Pathologic Thr 175 tau phosphorylation in CTE and CTE with ALS

Objective To investigate whether chronic traumatic encephalopathy (CTE) and CTE with amyotrophic lateral sclerosis (CTE-ALS) exhibit features previously observed in other tauopathies of pathologic phosphorylation of microtubule-associated protein tau at Thr 175 (pThr 175 tau) and Thr 231 (pThr 231 tau), and glycogen synthase kinase-3β (GSK3β) activation, and whether these pathologic features are a consequence of traumatic brain injury (TBI). Methods Tau isoform expression was assayed by western blot in 6 stage III CTE cases. We also used immunohistochemistry to analyze 5 cases each of CTE, CTE-ALS, and 5 controls for expression of activated GSK3β, pThr 175 tau, pThr 231 tau, and oligomerized tau within spinal cord tissue and hippocampus. Using a rat model of moderate TBI, we assessed tau pathology and phospho-GSK3β expression at 3 months postinjury. Results CTE and CTE-ALS are characterized by the presence of all 6 tau isoforms in both soluble and insoluble tau isolates. Activated GSK3β, pThr 175 tau, pThr 231 tau, and oligomerized tau protein expression was observed in hippocampal neurons and spinal motor neurons. We observed tau neuronal pathology (fibrillar inclusions and axonal damage) and increased levels of pThr 175 tau and activated GSK3β in moderate TBI rats. Conclusions Pathologic phosphorylation of tau at Thr 175 and Thr 231 and activation of GSK3β are features of the tauopathy of CTE and CTE-ALS. These features can be replicated in an animal model of moderate TBI

Evaluating The Roles Of Visual Openness And Edge Effects On Nest-Site Selection And Reproductive Success In Grassland Birds

In some species, habitat edges (ecotones) affect nest-site selection and nesting success. Openness, or how visually open a habitat is, has recently been shown to influence grassland bird density and may affect nest-site selection, possibly by reducing the risk of predation on adults, nests, or both. Because edge and openness are correlated, it is possible that effects of openness have been overlooked or inappropriately ascribed to edge effects. We tested the roles of edges and visual openness in nest-site selection and nesting success of two grassland passerines, the Bobolink (Dolichonyx oryzivorus) and Savannah Sparrow (Passerculus sandwichensis), in the Champlain Valley, Vermont. We also evaluated the sensitivity of our results to alternative definitions of edge on our landscape. Bobolink (n = 580) and Savannah Sparrow nests (n = 922) were located on seven hay fields and three pastures from 2002 to 2010. Both species avoided placing nests near edges and in less open habitat compared with expectations based on random placement. When the effects of openness and edge were separated, less open habitats were still avoided, but edge responses were less clear. These results were robust to different definitions of habitat edge. We found no strong relationships between either openness or edges and reproductive success (numbers of eggs and fledglings, percentage of eggs producing fledglings, and nest success), although there may be an edge-specific openness effect on timing of reproduction (clutch completion date). Our results support openness as an important factor in nest-site selection by grassland birds

Synergistic toxicity in an in vivo model of neurodegeneration through the co-expression of human TDP-43\u3csup\u3eM337V\u3c/sup\u3e and tau\u3csup\u3eT175D\u3c/sup\u3e protein

Although it has been suggested that the co-expression of multiple pathological proteins associated with neurodegeneration may act synergistically to induce more widespread neuropathology, experimental evidence of this is sparse. We have previously shown that the expression of Thr175Asp-tau (tauT175D) using somatic gene transfer with a stereotaxically-injected recombinant adeno-associated virus (rAAV9) vector induces tau pathology in rat hippocampus. In this study, we have examined whether the co-expression of human tauT175D with mutant human TDP-43 (TDP-43M337V) will act synergistically. Transgenic female Sprague-Dawley rats that inducibly express mutant human TDP-43M337V using the choline acetyltransferase (ChAT) tetracycline response element (TRE) driver with activity modulating tetracycline-controlled transactivator (tTA) were utilized in these studies. Adult rats were injected with GFP-tagged tau protein constructs in a rAAV9 vector through bilateral stereotaxic injection into the hippocampus. Injected tau constructs were: wild-type GFP-tagged 2N4R human tau (tauWT; n = 8), GFP-tagged tauT175D 2N4R human tau (tauT175D, pseudophosphorylated, toxic variant, n = 8), and GFP (control, n = 8). Six months post-injection, mutant TDP-43M337V expression was induced for 30 days. Behaviour testing identified motor deficits within 3 weeks after TDP-43 expression irrespective of tau expression, though social behaviour and sensorimotor gating remained unchanged. Increased tau pathology was observed in the hippocampus of both tauWT and tauT175D expressing rats and tauT175D pathology was increased in the presence of cholinergic neuronal expression of human TDP-43M337V. These data indicate that co-expression of pathological TDP-43 and tau protein exacerbate the pathology associated with either individual protein

