Viral activation and ecological restructuring characterize a microbiome axis of spaceflight-associated immune activation.

Maintenance of astronaut health during spaceflight will require monitoring and potentially modulating their microbiomes, which play a role in some space-derived health disorders. However, documenting the response of microbiota to spaceflight has been difficult thus far due to mission constraints that lead to limited sampling. Here, we executed a six-month longitudinal study centered on a three-day flight to quantify the high-resolution microbiome response to spaceflight.

Systems modeling of metabolic dysregulation in neurodegenerative diseases.

Neurodegenerative diseases (NDDs) encompass a wide range of conditions that arise owing to progressive degeneration and the ultimate loss of nerve cells in the brain and peripheral nervous system. NDDs such as Alzheimer's, Parkinson's, and Huntington's diseases negatively impact both length and quality of life, due to lack of effective disease-modifying treatments. Herein, we review the use of genome-scale metabolic models, network-based approaches, and integration with multiomics data to identify key biological processes that characterize NDDs.

The viral hypothesis: how herpesviruses may contribute to Alzheimer's disease.

The hypothesis that infectious agents, particularly herpesviruses, contribute to Alzheimer's disease (AD) pathogenesis has been investigated for decades but has long engendered controversy. In the past 3 years, several studies in mouse models, human tissue models, and population cohorts have reignited interest in this hypothesis. Collectively, these studies suggest that many of the hallmarks of AD, like amyloid beta production and neuroinflammation, can arise as a protective response to acute infection that becomes maladaptive in the case of chronic infection.

miR155 regulation of behavior, neuropathology, and cortical transcriptomics in Alzheimer's disease.

MicroRNAs are recognized as important regulators of many facets of physiological brain function while also being implicated in the pathogenesis of several neurological disorders. Dysregulation of miR155 is widely reported across a variety of neurodegenerative conditions, including Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, and traumatic brain injury. In previous work, we observed that experimentally validated miR155 gene targets were consistently enriched among genes identified as differentially expressed across multiple brain tissue and disease contexts.

A Novel Approach to Safer Glucocorticoid Receptor-Targeted Anti-lymphoma Therapy via REDD1 (Regulated in Development and DNA Damage 1) Inhibition.

Glucocorticoids are widely used for therapy of hematologic malignancies. Unfortunately, chronic treatment with glucocorticoids commonly leads to adverse effects including skin and muscle atrophy and osteoporosis. We found recently that REDD1 (regulated in development and DNA damage 1) plays central role in steroid atrophy.

Systematic Analysis of Environmental Chemicals That Dysregulate Critical Period Plasticity-Related Gene Expression Reveals Common Pathways That Mimic Immune Response to Pathogen.

The tens of thousands of industrial and synthetic chemicals released into the environment have an unknown but potentially significant capacity to interfere with neurodevelopment. Consequently, there is an urgent need for systematic approaches that can identify disruptive chemicals. Little is known about the impact of environmental chemicals on critical periods of developmental neuroplasticity, in large part, due to the challenge of screening thousands of chemicals.

Do infections have a role in the pathogenesis of Alzheimer disease?

The idea that infectious agents in the brain have a role in the pathogenesis of Alzheimer disease (AD) was proposed nearly 30 years ago. However, this theory failed to gain substantial traction and was largely disregarded by the AD research community for many years. Several recent discoveries have reignited interest in the infectious theory of AD, culminating in a debate on the topic at the Alzheimer's Association International Conference (AAIC) in July 2019.

Sexual dimorphism in atrophic effects of topical glucocorticoids is driven by differential regulation of atrophogene REDD1 in male and female skin.

Topical glucocorticoids, well-known anti-inflammatory drugs, induce multiple adverse effects, including skin atrophy. The sex-specific effects of systemic glucocorticoids are known, but sexual dimorphism of therapeutic and side effects of topical steroids has not been studied. We report here that female and male mice were equally sensitive to the anti-inflammatory effect of glucocorticoid fluocinolone acetonide (FA) in ear edema test.

Integrative transcriptome imputation reveals tissue-specific and shared biological mechanisms mediating susceptibility to complex traits.

Transcriptome-wide association studies integrate gene expression data with common risk variation to identify gene-trait associations. By incorporating epigenome data to estimate the functional importance of genetic variation on gene expression, we generate a small but significant improvement in the accuracy of transcriptome prediction and increase the power to detect significant expression-trait associations. Joint analysis of 14 large-scale transcriptome datasets and 58 traits identify 13,724 significant expression-trait associations that converge on biological processes and relevant phenotypes in human and mouse phenotype databases.

Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits.

Background: Genetic loss-of-function variants (LoFs) associated with disease traits are increasingly recognized as critical evidence for the selection of therapeutic targets. We integrated the analysis of genetic and clinical data from 10,511 individuals in the Mount Sinai BioMe Biobank to identify genes with loss-of-function variants (LoFs) significantly associated with cardiovascular disease (CVD) traits, and used RNA-sequence data of seven metabolic and vascular tissues isolated from 600 CVD patients in the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) study for validation. We also carried out in vitro functional studies of several candidate genes, and in vivo studies of one gene.

Genome-wide analysis indicates association between heterozygote advantage and healthy aging in humans.

Background: Genetic diversity is known to confer survival advantage in many species across the tree of life. Here, we hypothesize that such pattern applies to humans as well and could be a result of higher fitness in individuals with higher genomic heterozygosity.

Results: We use healthy aging as a proxy for better health and fitness, and observe greater heterozygosity in healthy-aged individuals.

Systems Pharmacology Identifies an Arterial Wall Regulatory Gene Network Mediating Coronary Artery Disease Side Effects of Antiretroviral Therapy.

