Mutations in CHMP2B in lower motor neuron predominant amyotrophic lateral sclerosis (ALS)

Background: Amyotrophic lateral sclerosis (ALS), a common late-onset neurodegenerative disease, is associated with fronto-temporal dementia (FTD) in 3-10% of patients. A mutation in CHMP2B was recently identified in a Danish pedigree with autosomal dominant FTD. Subsequently, two unrelated patients with familial ALS, one of whom also showed features of FTD, were shown to carry missense mutations in CHMP2B. The initial aim of this study was to determine whether mutations in CHMP2B contribute more broadly to ALS pathogenesis. Methodology/Principal Findings: Sequencing of CHMP2B in 433 ALS cases from the North of England identified 4 cases carrying 3 missense mutations, including one novel mutation, p. Thr104Asn, none of which were present in 500 neurologically normal controls. Analysis of clinical and neuropathological data of these 4 cases showed a phenotype consistent with the lower motor neuron predominant (progressive muscular atrophy (PMA)) variant of ALS. Only one had a recognised family history of ALS and none had clinically apparent dementia. Microarray analysis of motor neurons from CHMP2B cases, compared to controls, showed a distinct gene expression signature with significant differential expression predicting disassembly of cell structure; increased calcium concentration in the ER lumen; decrease in the availability of ATP; down-regulation of the classical and p38 MAPK signalling pathways, reduction in autophagy initiation and a global repression of translation. Transfection of mutant CHMP2B into HEK-293 and COS-7 cells resulted in the formation of large cytoplasmic vacuoles, aberrant lysosomal localisation demonstrated by CD63 staining and impairment of autophagy indicated by increased levels of LC3-II protein. These changes were absent in control cells transfected with wild-type CHMP2B. Conclusions/Significance: We conclude that in a population drawn from North of England pathogenic CHMP2B mutations are found in approximately 1% of cases of ALS and 10% of those with lower motor neuron predominant ALS. We provide a body of evidence indicating the likely pathogenicity of the reported gene alterations. However, absolute confirmation of pathogenicity requires further evidence, including documentation of familial transmission in ALS pedigrees which might be most fruitfully explored in cases with a LMN predominant phenotype

Habitat Features Predict the Distribution of Recreational Shooters in the Morley Nelson Snake River Birds of Prey National Conservation Area

The Morley Nelson Snake River Birds of Prey National Conservation Area (NCA) is a popular destination of many Treasure Valley residents. There, recreationists participate in various pastimes such as target shooting, recreational shooting/hunting, and wildlife viewing. However, these activities have the potential to interfere with one another. Recreational shooting of Piute ground squirrels (Urocitellus mollis) could affect prey availability and scavenging opportunities for associated raptor species, most notably local golden eagle (Aquila chrysaetos) populations. To assess possible interactions among shooters, prey and raptors, the spatial density and habitat preference of human shooters must be determined. We hypothesized that higher shooter density would be correlated with proximity to high-use roads and habitat with high visibility. To test this hypothesis, the spatial density and habitat preference of human shooters was determined. First, three routes of approximately 16 km each were established throughout the northwest section of the NCA through “hunter hotspots” of various habitat types. Routes were driven on weekends, starting in the morning, from February 28 to March 21, 2015. Data was collected opportunistically on all shooters observed including group size, demographics, location, and the habitat characteristics (e.g. proximity to roads and visibility) of shooting sites. These data were used to determine which habitat features best predicted shooting locations. This study may directly inform future research on golden eagle scavenging ecology, competition between hunters and eagles, and the potential for lead entry into the ecosystem through use of lead ammunition

Bisphenol A and Phthalates: Public Knowledge and Risk Perception

Introduction: Bisphenol A (BPA) and phthalates are chemicals used in the production of many plastics, including food containers, water bottles, and medical intravenous tubing. These chemicals can leach from the plastic, especially when heated, and are found in varying concentrations in the human body. There is concern about the widespread exposure to BPA and phthalates since studies indicate they may cause adverse health effects, particularly related to endocrine development and regulation in young children.https://scholarworks.uvm.edu/comphp_gallery/1041/thumbnail.jp

