Our cross-omics analyses provide novel critical molecular insights into AD.

Trends in medical students' health over 5 years: Does a wellbeing curriculum make a difference?

BACKGROUND: Trends in New Zealand (NZ) medical students' health and the influence of a wellbeing curricula are unknown. METHODS: The author's collected self-report data from NZ medical students on 'Graduation Day' from 2014 to 2018, using a serial cross-sectional survey design with validated scales assessing psychological health, stigma, coping, and lifestyle. Comparisons were made with NZ general population same-age peers. Analyses examined trends, differences between 'cohorts' of students receiving different exposures to a wellbeing curriculum, and correlations between students' own lifestyle practices and their frequency of talking with patients about those topics. RESULTS: Of 1,062 students, 886 participated. The authors found statistically significant self-reported increases from 2014 to 2018 for negative psychological indices, including scores for distress and burnout, suicidal thoughts in the preceding year, and the likelihood of being diagnosed with an anxiety disorder. There was a significant increase in numbers of students reporting having their own doctor as well as increased healthy coping strategies and a significant decrease in stigma scores. Academic cohorts of students who had completed a wellbeing curriculum were more likely to report high distress levels, having been diagnosed with a mood disorder, and being non-drinkers than students without wellbeing training. When compared to NZ peers, medical students smoked less, exercised more, and were less likely to have diagnosed mood and anxiety disorders, but reported more distress. The authors found a significant correlation between the amount of exercise students undertook and their likelihood to discuss exercise with patients. CONCLUSIONS: NZ medical students have better physical health than general population peers and are more likely to discuss exercise with patients if exercising themselves. However, cohorts of graduating students report increasing distress despite the implementation of a wellbeing curriculum. Research is needed into mechanisms between students' self-awareness, willingness to report distress, stigma, mind-set, coping, and psychological outcomes, to inform curriculum developers.

Weakly activated core neuroinflammation pathways were identified as a central signaling mechanism contributing to the chronic neurodegeneration in Alzheimer's disease.

Objectives: Neuroinflammation signaling has been identified as an important hallmark of Alzheimer's disease (AD) in addition to amyloid ß plaques (Aß) and neurofibrillary tangles (NFTs). However, the molecular mechanisms and biological processes of neuroinflammation remain unclear and have not well delineated using transcriptomics data available. Our objectives are to uncover the core neuroinflammation signaling pathways in AD using integrative network analysis on the transcriptomics data. Materials and methods: From a novel perspective, i.e., investigating weakly activated molecular signals (rather than the strongly activated molecular signals), we developed integrative and systems biology network analysis to uncover potential core neuroinflammation signaling targets and pathways in AD using the two large-scale transcriptomics datasets, i.e., Mayo Clinic (77 controls and 81 AD samples) and ROSMAP (97 controls and 260 AD samples). Results: Our analysis identified interesting core neuroinflammation signaling pathways, which are not systematically reported in the previous studies of AD. Specifically, we identified 7 categories of signaling pathways implicated on AD and related to virus infection: immune response, x-core signaling, apoptosis, lipid dysfunctional, biosynthesis and metabolism, and mineral absorption signaling pathways. More interestingly, most of the genes in the virus infection, immune response, and x-core signaling pathways are associated with inflammation molecular functions. The x-core signaling pathways were defined as a group of 9 signaling proteins: MAPK, Rap1, NF-kappa B, HIF-1, PI3K-Akt, Wnt, TGF-beta, Hippo, and TNF, which indicated the core neuroinflammation signaling pathways responding to the low-level and weakly activated inflammation and hypoxia and leading to the chronic neurodegeneration. It is interesting to investigate the detailed signaling cascades of these weakly activated neuroinflammation signaling pathways causing neurodegeneration in a chronic process, and consequently uncover novel therapeutic targets for effective AD treatment and prevention. Conclusions: The potential core neuroinflammation and associated signaling targets and pathways were identified using integrative network analysis on two large-scale transcriptomics datasets of AD.

Tumor Necrosis Factor dynamically regulates the mRNA stabilome in rheumatoid arthritis fibroblast-like synoviocytes.

During rheumatoid arthritis (RA), Tumor Necrosis Factor (TNF) activates fibroblast-like synoviocytes (FLS) inducing in a temporal order a constellation of genes, which perpetuate synovial inflammation. Although the molecular mechanisms regulating TNF-induced transcription are well characterized, little is known about the impact of mRNA stability on gene expression and the impact of TNF on decay rates of mRNA transcripts in FLS. To address these issues we performed RNA sequencing and genome-wide analysis of the mRNA stabilome in RA FLS. We found that TNF induces a biphasic gene expression program: initially, the inducible transcriptome consists primarily of unstable transcripts but progressively switches and becomes dominated by very stable transcripts. This temporal switch is due to: a) TNF-induced prolonged stabilization of previously unstable transcripts that enables progressive transcript accumulation over days and b) sustained expression and late induction of very stable transcripts. TNF-induced mRNA stabilization in RA FLS occurs during the late phase of TNF response, is MAPK-dependent, and involves several genes with pathogenic potential such as IL6, CXCL1, CXCL3, CXCL8/IL8, CCL2, and PTGS2. These results provide the first insights into genome-wide regulation of mRNA stability in RA FLS and highlight the potential contribution of dynamic regulation of the mRNA stabilome by TNF to chronic synovitis.

Prolonged tumor necrosis factor α primes fibroblast-like synoviocytes in a gene-specific manner by altering chromatin.

OBJECTIVE: During the course of rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) are chronically exposed to an inflammatory milieu. The purpose of this study was to test the hypothesis that prolonged exposure of FLS to tumor necrosis factor α (TNFα) augments inflammatory responses to secondary stimuli (priming effect). METHODS: FLS obtained from RA patients were exposed to TNFα for 3 days and were then stimulated with interferons (IFNs). Expression of IFN target genes was measured by real-time quantitative reverse transcription-polymerase chain reaction analysis and enzyme-linked immunosorbent assay. Total STAT-1 protein and IFN-mediated STAT-1 activation were evaluated by Western blotting. Total histone levels, histone acetylation, and NF-κB p65 and RNA polymerase II (Pol II) recruitment were measured at the CXCL10 promoter (encodes IFNγ-inducible 10-kd protein [IP-10]) by chromatin immunoprecipitation assays. RESULTS: Prolonged pre-exposure of FLS to TNFα enhanced the magnitude and extended the kinetics of CXCL10/IP-10, CXCL9, and CXCL11 production upon subsequent IFN stimulation. This phenotype was retained over a period of days, even after the removal of TNFα. Prolonged TNFα exposure decreased histone levels, increased acetylation of the remaining histones, and heightened recruitment of NF-κB p65 and Pol II to the CXCL10 promoter. In parallel, an increase in intracellular STAT-1 led to amplification of IFN-induced STAT-1 activation. CONCLUSION: Our study reveals a novel pathogenic function of TNFα, namely, prolonged and gene-specific priming of FLS for enhanced transcription of inflammatory chemokine genes due to the priming of chromatin, the sustained activation of NF-κB, and the amplification of STAT-1 activation downstream of IFNs. These data also suggest that FLS gain an "inflammatory memory" upon prolonged exposure to TNFα.