RNAseq Analyses Identify Tumor Necrosis Factor-Mediated Inflammation as a Major Abnormality in ALS Spinal Cord

ALS is a rapidly progressive, devastating neurodegenerative illness of adults that produces disabling weakness and spasticity arising from death of lower and upper motor neurons. No meaningful therapies exist to slow ALS progression, and molecular insights into pathogenesis and progression are sorely needed. In that context, we used high-depth, next generation RNA sequencing (RNAseq, Illumina) to define gene network abnormalities in RNA samples depleted of rRNA and isolated from cervical spinal cord sections of 7 ALS and 8 CTL samples. We aligned \u3e50 million 2X150 bp paired-end sequences/sample to the hg19 human genome and applied three different algorithms (Cuffdiff2, DEseq2, EdgeR) for identification of differentially expressed genes (DEG’s). Ingenuity Pathways Analysis (IPA) and Weighted Gene Co-expression Network Analysis (WGCNA) identified inflammatory processes as significantly elevated in our ALS samples, with tumor necrosis factor (TNF) found to be a major pathway regulator (IPA) and TNFα-induced protein 2 (TNFAIP2) as a major network “hub” gene (WGCNA). Using the oPOSSUM algorithm, we analyzed transcription factors (TF) controlling expression of the nine DEG/hub genes in the ALS samples and identified TF’s involved in inflammation (NFkB, REL, NFkB1) and macrophage function (NR1H2::RXRA heterodimer). Transient expression in human iPSC-derived motor neurons of TNFAIP2 (also a DEG identified by all three algorithms) reduced cell viability and induced caspase 3/7 activation. Using high-density RNAseq, multiple algorithms for DEG identification, and an unsupervised gene co-expression network approach, we identified significant elevation of inflammatory processes in ALS spinal cord with TNF as a major regulatory molecule. Overexpression of the DEG TNFAIP2 in human motor neurons, the population most vulnerable to die in ALS, increased cell death and caspase 3/7 activation. We propose that therapies targeted to reduce inflammatory TNFα signaling may be helpful in ALS patients

Acute Muscular Sarcocystosis: An International Investigation Among Ill Travelers Returning From Tioman Island, Malaysia, 2011-2012

A large outbreak of acute muscular sarcocystosis (AMS) among international tourists who visited Tioman Island, Malaysia, is described. Clinicians evaluating travelers returning ill from Malaysia with myalgia, with or without fever, should consider AMS in their differential diagnosi

MRI data part 1

Contains Bruker scan data (including localizer scans) as 2dseq files and can be easily read with Bruker ParaVision software. On request, data can be converted to Nifti/Dicom

MRI data part 2

Contains Bruker scan data (including localizer scans) as 2dseq files and can be easily read with Bruker ParaVision software. On request, data can be converted to Nifti/Dicom

Template and brain volumes

This zip file contains the following information: mouse brain template, brain ROIs, registration settings and the processed data. Each mouse brain was registered to a template mouse brain and volumes (whole brain + 22 structures) were extracted using the ROIs. Volumes are stored [per structure per mouse] and volumes are stored [per structure per strain]

Data from: Influence of full-length dystrophin on brain volumes in mouse models of Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) affects besides muscle also the brain, resulting in memory and behavioral problems. The consequences of dystrophinopathy on gross macroscopic alterations are unclear. To elucidate the effect of dystrophin expression on brain morphology, we used high-resolution post-mortem MRI in mouse models that either express 0% (mdx), 100% (BL10) or a low amount of full-length dystrophin (mdx-Xist∆hs). While absence or low amounts of dystrophin did not result in significantly different whole brain volume and skull morphology, we found differences in volume of individual brain structures. The found results are in line with observations in humans, where whole brain volume was found to be reduced only in patients lacking both full-length dystrophin and the shorter isoform Dp140

Data from: Influence of full-length dystrophin on brain volumes in mouse models of Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) affects besides muscle also the brain, resulting in memory and behavioral problems. The consequences of dystrophinopathy on gross macroscopic alterations are unclear. To elucidate the effect of dystrophin expression on brain morphology, we used high-resolution post-mortem MRI in mouse models that either express 0% (mdx), 100% (BL10) or a low amount of full-length dystrophin (mdx-Xist∆hs). While absence or low amounts of dystrophin did not result in significantly different whole brain volume and skull morphology, we found differences in volume of individual brain structures. The found results are in line with observations in humans, where whole brain volume was found to be reduced only in patients lacking both full-length dystrophin and the shorter isoform Dp140

Volumes (in mm³) of 22 brain structures in mouse models of Duchenne muscular dystrophy.

<p>The volumes of 22 segmented brain structures in <i>mdx</i>, BL10, <i>mdx</i>-<i>Xist</i>^Δhs and BL10-<i>Xist</i>^Δhs mice are presented in mm³. Body mass was measured just before sacrificing the mice, except for two <i>mdx-Xist</i>^Δhs mice of which body mass was not obtained. The volumes of these 22 structures were normalized to whole brain volume and compared using Welch’s T-tests within each genetic background (<i>mdx vs</i> BL10 and <i>mdx</i>-<i>Xist</i>^Δhs <i>vs</i> BL10-<i>Xist</i>^Δhs) and corrected for multiple comparisons using the false discovery rate. The corresponding <i>P</i>-values are presented and structures which are significantly different in volume are written in bold. The hippocampus, globus pallidus, caudate putamen and hypothalamus were different between <i>mdx</i> and BL10 mice. Thirteen structures were different between <i>mdx</i>-<i>Xist</i>^Δhs and BL10-<i>Xist</i>^Δhs mice, consisting of a mixture of both grey and white matter structures.</p