Functional Genomic Analysis of Remyelination Reveals Importance of Inflammation in Oligodendrocyte Regeneration

Tumor necrosis factor alpha (TNFalpha), a proinflammatory cytokine, was shown previously to promote remyelination and oligodendrocyte precursor proliferation in a murine model for demyelination and remyelination. We used Affymetrix microarrays in this study to identify (1) changes in gene expression that accompany demyelination versus remyelination and (2) changes in gene expression during the successful remyelination of wild-type mice versus the unsuccessful attempts in mice lacking TNFalpha. Alterations in inflammatory genes represented the most prominent changes, with major histocompatibility complex (MHC) genes dramatically enhanced in microglia and astrocytes during demyelination, remyelination, and as a consequence of TNFalpha stimulation. Studies to examine the roles of these genes in remyelination were then performed using mice lacking specific genes identified by the microarray. Analysis of MHC-II-null mice showed delayed remyelination and regeneration of oligodendrocytes, whereas removal of MHC-I had little effect. These data point to the induction of MHC-II by TNFalpha as an important regulatory event in remyelination and emphasize the active inflammatory response in regeneration after pathology in the brain

Loss of the receptor tyrosine kinase Axl leads to enhanced inflammation in the CNS and delayed removal of myelin debris during Experimental Autoimmune Encephalomyelitis

<p>Abstract</p> <p>Background</p> <p>Axl, together with Tyro3 and Mer, constitute the TAM family of receptor tyrosine kinases. In the nervous system, Axl and its ligand Growth-arrest-specific protein 6 (Gas6) are expressed on multiple cell types. Axl functions in dampening the immune response, regulating cytokine secretion, clearing apoptotic cells and debris, and maintaining cell survival. Axl is upregulated in various disease states, such as in the cuprizone toxicity-induced model of demyelination and in multiple sclerosis (MS) lesions, suggesting that it plays a role in disease pathogenesis. To test for this, we studied the susceptibility of Axl-/- mice to experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis.</p> <p>Methods</p> <p>WT and Axl-/- mice were immunized with myelin oligodendrocyte glycoprotein (MOG)_35-55peptide emulsified in complete Freund's adjuvant and injected with pertussis toxin on day 0 and day 2. Mice were monitored daily for clinical signs of disease and analyzed for pathology during the acute phase of disease. Immunological responses were monitored by flow cytometry, cytokine analysis and proliferation assays.</p> <p>Results</p> <p>Axl-/- mice had a significantly more severe acute phase of EAE than WT mice. Axl-/- mice had more spinal cord lesions with larger inflammatory cuffs, more demyelination, and more axonal damage than WT mice during EAE. Strikingly, lesions in Axl-/- mice had more intense Oil-Red-O staining indicative of inefficient clearance of myelin debris. Fewer activated microglia/macrophages (Iba1+) were found in and/or surrounding lesions in Axl-/- mice relative to WT mice. In contrast, no significant differences were noted in immune cell responses between naïve and sensitized animals.</p> <p>Conclusions</p> <p>These data show that Axl alleviates EAE disease progression and suggests that in EAE Axl functions in the recruitment of microglia/macrophages and in the clearance of debris following demyelination. In addition, these data provide further support that administration of the Axl ligand Gas6 could be therapeutic for immune-mediated demyelinating diseases.</p

Melting Alpine Glaciers Enrich High-Elevation Lakes with Reactive Nitrogen

Alpine glaciers have receded substantially over the last century in many regions of the world. Resulting changes in glacial runoff not only affect the hydrological cycle, but can also alter the physical (i.e., turbidity from glacial flour) and biogeochemical properties of downstream ecosystems. Here we compare nutrient concentrations, transparency gradients, algal biomass, and fossil diatom species richness in two sets of high-elevation lakes: those fed by snowpack melt alone (SF lakes) and those fed by both glacial and snowpack meltwaters (GSF lakes). We found that nitrate (NO3-) concentrations in the GSF lakes were 1-2 orders of magnitude higher than in SF lakes. Although nitrogen (N) limitation is common in alpine lakes, algal biomass was lower in highly N-enriched GSF lakes than in the N-poor SF lakes. Contrary to expectations, GSF lakes were more transparent than SF lakes to ultraviolet and equally transparent to photosynthetically active radiation.Sediment diatom assemblages had lower taxonomic richness in the GSF lakes, a feature that has persisted over the last century. Our results demonstrate that the presence of glaciers on alpine watersheds more strongly influences NO3- concentrations in high-elevation lake ecosystems than any other geomorphic or biogeographic characteristic

Melting Alpine Glaciers Enrich High-Elevation Lakes with Reactive Nitrogen

Alpine glaciers have receded substantially over the last century in many regions of the world. Resulting changes in glacial runoff not only affect the hydrological cycle, but can also alter the physical (i.e., turbidity from glacial flour) and biogeochemical properties of downstream ecosystems. Here we compare nutrient concentrations, transparency gradients, algal biomass, and fossil diatom species richness in two sets of high-elevation lakes: those fed by snowpack melt alone (SF lakes) and those fed by both glacial and snowpack meltwaters (GSF lakes). We found that nitrate (NO3-) concentrations in the GSF lakes were 1-2 orders of magnitude higher than in SF lakes. Although nitrogen (N) limitation is common in alpine lakes, algal biomass was lower in highly N-enriched GSF lakes than in the N-poor SF lakes. Contrary to expectations, GSF lakes were more transparent than SF lakes to ultraviolet and equally transparent to photosynthetically active radiation.Sediment diatom assemblages had lower taxonomic richness in the GSF lakes, a feature that has persisted over the last century. Our results demonstrate that the presence of glaciers on alpine watersheds more strongly influences NO3- concentrations in high-elevation lake ecosystems than any other geomorphic or biogeographic characteristic

