125 research outputs found

    Plasma lipocalin-2/NGAL is stable over 12 weeks and is not modulated by exercise or dieting

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    Amongst other immune cells, neutrophils play a key role in systemic inflammation leading to cardiovascular disease and can release inflammatory factors, including lipocalin-2 (LCN2). LCN2 drives cardiac hypertrophy and plays a role in maladaptive remodelling of the heart and has been associated with renal injury. While lifestyle factors such as diet and exercise are known to attenuate low-grade inflammation, their ability to modulate plasma LCN2 levels is unknown. Forty-eight endurance athletes and 52 controls (18–55 years) underwent measurement for various cardiovascular health indicators, along with plasma LCN2 concentration. No significant difference in LCN2 concentration was seen between the two groups. LCN2 was a very weak predictor or absent from models describing blood pressures or predicting athlete status. In another cohort, 57 non-diabetic overweight or obese men and post-menopausal women who fulfilled Adult Treatment Panel III metabolic syndrome criteria were randomly allocated into either a control, modified Dietary Approaches to Stop Hypertension (DASH) diet, or DASH and exercise group. Pre- and post-intervention demographic, cardiovascular health indicators, and plasma LCN2 expression were measured in each individual. While BMI fell in intervention groups, LCN2 levels remained unchanged within and between all groups, as illustrated by strong correlations between LCN2 concentrations pre- and 12 weeks post-intervention (r = 0.743, P < 0.0001). This suggests that circulating LCN2 expression are stable over a period of at least 12 weeks and is not modifiable by diet and exercise. © 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 “Priscilla Prestes, Brendan O'Brien, Fadi Charchar and Francine Marques” is provided in this record**

    Telomeres, aging and exercise : Guilty by association?

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    Telomeres are repetitive tandem DNA sequences that cap chromosomal ends protecting genomic DNA from enzymatic degradation. Telomeres progressively shorten with cellular replication and are therefore assumed to correlate with biological and chronological age. An expanding body of evidence suggests (i) a predictable inverse association between telomere length, aging and age-related diseases and (ii) a positive association between physical activity and telomere length. Both hypotheses have garnered tremendous research attention and broad consensus; however, the evidence for each proposition is inconsistent and equivocal at best. Telomere length does not meet the basic criteria for an aging biomarker and at least 50% of key studies fail to find associations with physical activity. In this review, we address the evidence in support and refutation of the putative associations between telomere length, aging and physical activity. We finish with a brief review of plausible mechanisms and potential future research directions. © 2017 by the authors. Licensee MDPI, Basel, Switzerland

    Localization of the paranodal protein Caspr in the mammalian retina

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    Purpose: The retina has the demanding task of encoding all aspects of the visual scene within the space of one fixation period lasting only a few hundred milliseconds. To accomplish this feat, information is encoded in specialized parallel channels and passed on to numerous central nuclei via the optic nerve. These parallel channels achieve specialization in at least three ways: the synaptic networks in which they participate, the neurotransmitter receptors expressed and the types and locations of ion channels or transporters used. Subcellular localization of receptors, channels and transporters is made yet more complex in the retina by the double duty many retinal processes serve. In the present work, we show that the protein Caspr (Contactin Associated Protein), best known for its critical role in the localization of voltage-gated ion channels at the nodes of Ranvier, is present in several types of retinal neurons including amacrine, bipolar, horizontal, and ganglion cells. Methods: Using standard double label immunofluorescence protocols, we characterized the pattern of Caspr expression in the rodent retina. Results: Caspr labeling was observed through much of the retina, including horizontal, bipolar, amacrine, and ganglion cells. Among amacrine cells, Caspr was observed in AII amacrine cells through co-localization with Parvalbumin and Disabled-1 in rat and mouse retinas, respectively. An additional amacrine cell type containing Calretinin also co-localized with Caspr, but did not co-localize with choline-acetyltransferase. Nearly all cells in the ganglion cell layer contain Caspr, including both displaced amacrine and ganglion cells. In the outer retina, Caspr was co-localized with PKC labeling in rod bipolar cell dendrites. In addition, Caspr labeling was found inside syntaxin-4 'sandwiches' in the outer plexiform layer, most likely indicating its presence in cone bipolar cell dendrites. Finally, Caspr was co-localized in segments of horizontal cell dendrites labeled with Calbindin-D28k. Conclusions: Caspr is best known for its role in organizing the localization of different voltage-gated ion channels in and around nodes of Ranvier. As neuronal processes in the retina often play a dual role involving both input and output, it is possible that the localization of Caspr in the retina will help us decipher the way retinal cells localize ion channels in their processes to increase computational capacity

