Project description:Molecular mechanisms that influence susceptibility to multiple sclerosis are poorly understood. We conducted a gene expression study in healthy subjects that subsequently developed the disease. Gene expression profiles (HG U133A and A2, Affymetrix, 22,215 transcripts) of peripheral blood mononuclear cells were analyzed in 9 healthy subjects (mean age 19.8+1.1 years) up to 9 years (mean 5.1±1.2 years) before onset of MS (MS to be, MS2b), 11 age-, gender-, and origin-matched subjects that remained MS-free (MSf), and 31 clinically isolated syndrome (CIS) patients. Most informative genes (p<0.05) and significant biological processes were compared. 1051 genes (611 up-regulated, 440 down-regulated) were significantly different between MS2b and MSf subjects. MS2b signature was characterized by down-regulation of the nuclear receptor (NR) family genes including NR subfamily 4 group A member1 (NR4A1, p=0.01), member 3 (NR4A3, p=0.01), NR subfamily 2 group F member 2 (NR2F1, p=0.03) and vitamin D receptor (VDR, p=0.02), all known to be involved in T-cell regulation by apoptosis. Comparison between MS2b and CIS operating networks demonstrated evolution of the altered NR dependent apoptosis regulation. Decreased NR4A1 expression was verified at the mRNA and protein level in an independent cohort of 20 relapsing-remitting MS patients. The identified MS trait is associated with suppressed transcription of NR networks that leads to altered apoptosis of activated T cells and the development of clinical disease. MS2b subjects have already an ongoing process that eventually will lead to clinical disease and our finding are of importance as they suggest the possibility of early detection and prevention of MS. Keywords: disease state analysis Blood samples of healthy subjects that later developed MS (MS-to-be, MS2b, N=9) were identified and used for gene expression study. For each sample of MS2b subject, a sample of an age and gender matched subject that remained MS-free (MSf, N=11) was randomly selected. A cohort of 31 CIS patients who gave blood sample for gene expression analysis within 3 months of the onset of their first neurological event, was used for comparison with the MS2b gene expression signature. For establishment of the CIS gene expression signature, microarray data from 13 age- and sex- matched healthy subjects were used.

Project description:The exact role of epigenetics in the pathogenesis of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) is unclear. Herein we have hypothesized that viral micro RNAs (miRNAs) may modulate host cellular and immune responses which may lead to varied clinical presentations. Using bioinformatics tools, we have first predicted putative miRNAs in the genotype of the SARS-CoV-2 and their potential gene targets. Thereafter, quantification of mRNA of key genes regulating inflammation, coagulation, neuropsychiatric functions, fibrosis and glucose metabolism was evaluated in the peripheral blood mononuclear cells and bone marrow of patients suffering from different severities of SARS-CoV-2 infection. Key genes regulating innate immunity, lymphopoiesis, T-cell and B-cell development, cytokine storm, coagulation pathways, fibrosis, neuropsychiatric manifestations, glucose metabolism, and olfaction were significantly downregulated in severe infection when compared with mild infection. Downregulated genes mRNA recovered to normal/near normal levels on recovery from infection. SARS-CoV-2 miRNAs appear promising players in the pathogenesis of COVID-19. Strategies silencing these miRNAs may be explored further as potential therapeutic targets. Patients with severe illness were defined as: respiratory rate ≥30 per min or SpO2 <90% in ambient air, or acute respiratory distress syndrome or septic shock and those with mild illness as: patients with any of the symptoms like fever, cough, sore throat, malaise, headache, muscle pain, nausea, vomiting, diarrhea, loss of taste and smell, but no dyspnea, or abnormal chest imaging. There were 4 severe SARS CoV-2 patients, Median age 57.5 years (Range 50-72 years), all males, median disease duration 7.5 days, duration of hospital stay 38 days with outcome as 3 deaths and one Post covid lung fibrosis. All 4 mild cases had median age 55.5 years (range 42-0 years), 3 males and one female, mean disease duration 2.8 days, mean duration of hospitalization 14.5 days and all recovered. Median age of all 4 recovered cases was 59 years (range 43-77 years), 3 males and one female, mean disease duration of 6 days, mean disease duration of 22 days and all recovered. There were 4 healthy subjects with median age 50 years (range 42-54 years) and there were 3 males and one female. All 3 patients who underwent bone marrow examination had severe Covid-19 and were different then the ones whose peripheral blood was analyed by qRT-PCR. Amongst Disease control subjects (n=3) who underwent bone marrow examination, two had adult onset immune thrombocytopenia and one had a suspicion of myelodysplastic syndrome which was reported to be normal.

