The topology, structure and PE interaction of LITAF underpin a Charcot-Marie-Tooth disease type 1C

BACKGROUND: Mutations in Lipopolysaccharide-induced tumour necrosis factor-α factor (LITAF) cause the autosomal dominant inherited peripheral neuropathy, Charcot-Marie-Tooth disease type 1C (CMT1C). LITAF encodes a 17 kDa protein containing an N-terminal proline-rich region followed by an evolutionarily-conserved C-terminal 'LITAF domain', which contains all reported CMT1C-associated pathogenic mutations. RESULTS: Here, we report the first structural characterisation of LITAF using biochemical, cell biological, biophysical and NMR spectroscopic approaches. Our structural model demonstrates that LITAF is a monotopic zinc-binding membrane protein that embeds into intracellular membranes via a predicted hydrophobic, in-plane, helical anchor located within the LITAF domain. We show that specific residues within the LITAF domain interact with phosphoethanolamine (PE) head groups, and that the introduction of the V144M CMT1C-associated pathogenic mutation leads to protein aggregation in the presence of PE. CONCLUSIONS: In addition to the structural characterisation of LITAF, these data lead us to propose that an aberrant LITAF-PE interaction on the surface of intracellular membranes contributes to the molecular pathogenesis that underlies this currently incurable disease.Wellcome-Beit Prize; Intermediate Clinical Fellowship (093809/Z/10/Z); Wellcome Trust Strategic Award 100140; Wellcome Trust grant 09302

Psychological principles of successful aging technologies: A mini-review

Based on resource-oriented conceptions of successful life-span development, we propose three principles for evaluating assistive technology: (a) net resource release; (b) person specificity, and (c) proximal versus distal frames of evaluation. We discuss how these general principles can aid the design and evaluation of assistive technology in adulthood and old age, and propose two technological strategies, one targeting sensorimotor and the other cognitive functioning. The sensorimotor strategy aims at releasing cognitive resources such as attention and working memory by reducing the cognitive demands of sensory or sensorimotor aspects of performance. The cognitive strategy attempts to provide adaptive and individualized cuing structures orienting the individual in time and space by providing prompts that connect properties of the environment to the individual's action goals. We argue that intelligent assistive technology continuously adjusts the balance between `environmental support' and `self-initiated processing' in person-specific and aging-sensitive ways, leading to enhanced allocation of cognitive resources. Furthermore, intelligent assistive technology may foster the generation of formerly latent cognitive resources by activating developmental reserves (plasticity). We conclude that `lifespan technology', if co-constructed by behavioral scientists, engineers, and aging individuals, offers great promise for improving both the transition from middle adulthood to old age and the degree of autonomy in old age in present and future generations. Copyright (C) 2008 S. Karger AG, Basel

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Immunomodulatory strategies prevent the development of autoimmune emphysema

<p>Abstract</p> <p>Background</p> <p>The presence of anti-endothelial cell antibodies and pathogenic T cells may reflect an autoimmune component in the pathogenesis of emphysema. Whether immune modulatory strategies can protect against the development of emphysema is not known.</p> <p>Methods</p> <p>Sprague Dawley rats were immunized with human umbilical vein endothelial cells (HUVEC) to induce autoimmune emphysema and treated with intrathymic HUVEC-injection and pristane. Measurements of alveolar airspace enlargement, cytokine levels, immuno histochemical, western blot analysis, and T cell repertoire of the lung tissue were performed.</p> <p>Results</p> <p>The immunomodulatory strategies protected lungs against cell death as demonstrated by reduced numbers of TUNEL and active caspase-3 positive cells and reduced levels of active caspase-3, when compared with lungs from HUVEC-immunized rats. Immunomodulatory strategies also suppressed anti-endothelial antibody production and preserved CNTF, IL-1alpha and VEGF levels. The immune deviation effects of the intrathymic HUVEC-injection were associated with an expansion of CD4+CD25+Foxp3+ regulatory T cells. Pristane treatment decreased the proportion of T cells expressing receptor beta-chain, Vβ16.1 in the lung tissue.</p> <p>Conclusions</p> <p>Our data demonstrate that interventions classically employed to induce central T cell tolerance (thymic inoculation of antigen) or to activate innate immune responses (pristane treatment) can prevent the development of autoimmune emphysema.</p

Meta-ethnography of experiences of early discharge, with a focus on paediatric febrile neutropenia

PURPOSE (STATING THE MAIN PURPOSES AND RESEARCH QUESTION): Many children have no significant sequelae of febrile neutropenia. A systematic review of clinical studies demonstrated patients at low risk of septic complications can be safely treated as outpatients using oral antibiotics with low rates of treatment failure. Introducing earlier discharge may improve quality of life, reduce hospital acquired infection and reduce healthcare service pressures. However, the review raised concerns that this might not be acceptable to patients, families and healthcare professionals. METHODS: This qualitative synthesis explored experiences of early discharge in paediatric febrile neutropenia, including reports from studies of adult febrile neutropenia and from other paediatric conditions. Systematic literature searching preceded meta-ethnographic analysis, including reading the studies and determining relationships between studies, translation of studies and synthesis of these translations. RESULTS: Nine papers were included. The overarching experience of early discharge is that decision-making is complex and difficult and influenced by fear, timing and resources. From this background, we identified two distinct themes. First, participants struggled with practical consequences of treatment regimens, namely childcare, finances and follow-up. A second theme identified social and emotional issues, including isolation, relational and environmental challenges. Linking these, participants considered continuity of care and the need for information important. CONCLUSIONS: Trust and confidence appeared interdependent with resources available to families-both are required to manage early discharge. Socially informed resilience is relevant to facilitating successful discharge strategies. Interventions which foster resilience may mediate the ability and inclination of families to accept early discharge. Services have an important role in recognising and enhancing resilience

A school-based resilience intervention to decrease tobacco, alcohol and marijuana use in high school students

<p>Abstract</p> <p>Background</p> <p>Despite schools theoretically being an ideal setting for accessing adolescents and preventing initiation of substance use, there is limited evidence of effective interventions in this setting. Resilience theory provides one approach to achieving such an outcome through improving adolescent mental well-being and resilience. A study was undertaken to examine the potential effectiveness of such an intervention approach in improving adolescent resilience and protective factor scores; and reducing the prevalence of adolescent tobacco, alcohol and marijuana use in three high schools.</p> <p>Methods</p> <p>A non-controlled before and after study was undertaken. Data regarding student resilience and protective factors, and measures of tobacco, alcohol and marijuana use were collected from grade 7 to 10 students at baseline (n = 1449) and one year following a three year intervention (n = 1205).</p> <p>Results</p> <p>Significantly higher resilience and protective factors scores, and significantly lower prevalence of substance use were evident at follow up.</p> <p>Conclusions</p> <p>The results suggest that the intervention has the potential to increase resilience and protective factors, and to decrease the use of tobacco, alcohol and marijuana by adolescents. Further more rigorous research is required to confirm this potential.</p

Developmental malformation of the corpus callosum: a review of typical callosal development and examples of developmental disorders with callosal involvement

This review provides an overview of the involvement of the corpus callosum (CC) in a variety of developmental disorders that are currently defined exclusively by genetics, developmental insult, and/or behavior. I begin with a general review of CC development, connectivity, and function, followed by discussion of the research methods typically utilized to study the callosum. The bulk of the review concentrates on specific developmental disorders, beginning with agenesis of the corpus callosum (AgCC)—the only condition diagnosed exclusively by callosal anatomy. This is followed by a review of several genetic disorders that commonly result in social impairments and/or psychopathology similar to AgCC (neurofibromatosis-1, Turner syndrome, 22q11.2 deletion syndrome, Williams yndrome, and fragile X) and two forms of prenatal injury (premature birth, fetal alcohol syndrome) known to impact callosal development. Finally, I examine callosal involvement in several common developmental disorders defined exclusively by behavioral patterns (developmental language delay, dyslexia, attention-deficit hyperactive disorder, autism spectrum disorders, and Tourette syndrome)

Search for High-Mass Resonances Decaying to τν in pp Collisions at √s=13 TeV with the ATLAS Detector

A search for high-mass resonances decaying to τν using proton-proton collisions at √s=13 TeV produced by the Large Hadron Collider is presented. Only τ-lepton decays with hadrons in the final state are considered. The data were recorded with the ATLAS detector and correspond to an integrated luminosity of 36.1 fb−1. No statistically significant excess above the standard model expectation is observed; model-independent upper limits are set on the visible τν production cross section. Heavy W′ bosons with masses less than 3.7 TeV in the sequential standard model and masses less than 2.2–3.8 TeV depending on the coupling in the nonuniversal G(221) model are excluded at the 95% credibility level

Combined measurement of differential and total cross sections in the H → γγ and the H → ZZ* → 4ℓ decay channels at s=13 TeV with the ATLAS detector

A combined measurement of differential and inclusive total cross sections of Higgs boson production is performed using 36.1 fb−1 of 13 TeV proton–proton collision data produced by the LHC and recorded by the ATLAS detector in 2015 and 2016. Cross sections are obtained from measured H→γγ and H→ZZ*(→4ℓ event yields, which are combined taking into account detector efficiencies, resolution, acceptances and branching fractions. The total Higgs boson production cross section is measured to be 57.0−5.9 +6.0 (stat.) −3.3 +4.0 (syst.) pb, in agreement with the Standard Model prediction. Differential cross-section measurements are presented for the Higgs boson transverse momentum distribution, Higgs boson rapidity, number of jets produced together with the Higgs boson, and the transverse momentum of the leading jet. The results from the two decay channels are found to be compatible, and their combination agrees with the Standard Model predictions