697 research outputs found

    ROLE OF THE SIXTH TRANSMEMBRANE DOMAIN IN THE CALCIUM-DEPENDENT GATING OF THE INTERMEDIATE CONDUCTANCE CALCIUM-ACTIVATED POTASSIUM CHANNEL, KCa3.1.

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    Ion channels are the molecular units that underlie electrical signaling in cells. Many physiological processes are dependent upon this signaling mechanism, as dysregulation often leads to severe pathophysiological consequences. The intermediate conductance calcium-activated potassium channel (KCa3.1) functions as heteromeric complexes with calmodulin (CaM), which is constitutively bound to the calmodulin-binding domain (CaMBD) of KCa3.1 located in the C-terminus, just distal to the sixth transmembrane domain (S6). This arrangement enables CaM to function as an intracellular Ca2+-sensor, coupling changes in the intracellular Ca2+ concentration to the regulation of channel activity. Understanding how channels gate or transition from the closed to the open conformation is a fundamental question in the field of ion channel biophysics. A chemomechanical gating model was proposed to explain how Ca2+-binding causes the channel to transition from a non-conducting to a conducting configuration. However, this model lacks a specific mechanism explaining how the conformational change in the CaMBD is coupled to the activation gate. Therefore, the goal of this dissertation was to investigate the role of S6 in the activation mechanism of KCa3.1. Specifically, I tested the hypothesis that the non-luminal residues in the C-terminal portion of S6 function as an interacting surface to couple CaM to the activation gate. Biochemical perturbation and site directed mutagenesis targeting predicted non-luminal residues in S6 act to shift the gatingequilibrium toward the open state by increasing the apparent Ca2+ affinity and dramatically slowing the deactivation process. Kinetic modeling using a 6-state gating scheme showed these perturbations act to slow the transition between the open state back to the closed state. The modification in the steady-state and kinetic behavior of the channel in combination with the kinetic analysis indicate the shift in gating equilibrium is caused by slowing the closing transition, suggesting the non-luminal surface of S6 is allosterically coupled to the activation gate. Therefore, in addition to being a structural component of the pore; S6 is also a dynamic component of the activation mechanism. Continuing to identify regions of the channel participating in the activation mechanism is critical to understand how Ca2+ binding leads to channel opening

    Gender Bias in Depression Detection Using Audio Features

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    Depression is a large-scale mental health problem and a challenging area for machine learning researchers in detection of depression. Datasets such as Distress Analysis Interview Corpus - Wizard of Oz (DAIC-WOZ) have been created to aid research in this area. However, on top of the challenges inherent in accurately detecting depression, biases in datasets may result in skewed classification performance. In this paper we examine gender bias in the DAIC-WOZ dataset. We show that gender biases in DAIC-WOZ can lead to an overreporting of performance. By different concepts from Fair Machine Learning, such as data re-distribution, and using raw audio features, we can mitigate against the harmful effects of bias.Comment: 5 pages, 2 figures, to be published at EUSIPCO 202

    Using GPS telemetry to validate least-cost modeling of gray squirrel ( Sciurus carolinensis) movement within a fragmented landscape

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    In Britain, the population of native red squirrels Sciurus vulgaris has suffered population declines and local extinctions. Interspecific resource competition and disease spread by the invasive gray squirrel Sciurus carolinensis are the main factors behind the decline. Gray squirrels have adapted to the British landscape so efficiently that they are widely distributed. Knowledge on how gray squirrels are using the landscape matrix and being able to predict their movements will aid management. This study is the first to use global positioning system (GPS) collars on wild gray squirrels to accurately record movements and land cover use within the landscape matrix. This data were used to validate Geographical Information System (GIS) least-cost model predictions of movements and provided much needed information on gray squirrel movement pathways and network use. Buffered least-cost paths and least-cost corridors provide predictions of the most probable movements through the landscape and are seen to perform better than the more expansive least-cost networks which include all possible movements. Applying the knowledge and methodologies gained to current gray squirrel expansion areas, such as Scotland and in Italy, will aid in the prediction of potential movement areas and therefore management of the invasive gray squirrel. The methodologies presented in this study could potentially be used in any landscape and on numerous species

    Blood–brain barrier disruption and ventricular enlargement are the earliest neuropathological changes in rats with repeated sub-concussive impacts over 2 weeks

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    Repeated sub-concussive impact (e.g. soccer ball heading), a significantly lighter form of mild traumatic brain injury, is increasingly suggested to cumulatively alter brain structure and compromise neurobehavioural function in the long-term. However, the underlying mechanisms whereby repeated long-term sub-concussion induces cerebral structural and neurobehavioural changes are currently unknown. Here, we utilised an established rat model to investigate the effects of repeated sub-concussion on size of lateral ventricles, cerebrovascular blood–brain barrier (BBB) integrity, neuroinflammation, oxidative stress, and biochemical distribution. Following repeated sub-concussion 3 days per week for 2 weeks, the rats showed significantly enlarged lateral ventricles compared with the rats receiving sham-only procedure. The sub-concussive rats also presented significant BBB dysfunction in the cerebral cortex and hippocampal formation, whilst neuromotor function assessed by beamwalk and rotarod tests were comparable to the sham rats. Immunofluorescent and spectroscopic microscopy analyses revealed no significant changes in neuroinflammation, oxidative stress, lipid distribution or protein aggregation, within the hippocampus and cortex. These data collectively indicate that repeated sub-concussion for 2 weeks induce significant ventriculomegaly and BBB disruption, preceding neuromotor deficits. © 2021, The Author(s). *Please note that there are multiple authors for this article therefore only the name of the first 5 including Federation University Australia affiliate “Andrew Lavender” is provided in this record*

