Amyotrophic lateral sclerosis: new genes, new models, and new mechanisms

Research aimed at understanding amyotrophic lateral sclerosis (ALS) has seen exceptional growth in the past few years. New genes, new models, and new mechanisms have not only improved our understanding, but also contributed to the increasing complexity of ALS pathogenesis. The focus of this piece is to highlight some of the more notable developments in the field and to encourage a re-appreciation for the superoxide dismutase 1 (SOD1) mouse models

High Levels of Genetic Differentiation between Ugandan Glossina fuscipes fuscipes Populations Separated by Lake Kyoga

The two types of sleeping sickness in West and East Africa are markedly distinct, require different treatments, and are caused by different parasites. The only country where both parasites are present is Uganda, where they are separated by a narrow 160 km disease-free belt. Because there is no restriction on the movement of humans and animals between the two disease zones, this separation is puzzling. We asked whether this disjunct distribution can be explained by variation within the tsetse fly that is largely responsible for transmitting both diseases in Uganda, Glossina fuscipes fuscipes. We therefore examined whether this tsetse subspecies is genetically uniform across Uganda. Our results indicate that G. f. fusicipes is not genetically different between the two disease zones, but there are clear genetic differences between northern and southern populations, which are separated by Lake Kyoga. Therefore, it is unlikely that variation in the tsetse fly determines the distribution of the two parasites. This implies that the two diseases may fuse in the near future, which would greatly complicate diagnosis and treatment of sleeping sickness in any potential area of overlap

A direct interaction between two Restless Legs Syndrome predisposing genes : MEIS1 and SKOR1

Restless Legs syndrome (RLS) is a common sleep disorder for which the genetic contribution remains poorly explained. In 2007, the frst large scale genome wide association study (GWAS) identifed three genomic regions associated with RLS. MEIS1, BTBD9 and MAP2K5/SKOR1 are the only known genes located within these loci and their association with RLS was subsequently confrmed in a number of follow up GWAS. Following this fnding, our group reported the MEIS1 risk haplotype to be associated with its decreased expression at the mRNA and protein levels. Here we report the efect of the risk variants of the three other genes strongly associated with RLS. While these variants had no efect on the mRNA levels of the genes harboring them, we fnd that the homeobox transcription factor MEIS1 positively regulates the expression of the transcription co-repressor SKOR1. This regulation appears mediated through the binding of MEIS1 at two specifc sites located in the SKOR1 promoter region and is modifed by an RLS associated SNP in the promoter region of the gene. Our fndings directly link MEIS1 and SKOR1, two signifcantly associated genes with RLS and also prioritize SKOR1 over MAP2K5 in the RLS associated intergenic region of MAP2K5/SKOR1 found by GWAS

Metal fire implications for advanced reactors. Part 2, PIRT results.

This report documents the results of a Phenomena Identification and Ranking Table (PIRT) exercise performed at Sandia National Laboratories (SNL) as well as the experimental and modeling program that have been designed based on the PIRT results. A PIRT exercise is a structured and facilitated expert elicitation process. In this case, the expert panel was comprised of nine recognized fire science and aerosol experts. The objective of a PIRT exercise is to identify phenomena associated with the intended application and to then rank the current state of knowledge relative to each identified phenomenon. In this particular PIRT exercise the intended application was sodium fire modeling related to sodium-cooled advanced reactors. The panel was presented with two specific fire scenarios, each based on a hypothetical sodium leak in an Advanced Breeder Test Reactor (ABTR) design. For both scenarios the figure of merit was the ability to predict the thermal and aerosol insult to nearby equipment (i.e. heat exchangers and other electrical equipment). When identifying phenomena of interest, and in particular when ranking phenomena importance and the adequacy of existing modeling tools and data, the panel was asked to subjectively weigh these factors in the context of the specified figure of merit. Given each scenario, the panel identified all those related phenomena that are of potential interest to an assessment of the scenario using fire modeling tools to evaluate the figure of merit. Each phenomenon is then ranked relative to its importance in predicting the figure of merit. Each phenomenon is then further ranked for the existing state of knowledge with respect to the ability of existing modeling tools to predict that phenomena, the underlying base of data associated with the phenomena, and the potential for developing new data to support improvements to the existing modeling tools. For this PIRT two hypothetical sodium leak scenarios were evaluated for the ABTR design. The first scenario was a leak in the hot side of the intermediate heat transport system (IHTS) resulting in a sodium pool fire. The second scenario was a leak in the cold side of the IHTS resulting in a sodium spray fire