Project description:The exact role of epigenetics in the pathogenesis of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) is unclear. Herein we have hypothesized that viral micro RNAs (miRNAs) may modulate host cellular and immune responses which may lead to varied clinical presentations. Using bioinformatics tools, we have first predicted putative miRNAs in the genotype of the SARS-CoV-2 and their potential gene targets. Thereafter, quantification of mRNA of key genes regulating inflammation, coagulation, neuropsychiatric functions, fibrosis and glucose metabolism was evaluated in the peripheral blood mononuclear cells and bone marrow of patients suffering from different severities of SARS-CoV-2 infection. Key genes regulating innate immunity, lymphopoiesis, T-cell and B-cell development, cytokine storm, coagulation pathways, fibrosis, neuropsychiatric manifestations, glucose metabolism, and olfaction were significantly downregulated in severe infection when compared with mild infection. Downregulated genes mRNA recovered to normal/near normal levels on recovery from infection. SARS-CoV-2 miRNAs appear promising players in the pathogenesis of COVID-19. Strategies silencing these miRNAs may be explored further as potential therapeutic targets. Patients with severe illness were defined as: respiratory rate ≥30 per min or SpO2 <90% in ambient air, or acute respiratory distress syndrome or septic shock and those with mild illness as: patients with any of the symptoms like fever, cough, sore throat, malaise, headache, muscle pain, nausea, vomiting, diarrhea, loss of taste and smell, but no dyspnea, or abnormal chest imaging. There were 4 severe SARS CoV-2 patients, Median age 57.5 years (Range 50-72 years), all males, median disease duration 7.5 days, duration of hospital stay 38 days with outcome as 3 deaths and one Post covid lung fibrosis. All 4 mild cases had median age 55.5 years (range 42-0 years), 3 males and one female, mean disease duration 2.8 days, mean duration of hospitalization 14.5 days and all recovered. Median age of all 4 recovered cases was 59 years (range 43-77 years), 3 males and one female, mean disease duration of 6 days, mean disease duration of 22 days and all recovered. There were 4 healthy subjects with median age 50 years (range 42-54 years) and there were 3 males and one female.

Project description:Background: Major Depressive Disorder (MDD) is a moderately heritable disorder with a high lifetime prevalence. At present, laboratory blood tests to support MDD diagnosis are not available. Methods: We used a classifier approach on blood gene expression profiles of a unique set of non-medicated subjects (MDD patients and controls) to select genes of which expression is predictive for disease status. To reveal blood gene expression changes related to MDD disease, we applied a powerful ex vivo stimulus to the blood, i.e. incubation with lipopolysaccharide (LPS; 10 ng/ml blood). Results: Based on LPS-stimulated blood gene expression using whole-genome microarrays in 42 subjects (primary cohort; 21 MDD patients (mean age 42.3 years), 21 healthy controls (mean age 41.9 years)), we identified a set of genes (CAPRIN1, CLEC4A, KRT23, MLC1, PLSCR1, PROK2, ZBTB16) that serves as a molecular signature of MDD. These findings were validated for the primary cohort using an independent quantitative PCR method (P = 0.007). The difference between depressive patients and controls was confirmed (P = 0.019) in a replication cohort of 13 patients with MDD (mean age 42.8 years) and 14 controls (mean age 45.6 years). The MDD-signature score comprised of expression levels of 7 genes could discriminate depressive patients from controls with sensitivity of 76.9% and specificity of 71.8%. Conclusions: We show for the first time that molecular analysis of stimulated blood cells can be used as an endophenotype for MDD diagnosis, which is a milestone in establishing biomarkers for neuropsychiatric disorders with moderate heritability in general. Our results may provide a new entry point for following and predicting treatment outcome, as well as prediction of severity and recurrence of MDD. In total, 33 MDD patients and 34 healthy controls were analyzed using basal gene expression in whole blood, and gene expression from whole blood that was stimulated with LPS for 5-6 h, using microarrays. Patients were arbitrarily selected from all patients to serve as primary cohort (nMDD = 21 (MDD01-MDD21); nControls = 21 (Con01-Con21)), or replication cohort (nMDD = 12 (MDD22-MDD35); nControls = 13 (Con22-Con37)) using microarrays. This submission does not include Samples CON21_LPS or CON30_LPS.

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The trait of MS: Altered transcription regulation of nuclear receptors networks operate in the pre-disease state

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