    Bacterial physiological adaptations to contrasting edaphic conditions identified using landscape scale metagenomics

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    This project was funded by the UK Natural Environment Research Council (standard grant NE/E006353/1 to R.I.G., A.S.W., and M.B. and Soil Security grant NE/M017125/1 to R.I.G.). A.A.M. has received funding from the European Union’s Horizon 2020 Research and Innovation Program under Marie Skłodowska-Curie grant no. 655240. We wish to further acknowledge the lab assistance of Phillip James and the staff at the NERC Biomolecular Analysis Facility, University of Liverpool, United Kingdom.Peer reviewedPublisher PD

    Repeated long-term sub-concussion impacts induce motor dysfunction in rats : a potential rodent model

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    Whilst detrimental effects of repeated sub-concussive impacts on neurophysiological and behavioral function are increasingly reported, the underlying mechanisms are largely unknown. Here, we report that repeated sub-concussion with a light weight drop (25 g) in wild-type PVG rats for 2 weeks does not induce detectable neuromotor dysfunction assessed by beamwalk and rotarod tests. However, after 12 weeks of repeated sub-concussion, the rats exhibited moderate neuromotor dysfunction. This is the first study to demonstrate development of neuromotor dysfunction following multiple long-term sub-concussive impacts in rats. The outcomes may offer significant opportunity for future studies to understand the mechanisms of sub-concussion-induced neuropsychological changes. © Copyright © 2020 Lavender, Rawlings, Warnock, McGonigle, Hiles-Murison, Nesbit, Lam, Hackett, Fitzgerald and Takechi

    Genome-wide association study of multisite chronic pain in UK Biobank

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    Chronic pain is highly prevalent worldwide and represents a significant socioeconomic and public health burden. Several aspects of chronic pain, for example back pain and a severity-related phenotype ‘chronic pain grade’, have been shown previously to be complex heritable traits with a polygenic component. Additional pain-related phenotypes capturing aspects of an individual’s overall sensitivity to experiencing and reporting chronic pain have also been suggested as a focus for investigation. We made use of a measure of the number of sites of chronic pain in individuals within the UK general population. This measure, termed Multisite Chronic Pain (MCP), is a complex trait and its genetic architecture has not previously been investigated. To address this, we carried out a large-scale genome-wide association study (GWAS) of MCP in ~380,000 UK Biobank participants. Our findings were consistent with MCP having a significant polygenic component, with a Single Nucleotide Polymorphism (SNP) heritability of 10.2%. In total 76 independent lead SNPs at 39 risk loci were associated with MCP. Additional gene-level association analyses identified neurogenesis, synaptic plasticity, nervous system development, cell-cycle progression and apoptosis genes as enriched for genetic association with MCP. Genetic correlations were observed between MCP and a range of psychiatric, autoimmune and anthropometric traits, including major depressive disorder (MDD), asthma and Body Mass Index (BMI). Furthermore, in Mendelian randomisation (MR) analyses a causal effect of MCP on MDD was observed. Additionally, a polygenic risk score (PRS) for MCP was found to significantly predict chronic widespread pain (pain all over the body), indicating the existence of genetic variants contributing to both of these pain phenotypes. Overall, our findings support the proposition that chronic pain involves a strong nervous system component with implications for our understanding of the physiology of chronic pain. These discoveries may also inform the future development of novel treatment approaches

    Alzheimer disease genetic risk factor APOE e4, and cognitive abilities in 111,739 UK Biobank participants

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    Background: the apolipoprotein (APOE) e4 locus is a genetic risk factor for dementia. Carriers of the e4 allele may be more vulnerable to conditions that are independent risk factors for cognitive decline, such as cardiometabolic diseases. Objective: we tested whether any association with APOE e4 status on cognitive ability was larger in older ages or in those with cardiometabolic diseases. Subjects: UK Biobank includes over 500,000 middle- and older aged adults who have undergone detailed medical and cognitive phenotypic assessment. Around 150,000 currently have genetic data. We examined 111,739 participants with complete genetic and cognitive data. Methods: baseline cognitive data relating to information processing speed, memory and reasoning were used. We tested for interactions with age and with the presence versus absence of type 2 diabetes (T2D), coronary artery disease (CAD) and hypertension. Results: in several instances, APOE e4 dosage interacted with older age and disease presence to affect cognitive scores. When adjusted for potentially confounding variables, there was no APOE e4 effect on the outcome variables. Conclusions: future research in large independent cohorts should continue to investigate this important question, which has potential implications for aetiology related to dementia and cognitive impairment

    Target Selection for the LBTI Exozodi Key Science Program

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    The Hunt for Observable Signatures of Terrestrial planetary Systems (HOSTS) on the Large Binocular Telescope Interferometer will survey nearby stars for faint emission arising from ~300 K dust (exozodiacal dust), and aims to determine the exozodiacal dust luminosity function. HOSTS results will enable planning for future space telescopes aimed at direct spectroscopy of habitable zone terrestrial planets, as well as greater understanding of the evolution of exozodiacal disks and planetary systems. We lay out here the considerations that lead to the final HOSTS target list. Our target selection strategy maximizes the ability of the survey to constrain the exozodi luminosity function by selecting a combination of stars selected for suitability as targets of future missions and as sensitive exozodi probes. With a survey of approximately 50 stars, we show that HOSTS can enable an understanding of the statistical distribution of warm dust around various types of stars and is robust to the effects of varying levels of survey sensitivity induced by weather conditions.Comment: accepted to ApJ
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