A wireless sensor network system deployment for detecting stick slip motion in glaciers

The behaviour of glaciers is an area in which only limited research has been carried out due to the difficulties of monitoring sub-glacial movements. The authors believe that this can be addressed by the deployment of a wireless sensor network, consisting of heterogeneous sensors to instrument this activity. By deploying a sensor network measurements can be taken for a longer period than would otherwise be possible. The initial designs for this sensor network are presented along with details of some of the challenges posed by the project

Differential impact of environmental factors on systemic and localized autoimmunity

The influence of environmental factors on the development of autoimmune disease is being broadly investigated to better understand the multifactorial nature of autoimmune pathogenesis and to identify potential areas of intervention. Areas of particular interest include the influence of lifestyle, nutrition, and vitamin deficiencies on autoimmunity and chronic inflammation. In this review, we discuss how particular lifestyles and dietary patterns may contribute to or modulate autoimmunity. We explored this concept through a spectrum of several autoimmune diseases including Multiple Sclerosis (MS), Systemic Lupus Erythematosus (SLE) and Alopecia Areata (AA) affecting the central nervous system, whole body, and the hair follicles, respectively. A clear commonality between the autoimmune conditions of interest here is low Vitamin D, a well-researched hormone in the context of autoimmunity with pleiotropic immunomodulatory and anti-inflammatory effects. While low levels are often correlated with disease activity and progression in MS and AA, the relationship is less clear in SLE. Despite strong associations with autoimmunity, we lack conclusive evidence which elucidates its role in contributing to pathogenesis or simply as a result of chronic inflammation. In a similar vein, other vitamins impacting the development and course of these diseases are explored in this review, and overall diet and lifestyle. Recent work exploring the effects of dietary interventions on MS showed that a balanced diet was linked to improvement in clinical parameters, comorbid conditions, and overall quality of life for patients. In patients with MS, SLE and AA, certain diets and supplements are linked to lower incidence and improved symptoms. Conversely, obesity during adolescence was linked with higher incidence of MS while in SLE it was associated with organ damage. Autoimmunity is thought to emerge from the complex interplay between environmental factors and genetic background. Although the scope of this review focuses on environmental factors, it is imperative to elaborate the interaction between genetic susceptibility and environment due to the multifactorial origin of these disease. Here, we offer a comprehensive review about the influence of recent environmental and lifestyle factors on these autoimmune diseases and potential translation into therapeutic interventions

Multi-omic Directed Networks Describe Features of Gene Regulation in Aged Brains and Expand the Set of Genes Driving Cognitive Decline

Multiple aspects of molecular regulation, including genetics, epigenetics, and mRNA collectively influence the development of age-related neurologic diseases. Therefore, with the ultimate goal of understanding molecular systems associated with cognitive decline, we infer directed interactions among regulatory elements in the local regulatory vicinity of individual genes based on brain multi-omics data from 413 individuals. These local regulatory networks (LRNs) capture the influences of genetics and epigenetics on gene expression in older adults. LRNs were confirmed through correspondence to known transcription biophysics. To relate LRNs to age-related neurologic diseases, we then incorporate common neuropathologies and measures of cognitive decline into this framework. This step identifies a specific set of largely neuronal genes, such as STAU1 and SEMA3F, predicted to control cognitive decline in older adults. These predictions are validated in separate cohorts by comparison to genetic associations for general cognition. LRNs are shared through www.molecular.network on the Rush Alzheimer’s Disease Center Resource Sharing Hub (www.radc.rush.edu)

The Molecular and Neuropathological Consequences of Genetic Risk for Alzheimer's Dementia

Alzheimer's dementia commonly impacts the health of older adults and lacks any preventative therapy. While Alzheimer's dementia risk has a substantial genetic component, the specific molecular mechanisms and neuropathologies triggered by most of the known genetic variants are unclear. Resultantly, they have shown limited influence on drug development portfolios to date. To facilitate our understanding of the consequences of Alzheimer's dementia susceptibility variants, we examined their relationship to a wide range of clinical, molecular and neuropathological features. Because the effect size of individual variants is typically small, we utilized a polygenic (overall) risk approach to identify the global impact of Alzheimer's dementia susceptibility variants. Under this approach, each individual has a polygenic risk score (PRS) that we related to clinical, molecular and neuropathological phenotypes. Applying this approach to 1,272 individuals who came to autopsy from one of two longitudinal aging cohorts, we observed that an individual's PRS was associated with cognitive decline and brain pathologies including beta-amyloid, tau-tangles, hippocampal sclerosis, and TDP-43, MIR132, four proteins including VGF, IGFBP5, and STX1A, and many chromosomal regions decorated with acetylation on histone H3 lysine 9 (H3K9Ac). While excluding the APOE/TOMM40 region (containing the single largest genetic risk factor for late-onset Alzheimer's dementia) in the calculation of the PRS resulted in a slightly weaker association with the molecular signatures, results remained significant. These PRS-associated brain pathologies and molecular signatures appear to mediate genetic risk, as they attenuated the association of the PRS with cognitive decline. Notably, the PRS induced changes in H3K9Ac throughout the genome, implicating it in large-scale chromatin changes. Thus, the PRS for Alzheimer's dementia (AD-PRS) showed effects on diverse clinical, molecular, and pathological systems, ranging from the epigenome to specific proteins. These convergent targets of a large number of genetic risk factors for Alzheimer's dementia will help define the experimental systems and models needed to test therapeutic targets, which are expected to be broadly effective in the aging population that carries diverse genetic risks for Alzheimer's dementia

Identifications of Four INTEGRAL Sources in the Galactic Plane via Chandra Localizations

Hard X-ray imaging of the Galactic plane by the INTEGRAL satellite is uncovering large numbers of 20-100 keV "IGR" sources. We present results from Chandra, INTEGRAL, optical, and IR observations of 4 IGR sources: 3 sources in the Norma region of the Galaxy (IGR J16195-4945, IGR J16207-5129, and IGR J16167-4957) and one that is closer to the Galactic center (IGR J17195-4100). In all 4 cases, one relatively bright Chandra source is seen in the INTEGRAL error circle, and these are likely to be the soft X-ray counterparts of the IGR sources. They have hard 0.3-10 keV spectra with power-law photon indices of 0.5 to 1.1. While many previously studied IGR sources show high column densities, only IGR J16195-4945 has a column density that could be as high as 10^23 cm^-2. Using optical and IR sky survey catalogs and our own photometry, we have obtained identifications for all 4 sources. The J-band magnitudes are in the range 14.9-10.4, and we have used the optical/IR spectral energy distributions (SEDs) to constrain the nature of the sources. Blackbody components with temperature lower limits of >9400 K for IGR J16195-4945 and >18,000 K for IGR J16207-5129 indicate that these are very likely High-Mass X-ray Binaries (HMXBs). However, for IGR J16167-4957 and IGR J17195-4100, low extinction and the SEDs indicate later spectral types for the putative companions, indicating that these are not HMXBs.Comment: Accepted by the Astrophysical Journal after some reduction in the length of the paper and removal of one figur

The Evolution of Massive Stars. I. Red Supergiants in the Magellanic Clouds

We investigate the red supergiant (RSG) content of the SMC and LMC using multi-object spectroscopy on a sample of red stars previously identified by {\it BVR} CCD photometry. We obtained high accuracy ($<1$ km s$^{-1}$) radial velocities for 118 red stars seen towards the SMC and 167 red stars seen towards the LMC, confirming most of these (89% and 95%, respectively) as red supergiants (RSGs). Spectral types were also determined for most of these RSGs. We find that the distribution of spectral types is skewed towards earlier type at lower metallicities: the average (median) spectral type is K5-7 I in the SMC, M1 I in the LMC, and M2 I in the Milky Way. We argue that RSGs in the Magellanic Clouds are 100deg (LMC) and 300deg (SMC) cooler than Galactic RSGs of the same spectral type. We compare the distribution of RSGs in the H-R diagram to that of various stellar evolutionary models; we find that none of the models produce RSGs as cool and luminous as what is actually observed. In all of our H-R diagrams, however, there is an elegant sequence of decreasing effective temperatures with increasing luminosities; explaining this will be an important test of future stellar evolutionary models.Comment: Version with eps figures embedded can be obtained from ftp://ftp.lowell.edu/pub/massey/rsgs.ps.gz Accepted by the Astronomical Journa

No sex-specific difference in disease trajectory in multiple sclerosis patients before and after age 50

Background: The disease course in multiple sclerosis (MS) is influenced by many factors, including age, sex, and sex hormones. Little is known about sex-specific changes in disease course around age 50, which may represent a key biological transition period for reproductive aging. Methods: Male and female subjects with no prior chemotherapy exposure were selected from a prospective MS cohort to form groups representing the years before (38–46 years, N=351) and after (54–62 years, N=200)age 50. Primary analysis assessed for interaction between effects of sex and age on clinical (Expanded Disability Status Scale, EDSS; relapse rate) and radiologic (T2 lesion volume, T2LV; brain parenchymal fraction, BPF) outcomes. Secondarily, we explored patient-reported outcomes (PROs). Results: As expected, there were age- and sex- related changes with male and older cohorts showing worse disease severity (EDSS), brain atrophy (BPF), and more progressive course. There was no interaction between age and sex on cross-sectional adjusted clinical (EDSS, relapse rate) or radiologic (BPF, T2LV) measures, or on 2-year trajectories of decline. There was a significant interaction between age and sex for a physical functioning PRO (SF-36): the older female cohort reported lower physical functioning than men (p=0.002). There were no differences in depression (Center for Epidemiological Study – Depression, CES-D) or fatigue (Modified Fatigue Impact Scale, MFIS) scores. Conclusions: There was no interaction between age and sex suggestive of an effect of reproductive aging on clinical or radiologic progression. Prospective analyses across the menopausal transition are needed

Temporal Tracking of Microglia Activation in Neurodegeneration at Single-Cell Resolution