    Youth Suicide and Self-Harm: Latent Class Profiles of Adversity and the Moderating Roles of Perceived Support and Sense of Safety

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    Research suggests that exposure to adversity can lead to an increased risk of experiencing suicidal and self-injurious thoughts or behaviours, but few studies have examined whether different patterns of adversity are differentially associated with youth suicide/self-harm. The current study aims to explore the relationship between exposure to adversity across various social domains and youth self-harm and suicidality, using a person centred approach, and examines whether access to social support and a sense of safety across home, peer or school settings buffer the relationship between adversity and self-harm/suicidality. Secondary data analyses were carried out on cross-sectional self-report data collected from 4848 (Mage=15.78, SDĂą =Ăą 0.59; 50% female) adolescents who participated in the Irish Planet Youth survey. Latent Class Analyses identified four distinct profiles of adversity; low-adversity (nĂą =Ăą 2043, 42%); peer-adversity (nĂą =Ăą 972, 20%); parental-adversity (nĂą =Ăą 1189, 25%); and multiple-adversity (nĂą =Ăą 644, 13%). Findings from logistic moderated regressions indicated that there were significant differences in self-harm and suicidality across the adversity classes. Although parental support and perceived safety at school were negatively associated with suicidality and self-harm outcomes, no significant moderation effects were observed. These findings suggest that youth who experience adversity across multiple social domains are more likely to report suicidal and self-harm thoughts and behaviours, and should be key targets for intervention/prevention efforts. While parental support and school safety may act as significant compensatory factors, further work is needed to identify the social resources that can offset the risk imposed by youthĂą s adverse experiences.This research was funded by the Health Research Board. Grant Number: SDAP-2021-025. Open Access funding provided by the IReL Consortium.peer-reviewe

    Observing an intermediate-mass black hole GW190521 with minimal assumptions

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    On May 21, 2019 the Advanced LIGO and Advanced Virgo detectors observed a gravitationalwave transient GW190521, the heaviest binary black-hole merger detected to date with remnant mass of 142 M⊙ that was published recently. This observation is the first strong evidence for the existence of intermediate-mass black holes. The significance of this observation was determined by the coherent WAVEBURST (cWB) search algorithm, which identified GW190521 with minimal assumptions of its source model. In this paper, we show the performance of cWB for the detection of the binary black-hole mergers without use of the signal templates, describe the details of the GW190521 detection, and establish the consistency of the model-agnostic reconstruction of GW190521 by cWB with the theoretical waveform model of a binary black hole

    OpenFermion: The Electronic Structure Package for Quantum Computers

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    Quantum simulation of chemistry and materials is predicted to be an important application for both near-term and fault-tolerant quantum devices. However, at present, developing and studying algorithms for these problems can be difficult due to the prohibitive amount of domain knowledge required in both the area of chemistry and quantum algorithms. To help bridge this gap and open the field to more researchers, we have developed the OpenFermion software package (www.openfermion.org). OpenFermion is an open-source software library written largely in Python under an Apache 2.0 license, aimed at enabling the simulation of fermionic models and quantum chemistry problems on quantum hardware. Beginning with an interface to common electronic structure packages, it simplifies the translation between a molecular specification and a quantum circuit for solving or studying the electronic structure problem on a quantum computer, minimizing the amount of domain expertise required to enter the field. The package is designed to be extensible and robust, maintaining high software standards in documentation and testing. This release paper outlines the key motivations behind design choices in OpenFermion and discusses some basic OpenFermion functionality which we believe will aid the community in the development of better quantum algorithms and tools for this exciting area of research.Comment: 22 page

    Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins

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    Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response

    Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

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    A. Palotie on työryhmÀn Schizophrenia Working Grp Psychiat jÀsen.We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P = 1 x 10(-4)) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P = 8.4 x 10(-7)). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.Peer reviewe

    AI is a viable alternative to high throughput screening: a 318-target study

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    : High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNetÂź convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNetÂź model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery
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