Citations

AbstractObjectiveOnset of multiple sclerosis (MS) occurs in childhood for approximately 5% of cases (pediatricMS, or ped‐MS). Epigenetic influences are strongly implicated inMSpathogenesis in adults, including the contribution from microRNAs (miRNAs), small noncodingRNAs that affect gene expression by binding target genemRNAs. Few studies have specifically examined miRNAs in ped‐MS, but individuals developingMSat an early age may carry a relatively high burden of genetic risk factors, and miRNAdysregulation may therefore play a larger role in the development of ped‐MSthan in adult‐onsetMS. This study aimed to look for evidence of miRNAinvolvement in ped‐MSpathogenesis.MethodsGWASresults from 486 ped‐MScases and 1362 controls from the U.S. PediatricMSNetwork and Kaiser Permanente Northern California membership were investigated for miRNA‐specific signals. First, enrichment of miRNA‐target gene network signals was evaluated usingMIGWASsoftware. Second,SNPs in miRNAgenes and in target gene binding sites (miR−SNPs) were tested for association with ped‐MS, and pathway analysis was performed on associated target genes.ResultsMIGWASanalysis showed that miRNA‐target gene signals were enriched inGWAS(P = 0.038) and identified 39 candidate biomarker miRNA‐target gene pairs, including immune and neuronal signaling genes. The miR‐SNPanalysis implicated dysregulation of miRNAbinding to target genes in five pathways, mainly involved in immune signaling.InterpretationEvidence fromGWASsuggests that miRNAs play a role in ped‐MSpathogenesis by affecting immune signaling and other pathways. Candidate biomarker miRNA‐target gene pairs should be further studied for diagnostic, prognostic, and/or therapeutic utility.

Bone marrow mesenchymal stem cells exist in a multipotential state, where osteogenic and adipogenic genomes are silenced in heterochromatin at the inner nuclear leaflet. Physical force, generated in the marrow space during dynamic exercise exerts control overexpression of differentiation. Mesenchymal stem cells experience mechanical force through their cytoskeletal attachments to substrate, inducing signaling that alters gene expression. The generated force is further transferred from the cytoskeleton to the nucleoskeleton through tethering of actin to Linker of Nucleus and Cytoskeleton (LINC) complexes. Forces exerted on LINC alter the shape and placement of the nucleus within the cell, and are ultimately transferred into the nucleus. LINC complexes transverse the nuclear membrane and connect to the internal nucleoskeleton that is made up of lamin filaments and actin. Force transfer through LINC thus causes structural rearrangements of the nuclear scaffolding upon which chromosomes are arranged. Gene availability is not only modulated through heterochromatin remodeling enzymes and active transcription factors but also by control of nucleoskeletal structure and nuclear enzymes that mediate actin polymerization in the nucleus. Nuclear actin structure may be affected by similar force-activated pathways as those controlling the cytoplasmic actin cytoskeleton and represent a critical determinant of mesenchymal stem cell lineage commitment. Impact statement Gene expression is controlled by nuclear structure which is modulated by both internal and external forces exerted on the nucleoskeleton. Extracellular forces experienced through the actin cytoskeleton are transmitted to the internal nucleoskeleton via Linker of Nucleus and Cytoskeleton (LINC) protein connections. LINC complexes directly alter nuclear shape and entry of molecules that regulate transcription. New mechanistic models indicate that nuclear actin is a dynamic component of the filamentous nucleoskeleton and modified by an intranuclear “actin toolbox”, a set of enzymes that regulate linear and branched polymerization of nuclear actin. External stimulation of both biomechanical and biochemical pathways alters nuclear actin structure and has profound effects on gene expression by controlling chromatin architecture and transcription factor access to gene targets. The available data indicate that nucleoskeletal control of gene expression is critical for self-renewal and mesenchymal lineage-allocation in stem cells.

Humans are sexually dimorphic, with sex being the most persistent difference among humans over the course of our evolutionary history. Beyond the visible sex differences that can be considered true dimorphisms, there are also sex differences at the molecular and cellular scales. The role of these biological sex differences for human health, while being increasingly recognized, have long been underappreciated and underexplored. Frequently, these differences are only recognized in sex–specific diseases, such as genitourinary diseases and cancers. However, given the evidence for sex differences in the most basic aspects of human biology, including metabolism, cellular composition, and immune activity, these differences could have consequences for the etiology and pathophysiology of a majority of diseases. It is thus essential to consider the extent to which these differences may influence the various mechanisms underlying disease processes, response to treatment, and the maintenance of health in order to better improve patient outcomes. Here we review the evidence for a broad array of biological sex differences in humans and discuss how they may relate to observed sex differences in various diseases, with an emphasis on cancer, specifically glioblastoma. We further propose that mathematical approaches can be useful for exploring the extent to which sex differences affect disease outcomes and accounting for those in the development of therapeutic strategies.

This systematic review showed lower capsule retention rates in suspected and established Crohn’s disease than older literature. Retention rates were further reduced after patency capsule and cross-sectional imaging. Retention rates were also lower in pediatric compared with adult Crohn’s disease.