Lymphotoxin β Receptor (LtβR): Dual Roles in Demyelination and Remyelination and Successful Therapeutic Intervention Using LtβR-Ig Protein

Inflammation mediated by macrophages is increasingly found to play a central role in diseases and disorders that affect a myriad of organs, prominent among these are diseases of the CNS. The neurotoxicant-induced, cuprizone model of demyelination is ideally suited for the analysis of inflammatory events. Demyelination on exposure to cuprizone is accompanied by predictable microglial activation and astrogliosis, and, after cuprizone withdrawal, this activation reproducibly diminishes during remyelination. This study demonstrates enhanced expression of lymphotoxin beta receptor (Lt betaR) during the demyelination phase of this model, and Lt betaR is found in areas enriched with microglial and astroglial cells. Deletion of the Lt betaR gene (Lt betaR-/-) resulted in a significant delay in demyelination but also a slight delay in remyelination. Inhibition of Lt betaR signaling by an Lt betaR-Ig fusion decoy protein successfully delayed demyelination in wild-type mice. Unexpectedly, this Lt betaR-Ig decoy protein dramatically accelerated the rate of remyelination, even after the maximal pathological disease state had been reached. This strongly indicates the beneficial role of Lt betaR-Ig in the delay of demyelination and the acceleration of remyelination. The discrepancy between remyelination rates in these systems could be attributed to developmental abnormalities in the immune systems of Lt betaR-/- mice. These findings bode well for the use of an inhibitory Lt betaR-Ig as a candidate biological therapy in demyelinating disorders, because it is beneficial during both demyelination and remyelination

Decision making and experiences of young adults undergoing presymptomatic genetic testing for familial cancer: A longitudinal grounded theory study

Enabling informed choice is an essential component of care when offering young adults presymptomatic testing for a genetic condition. A systematic review on this topic revealed that many young adults grew up with little information regarding their genetic risk and that parents had applied pressure to them during the testing decision-making process. However, none of the studies retrieved were conducted in South European countries. To address this gap, we undertook a qualitative study based on grounded theory to explore the psychosocial implications of presymptomatic testing for hereditary cancer in Italian young adults aged 18-30 years. Interviews were conducted on three occasions: 1 month before counselling, and 2 weeks and 6 months after results. Data were coded and grouped under themes. A total of 42 interviews were conducted. Four themes emerged: knowledge, genetic counselling process, decision making and dealing with test results. Although participants grew up with little or no information about their genetic risk, none expressed regret at having the test at a young age. Pre-test counselling was appreciated as a source of information, rather than support for decision making. Decisions were often made autonomously and sometimes conflicted with parents' wishes. Participants reported no changes in health behaviours after testing. This evidence highlights the need for a comprehensive, longitudinal counselling process with appropriate timing and setting, which supports 'parent-to-offspring' risk communication first and decision making by young adults about presymptomatic testing and risk management afterwards. In conclusion, it is clear that counselling approaches for presymptomatic testing may require modification both for young adults and their parents. &copy; 2017 European Society of Human Genetics

Upregulation of the stress-associated gene p8 in mouse models of demyelination and in multiple sclerosis tissues

Cuprizone-induced demyelination is a mouse model of multiple sclerosis (MS) as cuprizone-fed mice exhibit neuroin-flammation and demyelination in the brain. Upon removal of cuprizone from the diet, inflammation is resolved and reparative remyelination occurs. In an Affymetrix Gene-Chip analysis, the stress-associated gene p8 was strongly upregulated (>10×) during cuprizone-induced demyelination but not remyelination. We verified this upregulation (>15×) of p8 in the CNS during demyelination by real-time polymerase chain reaction (PCR). This upregulation is brain-specific, as p8 is not elevated in the liver, lung, kidney, spleen, and heart of cuprizone-treated mice. We also localized the cellular source of p8 during cuprizone treatment, and further found elevated expression during embryogenesis but not in normal adult brain. Compared with wild-type controls, the death of oligodendrocytes in p8−/− mice is delayed, as is microglial recruitment to areas of demyelination. The corpus callosum of p8−/− mice demyelinates at a slower rate than wild-type mice, suggesting that p8 exacerbates CNS inflammation and demyelination. Enhanced expression of p8 is also observed in the spinal cords of mice with acute experimental autoimmune encephalomyelitis (EAE) induced by PLP139–151 peptide (10×). Increased expression is detected during disease onset and expression wanes during the remission phase. Finally, p8 is found upregulated (8×) in post-mortem tissue from MS patients and is higher in the plaque tissue compared with adjacent normal-appearing white and gray matter. Thus, p8 is an excellent candidate as a novel biomarker of demyelination

Sex differences in the adult human brain:Evidence from 5216 UK Biobank participants

Sex differences in the human brain are of interest for many reasons: for example, there are sex differences in the observed prevalence of psychiatric disorders and in some psychological traits that brain differences might help to explain. We report the largest single-sample study of structural and functional sex differences in the human brain (2750 female, 2466 male participants; mean age 61.7 years, range 44–77 years). Males had higher raw volumes, raw surface areas, and white matter fractional anisotropy; females had higher raw cortical thickness and higher white matter tract complexity. There was considerable distributional overlap between the sexes. Subregional differences were not fully attributable to differences in total volume, total surface area, mean cortical thickness, or height. There was generally greater male variance across the raw structural measures. Functional connectome organization showed stronger connectivity for males in unimodal sensorimotor cortices, and stronger connectivity for females in the default mode network. This large-scale study provides a foundation for attempts to understand the causes and consequences of sex differences in adult brain structure and function

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention

Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity.

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels