Weighted gene co-expression network analysis of the peripheral blood from Amyotrophic Lateral Sclerosis patients

<p>Abstract</p> <p>Background</p> <p>Amyotrophic Lateral Sclerosis (ALS) is a lethal disorder characterized by progressive degeneration of motor neurons in the brain and spinal cord. Diagnosis is mainly based on clinical symptoms, and there is currently no therapy to stop the disease or slow its progression. Since access to spinal cord tissue is not possible at disease onset, we investigated changes in gene expression profiles in whole blood of ALS patients.</p> <p>Results</p> <p>Our transcriptional study showed dramatic changes in blood of ALS patients; 2,300 probes (9.4%) showed significant differential expression in a discovery dataset consisting of 30 ALS patients and 30 healthy controls. Weighted gene co-expression network analysis (WGCNA) was used to find disease-related networks (modules) and disease related hub genes. Two large co-expression modules were found to be associated with ALS. Our findings were replicated in a second (30 patients and 30 controls) and third dataset (63 patients and 63 controls), thereby demonstrating a highly significant and consistent association of two large co-expression modules with ALS disease status. Ingenuity Pathway Analysis of the ALS related module genes implicates enrichment of functional categories related to genetic disorders, neurodegeneration of the nervous system and inflammatory disease. The ALS related modules contain a number of candidate genes possibly involved in pathogenesis of ALS.</p> <p>Conclusion</p> <p>This first large-scale blood gene expression study in ALS observed distinct patterns between cases and controls which may provide opportunities for biomarker development as well as new insights into the molecular mechanisms of the disease.</p

UNC13A in amyotrophic lateral sclerosis: from genetic association to therapeutic target

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options and an incompletely understood pathophysiology. Although genomewide association studies (GWAS) have advanced our understanding of the disease, the precise manner in which risk polymorphisms contribute to disease pathogenesis remains unclear. Of relevance, GWAS have shown that a polymorphism (rs12608932) in the UNC13A gene is associated with risk for both ALS and frontotemporal dementia (FTD). Homozygosity for the C-allele at rs12608932 modifies the ALS phenotype, as these patients are more likely to have bulbar-onset disease, cognitive impairment and FTD at baseline as well as shorter survival. UNC13A is expressed in neuronal tissue and is involved in maintaining synaptic active zones, by enabling the priming and docking of synaptic vesicles. In the absence of functional TDP-43, risk variants in UNC13A lead to the inclusion of a cryptic exon in UNC13A messenger RNA, subsequently leading to nonsense mediated decay, with loss of functional protein. Depletion of UNC13A leads to impaired neurotransmission. Recent discoveries have identified UNC13A as a potential target for therapy development in ALS, with a confirmatory trial with lithium carbonate in UNC13A cases now underway and future approaches with antisense oligonucleotides currently under consideration. Considering UNC13A is a potent phenotypic modifier, it may also impact clinical trial outcomes. This present review describes the path from the initial discovery of UNC13A as a risk gene in ALS to the current therapeutic options being explored and how knowledge of its distinct phenotype needs to be taken into account in future trials

Sisyphus Cooling of Electrically Trapped Polyatomic Molecules

The rich internal structure and long-range dipole-dipole interactions establish polar molecules as unique instruments for quantum-controlled applications and fundamental investigations. Their potential fully unfolds at ultracold temperatures, where a plethora of effects is predicted in many-body physics, quantum information science, ultracold chemistry, and physics beyond the standard model. These objectives have inspired the development of a wide range of methods to produce cold molecular ensembles. However, cooling polyatomic molecules to ultracold temperatures has until now seemed intractable. Here we report on the experimental realization of opto-electrical cooling, a paradigm-changing cooling and accumulation method for polar molecules. Its key attribute is the removal of a large fraction of a molecule's kinetic energy in each step of the cooling cycle via a Sisyphus effect, allowing cooling with only few dissipative decay processes. We demonstrate its potential by reducing the temperature of about 10^6 trapped CH_3F molecules by a factor of 13.5, with the phase-space density increased by a factor of 29 or a factor of 70 discounting trap losses. In contrast to other cooling mechanisms, our scheme proceeds in a trap, cools in all three dimensions, and works for a large variety of polar molecules. With no fundamental temperature limit anticipated down to the photon-recoil temperature in the nanokelvin range, our method eliminates the primary hurdle in producing ultracold polyatomic molecules. The low temperatures, large molecule numbers and long trapping times up to 27 s will allow an interaction-dominated regime to be attained, enabling collision studies and investigation of evaporative cooling toward a BEC of polyatomic molecules

Медицинские и социальные аспекты коммерческого секса

Представлены демографические, медицинские, психологические и социальные характеристики женщин, оказывающих платные сексуальные услуги. Обсуждается проблема легализации и регламентации проституции в контексте профилактики инфекций, передающихся половым путем, и заражения ВИЧ.Demographic, medical, psychological and social characteristics of women rendering sexual services are described. The problem of legalization and regulation of prostitution in the context of prevention of sexually transmitted infections and HIV is discussed

Determinants of Life Expectancy and its Prospects under the Role of Economic Misery: A Case of Pakistan

The present study investigates the determinants of life expectancy in the presence of economic misery using Pakistan’s time series data over the period of 1972-2012. The stationary properties of the variables are examined by applying unit root test accommodating structural breaks. The ARDL bounds testing approach to cointegration is applied to examine the long run relationship between the variables. Our findings show that cointegration between the variables is confirmed. Moreover, health spending improves life expectancy. Food supply contributes to life expectancy. A rise in economic misery deteriorates life expectancy. Urbanization enhances life expectancy while illiteracy declines it. The causality analysis reveals that life expectancy is Granger cause of health spending, food supply, economic misery, urbanization and illiteracy. This paper opens up new insights for policy making authorities to consider the role of economic misery while formulating comprehensive economic policy to improve life expectancy in Pakistan

A High-Density Genome-Wide Association Screen of Sporadic ALS in US Veterans

Following reports of an increased incidence of amyotrophic lateral sclerosis (ALS) in U.S. veterans, we have conducted a high-density genome-wide association study (GWAS) of ALS outcome and survival time in a sample of U.S. veterans. We tested ∼1.3 million single nucleotide polymorphisms (SNPs) for association with ALS outcome in 442 incident Caucasian veteran cases diagnosed with definite or probable ALS and 348 Caucasian veteran controls. To increase power, we also included genotypes from 5909 publicly-available non-veteran controls in the analysis. In the survival analysis, we tested for association between SNPs and post-diagnosis survival time in 639 Caucasian veteran cases with definite or probable ALS. After this discovery phase, we performed follow-up genotyping of 299 SNPs in an independent replication sample of Caucasian veterans and non-veterans (ALS outcome: 183 cases and 961 controls; survival: 118 cases). Although no SNPs reached genome-wide significance in the discovery phase for either phenotype, three SNPs were statistically significant in the replication analysis of ALS outcome: rs6080539 (177 kb from PCSK2), rs7000234 (4 kb from ZNF704), and rs3113494 (13 kb from LOC100506746). Two SNPs located in genes that were implicated by previous GWA studies of ALS were marginally significant in the pooled analysis of discovery and replication samples: rs17174381 in DPP6 (p = 4.4×10−4) and rs6985069 near ELP3 (p = 4.8×10−4). Our results underscore the difficulty of identifying and convincingly replicating genetic associations with a rare and genetically heterogeneous disorder such as ALS, and suggest that common SNPs are unlikely to account for a substantial proportion of patients affected by this devastating disorder

Gene-Network Analysis Identifies Susceptibility Genes Related to Glycobiology in Autism

The recent identification of copy-number variation in the human genome has opened up new avenues for the discovery of positional candidate genes underlying complex genetic disorders, especially in the field of psychiatric disease. One major challenge that remains is pinpointing the susceptibility genes in the multitude of disease-associated loci. This challenge may be tackled by reconstruction of functional gene-networks from the genes residing in these loci. We applied this approach to autism spectrum disorder (ASD), and identified the copy-number changes in the DNA of 105 ASD patients and 267 healthy individuals with Illumina Humanhap300 Beadchips. Subsequently, we used a human reconstructed gene-network, Prioritizer, to rank candidate genes in the segmental gains and losses in our autism cohort. This analysis highlighted several candidate genes already known to be mutated in cognitive and neuropsychiatric disorders, including RAI1, BRD1, and LARGE. In addition, the LARGE gene was part of a sub-network of seven genes functioning in glycobiology, present in seven copy-number changes specifically identified in autism patients with limited co-morbidity. Three of these seven copy-number changes were de novo in the patients. In autism patients with a complex phenotype and healthy controls no such sub-network was identified. An independent systematic analysis of 13 published autism susceptibility loci supports the involvement of genes related to glycobiology as we also identified the same or similar genes from those loci. Our findings suggest that the occurrence of genomic gains and losses of genes associated with glycobiology are important contributors to the development of ASD

A proposal for a coordinated effort for the determination of brainwide neuroanatomical connectivity in model organisms at a mesoscopic scale

In this era of complete genomes, our knowledge of neuroanatomical circuitry remains surprisingly sparse. Such knowledge is however critical both for basic and clinical research into brain function. Here we advocate for a concerted effort to fill this gap, through systematic, experimental mapping of neural circuits at a mesoscopic scale of resolution suitable for comprehensive, brain-wide coverage, using injections of tracers or viral vectors. We detail the scientific and medical rationale and briefly review existing knowledge and experimental techniques. We define a set of desiderata, including brain-wide coverage; validated and extensible experimental techniques suitable for standardization and automation; centralized, open access data repository; compatibility with existing resources, and tractability with current informatics technology. We discuss a hypothetical but tractable plan for mouse, additional efforts for the macaque, and technique development for human. We estimate that the mouse connectivity project could be completed within five years with a comparatively modest budget.Comment: 41 page