Papers by Sergio Baranzini
Gene PSEVs created using v2 of SPOKE. Probability of random jump = 0.1
Gene sets are retrieved from WikiPathways and MSigDB v5.0 and combined into a single tsv.
<p>In this fileset we provide our processed forms of the LINCS L1000 data. Starting with si... more <p>In this fileset we provide our processed forms of the LINCS L1000 data. Starting with signature-level expression data from the L1000 project, we employ our pipeline (link below) to condense this information to consensus drug-level expression signatures.</p> <p> </p> <p>For a detailed overview of our approach, see the appended thinklab discussion link. In brief, our approach has 3 steps. (1) Pool set of LINCS gold signatures corresponding to drug of interest. (2) Compute weights for each signature, based on their mean Spearman correlation values with all other signatures. (3) Combine Z-scores across all signatures using Stouffer's method to create a consensus signature.</p> <p> </p> <p>These drug-level consensus signatures are provided in two drug vocabularies: LINCS perturbagens and DrugBank compounds. Rows are drugs, and columns are genes (Entrez Gene IDs). The values in both files are Z-scores, as per the LINCS L1000 standard. </p
This collection contains figshare uploads created during the course of the Rephetio project, whic... more This collection contains figshare uploads created during the course of the Rephetio project, which constructed an integrative hetnet for drug repurposing.
F1000Research, 2020
Background: Severe coronavirus disease 2019 (COVID-19) is associated with multiple comorbidities ... more Background: Severe coronavirus disease 2019 (COVID-19) is associated with multiple comorbidities and is characterized by an auto-aggressive inflammatory state leading to massive collateral damage. To identify preventive and therapeutic strategies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is important to ascertain the molecular interactions between virus and host, and how they translate into disease pathophysiology. Methods: We matched virus-human protein interactions of human coronaviruses and other respiratory viruses with lists of genes associated with autoimmune diseases and comorbidities associated to worse COVID-19 course. We then selected the genes included in the statistically significant intersection between SARS-CoV-2 network and disease associated gene sets, identifying a meta-interactome. We analyzed the meta-interactome genes expression in samples derived from lungs of infected humans, and their regulation by IFN-β. Finally, we performed a ...
The SARS-Cov-2 virus, which causes COVID 19, uses the cell surface protein ACE2 as receptor for e... more The SARS-Cov-2 virus, which causes COVID 19, uses the cell surface protein ACE2 as receptor for entry into cells. Critically ill COVID-19 patients often require prolonged mechanical ventilation which can cause mechanical stress to lung tissue. In vitro studies have shown that expression of ACE2 in alveolar cells is increased following mechanical stretch and inflammation. Therefore, we analyzed transcriptome datasets of 480 (non-COVID-19) lung tissues in the GTex tissue gene expression database. We found that mechanical ventilation of the tissue donors increased the expression of ACE2 by more than two-fold (p<10-6). Analysis of transcriptomes of mechanically ventilated mice deposited in the GEO database indicates that this alveolar cell response to stretch and inflammation is mediated by the chemokine midkine. We also found in transcriptomes of the LINCS database of pharmacological perturbations that corticosteroids down-regulate midkine in pulmonal cells, consistent with transcri...
Vitamin D deficiency is a major environmental risk factor for the development of multiple scleros... more Vitamin D deficiency is a major environmental risk factor for the development of multiple sclerosis (MS). The major circulating metabolite of vitamin D (25OHD) is converted to the active form (calcitriol) by the hydroxylase enzyme CYP27B1. In MS lesions the tyrosine kinase MerTK expressed by microglia and macrophages regulates phagocytosis of myelin debris and apoptotic cells that can accumulate and inhibit tissue repair and remyelination. We show that calcitriol downregulates MerTK mRNA and protein expression in adult human microglia and monocyte-derived macrophages, thereby inhibiting myelin phagocytosis and apoptotic cell clearance. Proinflammatory myeloid cells express high levels of CYP27B1 compared to homeostatic (TGFβ-treated) myeloid cells. Only proinflammatory cells in the presence of TNF-α generate calcitriol from 25OHD, resulting in repression of MerTK expression and function. The selective production of calcitriol in proinflammatory myeloid cells leading to downregulatio...