Asexuality: Classification and characterization

This is a post-print version of the article. The official published version can be obtaineed at the link below.The term “asexual” has been defined in many different ways and asexuality has received very little research attention. In a small qualitative study (N = 4), individuals who self-identified as asexual were interviewed to help formulate hypotheses for a larger study. The second larger study was an online survey drawn from a convenience sample designed to better characterize asexuality and to test predictors of asexual identity. A convenience sample of 1,146 individuals (N = 41 self-identified asexual) completed online questionnaires assessing sexual history, sexual inhibition and excitation, sexual desire, and an open-response questionnaire concerning asexual identity. Asexuals reported significantly less desire for sex with a partner, lower sexual arousability, and lower sexual excitation but did not differ consistently from non-asexuals in their sexual inhibition scores or their desire to masturbate. Content analyses supported the idea that low sexual desire is the primary feature predicting asexual identity

Predicting the mutations generated by repair of Cas9-induced double-strand breaks.

The DNA mutation produced by cellular repair of a CRISPR-Cas9-generated double-strand break determines its phenotypic effect. It is known that the mutational outcomes are not random, but depend on DNA sequence at the targeted location. Here we systematically study the influence of flanking DNA sequence on repair outcome by measuring the edits generated by >40,000 guide RNAs (gRNAs) in synthetic constructs. We performed the experiments in a range of genetic backgrounds and using alternative CRISPR-Cas9 reagents. In total, we gathered data for >109 mutational outcomes. The majority of reproducible mutations are insertions of a single base, short deletions or longer microhomology-mediated deletions. Each gRNA has an individual cell-line-dependent bias toward particular outcomes. We uncover sequence determinants of the mutations produced and use these to derive a predictor of Cas9 editing outcomes. Improved understanding of sequence repair will allow better design of gene editing experiments

Rapid intraoperative insulin assay: a novel method to differentiate insulinoma from nesidioblastosis in the pediatric patient

Introduction: Hyperinsulinism is the most common cause of recurrent and persistent hypoglycemia in infancy and childhood. Causes can include nesidioblastosis, pancreatic islet cell tumors such as insulinoma, and associations with multiple endocrine neoplasia syndromes. Although new, improved imaging techniques have allowed for more precise preoperative localization of insulinomas, the differentiation of nesidioblastosis and insulinoma, particularly in children, can be challenging. To improve intraoperative localization and confirmation of successful resection of insulinoma, a novel hormonal assay, the rapid intraoperative insulin assay, is reported for the first time in a pediatric patient. This intraoperative radioimmunoassay for insulin yields results within several minutes and confirms complete resection of insulinoma. Case description: We present a case of pancreatic insulinoma in a child with symptoms of severe hypoglycemia, causing seizures. The insulinoma was enucleated laparoscopically, and rapid intra-operative insulin assay used to determine the success of the procedure. Discussion and evaluation: This rapid intra-operative test provides a valuable adjunct for determining complete excision in complicated cases of recurrent or questionable insulinoma. Although not a common problem, for pediatric patients in whom the diagnosis is not clear, this test may provide a novel approach to confirming disease. Conclusion: We propose the use of this assay in facilitating intra-operative resection and confirmation of complete excision in pediatric patients. This population may especially benefit from this novel assay to confirm complete resection and to differentiate multiple etiologies of hyperinsulinism

Cerebellar Integrity in the Amyotrophic Lateral Sclerosis - Frontotemporal Dementia Continuum