Loss of neuronal potassium/chloride cotransporter 3 (KCC3) is responsible for the degenerative phenotype in a conditional mouse model of hereditary motor and sensory neuropathy associated with agenesis of the corpus callosum

Disruption of the potassium/chloride cotransporter 3 (KCC3), encoded by the SLC12A6 gene, causes hereditary motor and sensory neuropathy associated with agenesis of the corpus callosum (HMSN/ACC), a neurodevelopmental and neurodegenerative disorder affecting both the peripheral nervous system and CNS. However, the precise role of KCC3 in the maintenance of ion homeostasis in the nervous system and the pathogenic mechanisms leading to HMSN/ACC remain unclear. We established two Slc12a6 Cre/LoxP transgenic mouse lines expressing C-terminal truncated KCC3 in either a neuron-specific or ubiquitous fashion. Our results suggest that neuronal KCC3 expression is crucial for axon volume control. We also demonstrate that the neuropathic features of HMSN/ACC are predominantly due to a neuronal KCC3 deficit, while the auditory impairment is due to loss of non-neuronal KCC3 expression. Furthermore, we demonstrate that KCC3 plays an essential role in inflammatory pain pathways. Finally, we observed hypoplasia of the corpus callosum in both mouse mutants and a marked decrease in axonal tracts serving the auditory cortex in only the general deletion mutant. Together, these results establish KCC3 as an important player in both central and peripheral nervous system maintenance

Plasma natriuretic peptide levels reflect changes in heart failure symptoms, left ventricular size and function after surgical mitral valve repair

Background and aim: N-terminal pro-B-type natriuretic peptide (NT-proBNP) has diagnostic and prognostic value in patients with heart failure. The present prospective study was designed to assess whether changes in NT-proBNP levels after surgical mitral valve repair reflect changes in heart failure symptoms an

Paternal age explains a major portion of de novo germline mutation rate variability in healthy individuals

De novo mutations (DNM) are an important source of rare variants and are increasingly being linked to the development of many diseases. Recently, the paternal age effect has been the focus of a number of studies that attempt to explain the observation that increasing paternal age increases the risk for a number of diseases. Using disease-free familial quartets we show that there is a strong positive correlation between paternal age and germline DNM in healthy subjects. We also observed that germline CNVs do not follow the same trend, suggesting a different mechanism. Finally, we observed that DNM were not evenly distributed across the genome, which adds support to the existence of DNM hotspots

Regulatory domain or CpG site variation in SLC12A5, encoding the chloride transporter KCC2, in human autism and schizophrenia

Many encoded gene products responsible for neurodevelopmental disorders (NDs) like autism spectrum disorders (ASD), schizophrenia (SCZ), intellectual disability (ID), and idiopathic generalized epilepsy (IGE) converge on networks controlling synaptic function. An increase in KCC2 (SLC12A5) Cl− transporter activity drives the developmental GABA excitatory-inhibitory sequence, but the role of KCC2 in human NDs is essentially unknown. Here, we report two rare, non-synonymous (NS), functionally-impairing variants in the KCC2 C-terminal regulatory domain (CTRD) in human ASD (R952H and R1049C) and SCZ (R952H) previously linked with IGE and familial febrile seizures, and another novel NS KCC2 variant in ASD (R1048W) with highly-predicted pathogenicity. Exome data from 2517 simplex families in the ASD Simon Simplex Collection (SSC) revealed significantly more KCC2 CTRD variants in ASD cases than controls, and interestingly, these were more often synonymous and predicted to disrupt or introduce a CpG site. Furthermore, full gene analysis showed ASD cases are more likely to contain rare KCC2 variants affecting CpG sites than controls. These data suggest genetically-encoded dysregulation of KCC2-dependent GABA signaling may contribute to multiple human NDs