Neurology. Genetics, 2018
The neuroanatomical profile of behavioral variant frontotemporal dementia (bvFTD) suggests a comm... more The neuroanatomical profile of behavioral variant frontotemporal dementia (bvFTD) suggests a common biological etiology of disease despite disparate pathologic causes; we investigated the genetic underpinnings of this selective regional vulnerability to identify new risk factors for bvFTD. We used recently developed analytical techniques designed to address the limitations of genome-wide association studies to generate a protein interaction network of 63 bvFTD risk genes. We characterized this network using gene expression data from healthy and diseased human brain tissue, evaluating regional network expression patterns across the lifespan as well as the cell types and biological processes most affected in bvFTD. We found that bvFTD network genes show enriched expression across the human lifespan in vulnerable neuronal populations, are implicated in cell signaling, cell cycle, immune function, and development, and are differentially expressed in pathologically confirmed frontotempor...
Journal of Allergy and Clinical Immunology, 2017
Mesenchymal stem cells (MSC) display a therapeutic plasticity, due to their ability to modulate i... more Mesenchymal stem cells (MSC) display a therapeutic plasticity, due to their ability to modulate immunity, foster tissue repair and differentiate into mesodermal cells. IFNγ has been described to differently affect human and mouse MSC immunomodulation and differentiation, depending on the inflammatory milieu. We aimed at dissecting the relevant intracellular pathways through which IFNγ affects MSC plasticity and the consequence of their manipulation on MSC functions. Modification of relevant IFNγ-dependent pathways in mouse MSC was carried out in vitro through gene silencing or chemical inhibition of key components. Functional outcomes were assessed by western blotting, real-time PCR, differentiation and proliferation assays on MSC. The impact on T cells was addressed by T-cell proliferation assays; the effect of mTOR manipulation in MSC was studied in vivo in a mouse model of delayed-type hypersensitivity assay (DTH). To address whether similar mechanisms are involved also in human MSC upon IFNγ stimulation, the effect of chemical inhibition on the same intracellular pathways was assessed by western blotting and the final outcome on immunomodulatory properties evaluated by real-time PCR and on T-cell proliferation. We revealed that, in mouse MSC, IFNγ-induced immunoregulation is mediated by an early phosphorylation of STAT1 and STAT3, significantly enhanced by an ERK1/2-dependent mTOR inhibition, thereby promoting pSTAT1 nuclear translocation. Accordingly, following intracellular mTOR inhibition, MSC augmented their ability to inhibit T cell proliferation and control DTH in vivo. Similarly, upon mTOR blockade, human MSC also enhanced their immunoregulatory features. A sustained exposure to IFNγ lead to inhibition of STAT3 activity, which, in mouse MSC resulted in an impaired proliferation and differentiation. These results provide new insights about MSC intracellular pathways affected by IFNγ, demonstrating that pharmacological or genetic manipulation of MSC may enhance their immunomodulatory functions, which could be translated into novel therapeutic approaches.
Science translational medicine, Jan 11, 2015
Early regulators of disease may increase understanding of disease mechanisms and serve as markers... more Early regulators of disease may increase understanding of disease mechanisms and serve as markers for presymptomatic diagnosis and treatment. However, early regulators are difficult to identify because patients generally present after they are symptomatic. We hypothesized that early regulators of T cell-associated diseases could be found by identifying upstream transcription factors (TFs) in T cell differentiation and by prioritizing hub TFs that were enriched for disease-associated polymorphisms. A gene regulatory network (GRN) was constructed by time series profiling of the transcriptomes and methylomes of human CD4(+) T cells during in vitro differentiation into four helper T cell lineages, in combination with sequence-based TF binding predictions. The TFs GATA3, MAF, and MYB were identified as early regulators and validated by ChIP-seq (chromatin immunoprecipitation sequencing) and small interfering RNA knockdowns. Differential mRNA expression of the TFs and their targets in T c...
PloS one, 2015
Genotyping chips for rare and low-frequent variants have recently gained popularity with the intr... more Genotyping chips for rare and low-frequent variants have recently gained popularity with the introduction of exome chips, but the utility of these chips remains unclear. These chips were designed using exome sequencing data from mainly American-European individuals, enriched for a narrow set of common diseases. In addition, it is well-known that the statistical power of detecting associations with rare and low-frequent variants is much lower compared to studies exclusively involving common variants. We developed a simulation program adaptable to any exome chip design to empirically evaluate the power of the exome chips. We implemented the main properties of the Illumina HumanExome BeadChip array. The simulated data sets were used to assess the power of exome chip based studies for varying effect sizes and causal variant scenarios. We applied two widely-used statistical approaches for rare and low-frequency variants, which collapse the variants into genetic regions or genes. Under op...