Amyotrophic lateral sclerosis (ALS) and behavioural variant frontotemporal dementia (bvFTD) are multisystem neurodegenerative disorders that manifest overlapping cognitive, neuropsychiatric and motor features. The cerebellum has long been known to be crucial for intact motor function although emerging evidence over the past decade has attributed cognitive and neuropsychiatric processes to this structure. The current study set out i) to establish the integrity of cerebellar subregions in the amyotrophic lateral sclerosis-behavioural variant frontotemporal dementia spectrum (ALS-bvFTD) and ii) determine whether specific cerebellar atrophy regions are associated with cognitive, neuropsychiatric and motor symptoms in the patients. Seventy-eight patients diagnosed with ALS, ALS-bvFTD, behavioural variant frontotemporal dementia (bvFTD), most without C9ORF72 gene abnormalities, and healthy controls were investigated. Participants underwent cognitive, neuropsychiatric and functional evaluation as well as structural imaging using voxel-based morphometry (VBM) to examine the grey matter subregions of the cerebellar lobules, vermis and crus. VBM analyses revealed: i) significant grey matter atrophy in the cerebellum across the whole ALS-bvFTD continuum; ii) atrophy predominantly of the superior cerebellum and crus in bvFTD patients, atrophy of the inferior cerebellum and vermis in ALS patients, while ALS-bvFTD patients had both patterns of atrophy. Post-hoc covariance analyses revealed that cognitive and neuropsychiatric symptoms were particularly associated with atrophy of the crus and superior lobule, while motor symptoms were more associated with atrophy of the inferior lobules. Taken together, these findings indicate an important role of the cerebellum in the ALS-bvFTD disease spectrum, with all three clinical phenotypes demonstrating specific patterns of subregional atrophy that associated with different symptomology

Study of the footprints of short-term variation in XCO₂ observed by TCCON sites using NIES and FLEXPART atmospheric transport models

The Total Carbon Column Observing Network (TCCON) is a network of ground-based Fourier Transform Spectrometers (FTS) that record near-infrared (NIR) spectra of the Sun. From these spectra, accurate and precise observations of CO2 column-averaged dry-air mole fraction (denoted XCO2) are retrieved. TCCON FTS observations have previously been used to validate satellite estimations of XCO2; however, our knowledge of the short-term spatial and temporal variations in XCO2 surrounding the TCCON sites is limited. In this work, we use the National Institute for Environmental Studies (NIES) Eulerian three-dimensional transport model and the FLEXPART (FLEXible PARTicle) Lagrangian Particle Dispersion Model (LPDM) to determine the footprints of short-term variations in XCO2 observed by operational, past, future, and possible TCCON sites. We propose a footprint-based method for the colocation of satellite and TCCON XCO2 observations, and estimate the performance of the method using the NIES model and five GOSAT XCO2 product datasets. Comparison of the proposed approach with a standard geographic method shows higher number of colocation points and average bias reduction up to 0.15 ppm for a subset of 16 stations for the period from January 2010 to January 2014. Case studies of the Darwin and La Réunion sites reveal that when the footprint area is rather curved, non-uniform and significantly different from a geographical rectangular area, the differences between these approaches are more noticeable. This emphasizes that the colocation is sensitive to local meteorological conditions and flux distributions

Single hadron response measurement and calorimeter jet energy scale uncertainty with the ATLAS detector at the LHC

The uncertainty on the calorimeter energy response to jets of particles is derived for the ATLAS experiment at the Large Hadron Collider (LHC). First, the calorimeter response to single isolated charged hadrons is measured and compared to the Monte Carlo simulation using proton-proton collisions at centre-of-mass energies of sqrt(s) = 900 GeV and 7 TeV collected during 2009 and 2010. Then, using the decay of K_s and Lambda particles, the calorimeter response to specific types of particles (positively and negatively charged pions, protons, and anti-protons) is measured and compared to the Monte Carlo predictions. Finally, the jet energy scale uncertainty is determined by propagating the response uncertainty for single charged and neutral particles to jets. The response uncertainty is 2-5% for central isolated hadrons and 1-3% for the final calorimeter jet energy scale.Comment: 24 pages plus author list (36 pages total), 23 figures, 1 table, submitted to European Physical Journal

Standalone vertex finding in the ATLAS muon spectrometer

A dedicated reconstruction algorithm to find decay vertices in the ATLAS muon spectrometer is presented. The algorithm searches the region just upstream of or inside the muon spectrometer volume for multi-particle vertices that originate from the decay of particles with long decay paths. The performance of the algorithm is evaluated using both a sample of simulated Higgs boson events, in which the Higgs boson decays to long-lived neutral particles that in turn decay to bbar b final states, and pp collision data at √s = 7 TeV collected with the ATLAS detector at the LHC during 2011