Edge-coloring a graph GG so that every copy of a graph HH has an odd color class

Recently, Alon introduced the notion of an $H$-code for a graph $H$: a collection of graphs on vertex set $[n]$ is an $H$-code if it contains no two members whose symmetric difference is isomorphic to $H$. Let $D_{H}(n)$ denote the maximum possible cardinality of an $H$-code, and let $d_{H}(n)=D_{H}(n)/2^{n \choose 2}$. Alon observed that a lower bound on $d_{H}(n)$ can be obtained by attaining an upper bound on the number of colors needed to edge-color $K_n$ so that every copy of $H$ has an odd color class. Motivated by this observation, we define $g(G,H)$ to be the minimum number of colors needed to edge-color a graph $G$ so that every copy of $H$ has an odd color class. We prove $g(K_n,K_5) \le n^{o(1)}$ and $g(K_{n,n}, C_4) \le \frac{t}{2(t-1)}n+o(n)$ for all odd integers $t\geq 5$. The first result shows $d_{K_5}(n) \ge \frac{1}{n^{o(1)}}$ and was obtained independently in arXiv:2306.14682

Human tribbles-1 controls proliferation and chemotaxis of smooth muscle cells via MAPK signaling pathways

Migration and proliferation of smooth muscle cells are key to a number of physiological and pathological processes, including wound healing and the narrowing of the vessel wall.Previous work has shown links between inflammatory stimuli and vascular smooth muscle cell proliferation and migration through mitogen activated protein kinase (MAPK) activation, though the molecular mechanisms of this process are poorly understood. Here we report that tribbles-1, a recently described modulator of MAPK activation controls vascular smooth muscle cell proliferation and chemotaxis via the Jun Kinase pathway. Our findings demonstrate that this regulation takes place via direct interactions between tribbles-1 and MKK4/SEK1, a Jun activator kinase. The activity of this kinase is dependent on tribbles-1 levels, whilst the activation and the expression of MKK4/SEK1 is not. In addition, tribbles-1 expression is elevated in human atherosclerotic arteries compared to non-atherosclerotic controls, suggesting that this protein may pay a role in disease in vivo. In summary, the data presented here suggest an important regulatory role for trb-1 in vascular smooth muscle cell biology

The WiggleZ Dark Energy Survey: the selection function and z=0.6 galaxy power spectrum

We report one of the most accurate measurements of the three-dimensional large-scale galaxy power spectrum achieved to date, using 56,159 redshifts of bright emission-line galaxies at effective redshift z=0.6 from the WiggleZ Dark Energy Survey at the Anglo-Australian Telescope. We describe in detail how we construct the survey selection function allowing for the varying target completeness and redshift completeness. We measure the total power with an accuracy of approximately 5% in wavenumber bands of dk=0.01 h/Mpc. A model power spectrum including non-linear corrections, combined with a linear galaxy bias factor and a simple model for redshift-space distortions, provides a good fit to our data for scales k < 0.4 h/Mpc. The large-scale shape of the power spectrum is consistent with the best-fitting matter and baryon densities determined by observations of the Cosmic Microwave Background radiation. By splitting the power spectrum measurement as a function of tangential and radial wavenumbers we delineate the characteristic imprint of peculiar velocities. We use these to determine the growth rate of structure as a function of redshift in the range 0.4 < z < 0.8, including a data point at z=0.78 with an accuracy of 20%. Our growth rate measurements are a close match to the self-consistent prediction of the LCDM model. The WiggleZ Survey data will allow a wide range of investigations into the cosmological model, cosmic expansion and growth history, topology of cosmic structure, and Gaussianity of the initial conditions. Our calculation of the survey selection function will be released at a future date via our website wigglez.swin.edu.au.Comment: 21 pages, 22 figures, accepted for publication in MNRA

Online Ramsey numbers of ordered paths and cycles

An ordered graph is a graph with a linear ordering on its vertices. The online Ramsey game for ordered graphs $G$ and $H$ is played on an infinite sequence of vertices; on each turn, Builder draws an edge between two vertices, and Painter colors it red or blue. Builder tries to create a red $G$ or a blue $H$ as quickly as possible, while Painter wants the opposite. The online ordered Ramsey number $r_o(G,H)$ is the number of turns the game lasts with optimal play. In this paper, we consider the behavior of $r_o(G,P_n)$ for fixed $G$, where $P_n$ is the monotone ordered path. We prove an $O(n \log_2n)$ bound on $r_o(G,P_n)$ for all $G$ and an $O(n)$ bound when $G$ is $3$-ichromatic; we partially classify graphs $G$ with $r_o(G,P_n) = n + O(1)$. Many of these results extend to $r_o(G,C_n)$, where $C_n$ is an ordered cycle obtained from $P_n$ by adding one edge