Nature reviews. Neurology, 2010
Multiple sclerosis (MS) is a common and severe CNS disorder that is characterized by myelin loss,... more Multiple sclerosis (MS) is a common and severe CNS disorder that is characterized by myelin loss, chronic inflammation, axonal and oligodendrocyte pathology, and progressive neurological dysfunction. Extensive epidemiological data confirm that genetic variation is an important determinant of susceptibility to MS, and suggest that such variation also influences the timing of symptom onset, the course of the disease, and the treatment response. Multicenter international collaborations have allowed large and well-characterized sample collections to be assembled that, when coupled with high-powered laboratory technologies, afford the opportunity to analyze the genome with increasing resolution and detail. The seven MS genome-wide association screens that have been completed in the past 3 years have substantially lengthened the list of MS genetic risk associations. Nevertheless, our knowledge of MS genetics remains incomplete, with many risk alleles still to be revealed, although progres...
Journal of Neuroimmunology, 2014
2006 International Conference of the IEEE Engineering in Medicine and Biology Society, 2006
Genome medicine, 2014
Many common diseases, such as asthma, diabetes or obesity, involve altered interactions between t... more Many common diseases, such as asthma, diabetes or obesity, involve altered interactions between thousands of genes. High-throughput techniques (omics) allow identification of such genes and their products, but functional understanding is a formidable challenge. Network-based analyses of omics data have identified modules of disease-associated genes that have been used to obtain both a systems level and a molecular understanding of disease mechanisms. For example, in allergy a module was used to find a novel candidate gene that was validated by functional and clinical studies. Such analyses play important roles in systems medicine. This is an emerging discipline that aims to gain a translational understanding of the complex mechanisms underlying common diseases. In this review, we will explain and provide examples of how network-based analyses of omics data, in combination with functional and clinical studies, are aiding our understanding of disease, as well as helping to prioritize ...
Neurobiology of Aging, 2015
Although numerous genetic variants affecting aging and mortality have been identified, for exampl... more Although numerous genetic variants affecting aging and mortality have been identified, for example, apolipoprotein E ε4, the genetic component influencing cognitive aging has not been fully defined yet. A better knowledge of the genetics of aging will prove helpful in understanding the underlying biological processes. Here, we describe the whole genome sequences of 2 female octogenarians. We provide the repertoire of genomic variants that the 2 octogenarians have in common. We also describe the overlap with the previously reported genomes of 2 supercentenariansdindividuals aged !110 years. We assessed the genetic disease propensities of the octogenarians and non-aged control genomes and could not find support for the hypothesis that long-lived healthy individuals might exhibit greater genetic fitness than the general population. Furthermore, there is no evidence for an accumulation of previously described variants promoting longevity in the 2 octogenarians. These findings suggest that genetic fitness, as currently defined, is not the sole factor enabling an increased life span. We identified a number of healthy-cognitive-aging candidate genetic loci awaiting confirmation in larger studies.
Nature Genetics, 2013
Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis... more Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
Journal of Neuroimmunology, 2012
New &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;omi... more New &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;omic&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; technologies and their application to systems biology approaches offer new opportunities for biomarker discovery in complex disorders, including multiple sclerosis (MS). Recent studies using massive genotyping, DNA arrays, antibody arrays, proteomics, glycomics, and metabolomics from different tissues (blood, cerebrospinal fluid, brain) have identified many molecules associated with MS, defining both susceptibility and functional targets (e.g., biomarkers). Such discoveries involve many different levels in the complex organizational hierarchy of humans (DNA, RNA, protein, etc.), and integrating these datasets into a coherent model with regard to MS pathogenesis would be a significant step forward. Given the dynamic and heterogeneous nature of MS, validating biomarkers is mandatory. To develop accurate markers of disease prognosis or therapeutic response that are clinically useful, combining molecular, clinical, and imaging data is necessary. Such an integrative approach would pave the way towards better patient care and more effective clinical trials that test new therapies, thus bringing the paradigm of personalized medicine in MS one step closer.
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Papers by Sergio Baranzini