Microglia, the tissue-resident macrophages in the brain, are damage sensors that react to nearly any perturbation, including neurodegenerative diseases such as Alzheimer's disease (AD). Here, using single-cell RNA sequencing, we determined the transcriptome of more than 1,600 individual microglia cells isolated from the hippocampus of a mouse model of severe neurodegeneration with AD-like phenotypes and of control mice at multiple time points during progression of neurodegeneration. In this neurodegeneration model, we discovered two molecularly distinct reactive microglia phenotypes that are typified by modules of co-regulated type I and type II interferon response genes, respectively. Furthermore, our work identified previously unobserved heterogeneity in the response of microglia to neurodegeneration, discovered disease stage-specific microglia cell states, revealed the trajectory of cellular reprogramming of microglia in response to neurodegeneration, and uncovered the underlying transcriptional programs. Mathys et al. use single-cell RNA sequencing to determine the phenotypic heterogeneity of microglia during the progression of neurodegeneration. They identify multiple disease stage-specific cell states, including two molecularly distinct reactive microglia phenotypes that are typified by modules of co-regulated type I and type II interferon response genes, respectively.National Institutes of Health (U.S.) (Grant RF1 AG054321

Modeling the cumulative genetic risk for multiple sclerosis from genome-wide association data

Background: Multiple sclerosis (MS) is the most common cause of chronic neurologic disability beginning in early to middle adult life. Results from recent genome-wide association studies (GWAS) have substantially lengthened the list of disease loci and provide convincing evidence supporting a multifactorial and polygenic model of inheritance. Nevertheless, the knowledge of MS genetics remains incomplete, with many risk alleles still to be revealed. Methods: We used a discovery GWAS dataset (8,844 samples, 2,124 cases and 6,720 controls) and a multi-step logistic regression protocol to identify novel genetic associations. The emerging genetic profile included 350 independent markers and was used to calculate and estimate the cumulative genetic risk in an independent validation dataset (3,606 samples). Analysis of covariance (ANCOVA) was implemented to compare clinical characteristics of individuals with various degrees of genetic risk. Gene ontology and pathway enrichment analysis was done using the DAVID functional annotation tool, the GO Tree Machine, and the Pathway-Express profiling tool. Results: In the discovery dataset, the median cumulative genetic risk (P-Hat) was 0.903 and 0.007 in the case and control groups, respectively, together with 79.9% classification sensitivity and 95.8% specificity. The identified profile shows a significant enrichment of genes involved in the immune response, cell adhesion, cell communication/ signaling, nervous system development, and neuronal signaling, including ionotropic glutamate receptors, which have been implicated in the pathological mechanism driving neurodegeneration. In the validation dataset, the median cumulative genetic risk was 0.59 and 0.32 in the case and control groups, respectively, with classification sensitivity 62.3% and specificity 75.9%. No differences in disease progression or T2-lesion volumes were observed among four levels of predicted genetic risk groups (high, medium, low, misclassified). On the other hand, a significant difference (F = 2.75, P = 0.04) was detected for age of disease onset between the affected misclassified as controls (mean = 36 years) and the other three groups (high, 33.5 years; medium, 33.4 years; low, 33.1 years). Conclusions: The results are consistent with the polygenic model of inheritance. The cumulative genetic risk established using currently available genome-wide association data provides important insights into disease heterogeneity and completeness of current knowledge in MS genetics

Complex relation of HLA-DRB1*1501, age at menarche, and age at multiple sclerosis onset

Objective: To examine the relationship between 2 markers of early multiple sclerosis (MS) onset, 1 genetic (HLA-DRB1*1501) and 1 experiential (early menarche), in 2 cohorts. Methods: We included 540 white women with MS or clinically isolated syndrome (N = 156 with genetic data available) and 1,390 white women without MS but with a first-degree relative with MS (Genes and Environment in Multiple Sclerosis [GEMS]). Age at menarche, HLA-DRB1*1501 status, and age at MS onset were analyzed. Results: In both cohorts, participants with at least 1 HLA-DRB1*1501 allele had a later age at menarche than did participants with no risk alleles (MS: mean difference = 0.49, 95% confidence interval [CI] = [0.03–0.95], p = 0.036; GEMS: mean difference = 0.159, 95% CI = [0.012–0.305], p = 0.034). This association remained after we adjusted for body mass index at age 18 (available in GEMS) and for other MS risk alleles, as well as a single nucleotide polymorphism near the HLA-A region previously associated with age of menarche (available in MS cohort). Confirming previously reported associations, in our MS cohort, every year decrease in age at menarche was associated with a 0.65-year earlier MS onset (95% CI = [0.07–1.22], p = 0.027, N = 540). Earlier MS onset was also found in individuals with at least 1 HLA-DRB1*1501 risk allele (mean difference = −3.40 years, 95% CI = [−6.42 to −0.37], p = 0.028, N = 156). Conclusions: In 2 cohorts, a genetic marker for earlier MS onset (HLA-DRB1*1501) was inversely related to earlier menarche, an experiential marker for earlier symptom onset. This finding warrants broader investigations into the association between the HLA region and hormonal regulation in determining the onset of autoimmune disease