Quasiparticle interfacial level alignment of highly hybridized frontier levels: H2_2O on TiO2_2(110)

Knowledge of the frontier levels' alignment prior to photo-irradiation is necessary to achieve a complete quantitative description of H$_2$O photocatalysis on TiO$_2$(110). Although H$_2$O on rutile TiO$_2$(110) has been thoroughly studied both experimentally and theoretically, a quantitative value for the energy of the highest H$_2$O occupied levels is still lacking. For experiment, this is due to the H$_2$O levels being obscured by hybridization with TiO$_2$(110) levels in the difference spectra obtained via ultraviolet photoemission spectroscopy (UPS). For theory, this is due to inherent difficulties in properly describing many-body effects at the H$_2$O-TiO$_2$(110) interface. Using the projected density of states (DOS) from state-of-the-art quasiparticle (QP) $G_0W_0$, we disentangle the adsorbate and surface contributions to the complex UPS spectra of H$_2$O on TiO$_2$(110). We perform this separation as a function of H$_2$O coverage and dissociation on stoichiometric and reduced surfaces. Due to hybridization with the TiO$_2$(110) surface, the H$_2$O 3a$_1$ and 1b$_1$ levels are broadened into several peaks between 5 and 1 eV below the TiO$_2$(110) valence band maximum (VBM). These peaks have both intermolecular and interfacial bonding and antibonding character. We find the highest occupied levels of H$_2$O adsorbed intact and dissociated on stoichiometric TiO$_2$(110) are 1.1 and 0.9 eV below the VBM. We also find a similar energy of 1.1 eV for the highest occupied levels of H$_2$O when adsorbed dissociatively on a bridging O vacancy of the reduced surface. In both cases, these energies are significantly higher (by 0.6 to 2.6 eV) than those estimated from UPS difference spectra, which are inconclusive in this energy region. Finally, we apply self-consistent QP$GW$ (scQP$GW$1) to obtain the ionization potential of the H$_2$O-TiO$_2$(110) interface.Comment: 12 pages, 12 figures, 1 tabl

Genetic markers of Restless Legs Syndrome in Parkinson disease

INTRODUCTION: Several studies proposed that Restless Legs Syndrome (RLS) and Parkinson disease (PD) may be clinically and/or etiologically related. To examine this hypothesis, we aimed to determine whether the known RLS genetic markers may be associated with PD risk, as well as with PD subtype. METHODS: Two case-control cohorts from Tel-Aviv and New-York, including 1133 PD patients and 867 controls were genotyped for four RLS-related SNPs in the genes MEIS1, BTBD9, PTPRD and MAP2K5/SKOR1. The association between genotype, PD risk and phenotype was tested using multivariate regression models. RESULTS: None of the tested SNPs was significantly associated with PD risk, neither in any individual cohort nor in the combined analysis after correction for multiple comparisons. The MAP2K5/SKOR1 marker rs12593813 was associated with higher frequency of tremor in the Tel-Aviv cohort (61.0% vs. 46.5%, p = 0.001, dominant model). However, the risk allele for tremor in this gene has been associated with reduced RLS risk. Moreover, this association did not replicate in Tremor-dominant PD patients from New-York. CONCLUSION: RLS genetic risk markers are not associated with increased PD risk or subtype in the current study. Together with previous genetic, neuropathological and epidemiologic studies, our results further strengthen the notion that RLS and PD are likely to be distinct entities