Background: Antiretroviral therapy (ART) for HIV infection increases risk for coronary artery disease (CAD), presumably by causing dyslipidemia and increased atherosclerosis. We applied systems pharmacology to identify and validate specific regulatory gene networks through which ART drugs may promote CAD.

Methods: Transcriptional responses of human cell lines to 15 ART drugs retrieved from the Library of Integrated Cellular Signatures (overall 1127 experiments) were used to establish consensus ART gene/transcriptional signatures.

PI3K inhibitors protect against glucocorticoid-induced skin atrophy.

Background: Skin atrophy is a major adverse effect of topical glucocorticoids. We recently reported that REDD1 (regulated in development and DNA damage 1) and FKBP51 (FK506 binding protein 5), negative regulators of mTOR/Akt signaling, are induced by glucocorticoids in mouse and human skin and are central drivers of steroid skin atrophy. Thus, we hypothesized that REDD1/FKBP51 inhibitors could protect skin against catabolic effects of glucocorticoids.

Correction: Integrative approach to sporadic Alzheimer's disease: deficiency of TYROBP in cerebral Aβ amyloidosis mouse normalizes clinical phenotype and complement subnetwork molecular pathology without reducing Aβ burden.

This article was originally published under standard licence, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the paper have been modified accordingly.

Critical period plasticity-related transcriptional aberrations in schizophrenia and bipolar disorder.

Childhood critical periods of experience-dependent plasticity are essential for the development of environmentally appropriate behavior and cognition. Disruption of critical periods can alter development of normal function and confer risk for neurodevelopmental disorders. While genes and their expression relevant to neurodevelopment are associated with schizophrenia, the molecular relationship between schizophrenia and critical periods has not been assessed systematically.

Deletion of the glucocorticoid receptor chaperone FKBP51 prevents glucocorticoid-induced skin atrophy.

FKBP51 (FK506-binding protein 51) is a known co-chaperone and regulator of the glucocorticoid receptor (GR), which usually attenuates its activity. FKBP51 is one of the major GR target genes in skin, but its role in clinical effects of glucocorticoids is not known. Here, we used FKBP51 knockout (KO) mice to determine FKBP51's role in the major adverse effect of topical glucocorticoids, skin atrophy.

Integrative approach to sporadic Alzheimer's disease: deficiency of TYROBP in cerebral Aβ amyloidosis mouse normalizes clinical phenotype and complement subnetwork molecular pathology without reducing Aβ burden.

Integrative gene network approaches enable new avenues of exploration that implicate causal genes in sporadic late-onset Alzheimer's disease (LOAD) pathogenesis, thereby offering novel insights for drug-discovery programs. We previously constructed a probabilistic causal network model of sporadic LOAD and identified TYROBP/DAP12, encoding a microglial transmembrane signaling polypeptide and direct adapter of TREM2, as the most robust key driver gene in the network. Here, we show that absence of TYROBP/DAP12 in a mouse model of AD-type cerebral Aβ amyloidosis (APP/PSEN1) recapitulates the expected network characteristics by normalizing the transcriptome of APP/PSEN1 mice and repressing the induction of genes involved in the switch from homeostatic microglia to disease-associated microglia (DAM), including Trem2, complement (C1qa, C1qb, C1qc, and Itgax), Clec7a and Cst7.

Pharmacological risk factors associated with hospital readmission rates in a psychiatric cohort identified using prescriptome data mining.

Background: Worldwide, over 14% of individuals hospitalized for psychiatric reasons have readmissions to hospitals within 30 days after discharge. Predicting patients at risk and leveraging accelerated interventions can reduce the rates of early readmission, a negative clinical outcome (i.e.

Multiscale Analysis of Independent Alzheimer's Cohorts Finds Disruption of Molecular, Genetic, and Clinical Networks by Human Herpesvirus.

Investigators have long suspected that pathogenic microbes might contribute to the onset and progression of Alzheimer's disease (AD) although definitive evidence has not been presented. Whether such findings represent a causal contribution, or reflect opportunistic passengers of neurodegeneration, is also difficult to resolve. We constructed multiscale networks of the late-onset AD-associated virome, integrating genomic, transcriptomic, proteomic, and histopathological data across four brain regions from human post-mortem tissue.

A Network-Biology Informed Computational Drug Repositioning Strategy to Target Disease Risk Trajectories and Comorbidities of Peripheral Artery Disease.

Currently, drug discovery approaches focus on the design of therapies that alleviate an index symptom by reengineering the underlying biological mechanism in agonistic or antagonistic fashion. For example, medicines are routinely developed to target an essential gene that drives the disease mechanism. Therapeutic overloading where patients get multiple medications to reduce the primary and secondary side effect burden is standard practice.

Rapamycin Modulates Glucocorticoid Receptor Function, Blocks Atrophogene REDD1, and Protects Skin from Steroid Atrophy.

Glucocorticoids have excellent therapeutic properties; however, they cause significant adverse atrophogenic effects. The mTORC1 inhibitor REDD1 has been recently identified as a key mediator of glucocorticoid-induced atrophy. We performed computational screening of a connectivity map database to identify putative REDD1 inhibitors.

Exploring the Interaction Between eIF2α Dysregulation, Acute Endoplasmic Reticulum Stress and DYT1 Dystonia in the Mammalian Brain.

DYT1 dystonia is a neurological disease caused by dominant mutations in the TOR1A gene, encoding for the endoplasmic reticulum (ER)-resident protein torsinA. Recent reports linked expression of the DYT1-causing protein with dysregulation of eIF2α, a key component of the cellular response to ER stress known as the unfolded protein response (UPR). However, the response of the DYT1 mammalian brain to acute ER stress inducers has not been evaluated in vivo.