317 research outputs found
Chemically Aware Model Builder (camb): an R package for property and bioactivity modelling of small molecules.
BACKGROUND: In silico predictive models have proved to be valuable for the optimisation of compound potency, selectivity and safety profiles in the drug discovery process. RESULTS: camb is an R package that provides an environment for the rapid generation of quantitative Structure-Property and Structure-Activity models for small molecules (including QSAR, QSPR, QSAM, PCM) and is aimed at both advanced and beginner R users. camb's capabilities include the standardisation of chemical structure representation, computation of 905 one-dimensional and 14 fingerprint type descriptors for small molecules, 8 types of amino acid descriptors, 13 whole protein sequence descriptors, filtering methods for feature selection, generation of predictive models (using an interface to the R package caret), as well as techniques to create model ensembles using techniques from the R package caretEnsemble). Results can be visualised through high-quality, customisable plots (R package ggplot2). CONCLUSIONS: Overall, camb constitutes an open-source framework to perform the following steps: (1) compound standardisation, (2) molecular and protein descriptor calculation, (3) descriptor pre-processing and model training, visualisation and validation, and (4) bioactivity/property prediction for new molecules. camb aims to speed model generation, in order to provide reproducibility and tests of robustness. QSPR and proteochemometric case studies are included which demonstrate camb's application.Graphical abstractFrom compounds and data to models: a complete model building workflow in one package
CD24 expression does not affect dopamine neuronal survival in a mouse model of Parkinson's disease
Parkinson's disease (PD) is a progressive neurodegenerative condition that is characterised by the loss of specific populations of neurons in the brain. The mechanisms underlying this selective cell death are unknown but by using laser capture microdissection, the glycoprotein, CD24 has been identified as a potential marker of the populations of cells that are affected in PD. Using in situ hybridization and immunohistochemistry on sections of mouse brain, we confirmed that CD24 is robustly expressed by many of these subsets of cells. To determine if CD24 may have a functional role in PD, we modelled the dopamine cell loss of PD in Cd24 mutant mice using striatal delivery of the neurotoxin 6-OHDA. We found that Cd24 mutant mice have an anatomically normal dopamine system and that this glycoprotein does not modulate the lesion effects of 6-OHDA delivered into the striatum. We then undertook in situ hybridization studies on sections of human brain and found-as in the mouse brain-that CD24 is expressed by many of the subsets of the cells that are vulnerable in PD, but not those of the midbrain dopamine system. Finally, we sought to determine if CD24 is required for the neuroprotective effect of Glial cell-derived neurotrophic factor (GDNF) on the dopaminergic nigrostriatal pathway. Our results indicate that in the absence of CD24, there is a reduction in the protective effects of GDNF on the dopaminergic fibres in the striatum, but no difference in the survival of the cell bodies in the midbrain. While we found no obvious role for CD24 in the normal development and maintenance of the dopaminergic nigrostriatal system in mice, it may have a role in mediating the neuroprotective aspects of GDNF in this system.SRWS was funded by a Parkinson's UK Innovation grant (https://www.parkinsons.org.uk/); Cure Parkinsons's trust grant (https://www.cureparkinsons.org.uk/); and DDPDGENES (FP7-HEALTH #278871; http://cordis.europa.eu/project/rcn/101801_en.html). SH was also funded by DDPDGENES. TC & SG received no specific funding for this work (summer interns). JPS was funded by the Klinikum Mannheim gGmbH. RAB was funded by the NIHR Biomedical Research Centre and also receives funding from the UKRMP PSP hub
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Characterising loss and damage from climate change
Policy-makers are creating mechanisms to help developing countries cope with loss and damage from climate change, but the negotiations are largely neglecting scientific questions about what the impacts of climate change actually are.
Mitigation efforts have failed to prevent the continued increase of anthropogenic greenhouse gas (GHG) emissions. Adaptation is now unlikely to be sufficient to prevent negative impacts from current and future climate change1. In this context, vulnerable nations argue that existing frameworks to promote mitigation and adaptation are inadequate, and have called for a third international mechanism to deal with residual climate change impacts, or “loss and damage”2.
In 2013, the United Nations Framework Convention on Climate Change (UNFCCC) responded to these calls and established the Warsaw International Mechanism (WIM) to address loss and damage from the impacts of climate change in developing countries3. An interim Executive Committee of party representatives has been set up, and is currently drafting a two-year workplan comprising meetings, reports, and expert groups; and aiming to enhance knowledge and understanding of loss and damage, strengthen dialogue among stakeholders, and promote enhanced action and support. Issues identified as priorities for the WIM thus far include: how to deal with non-economic losses, such as loss of life, livelihood, and cultural heritage; and linkages between loss and damage and patterns of migration and displacement2. In all this, one fundamental issue still demands our attention: which losses and damages are relevant to the WIM? What counts as loss and damage from climate change
Determinants of response to a parent questionnaire about development and behaviour in 3 year olds: European multicentre study of congenital toxoplasmosis.
Background:
We aimed to determine how response to a parent-completed postal questionnaire measuring development, behaviour, impairment, and parental concerns and anxiety, varies in different European centres.
Methods:
Prospective cohort study of 3 year old children, with and without congenital toxoplasmosis, who were identified by prenatal or neonatal screening for toxoplasmosis in 11 centres in 7 countries. Parents were mailed a questionnaire that comprised all or part of existing validated tools. We determined the effect of characteristics of the centre and child on response, age at questionnaire completion, and response to child drawing tasks.
Results:
The questionnaire took 21 minutes to complete on average. 67% (714/1058) of parents responded. Few parents (60/1058) refused to participate. The strongest determinants of response were the score for organisational attributes of the study centre (such as direct involvement in follow up and access to an address register), and infection with congenital toxoplasmosis. Age at completion was associated with study centre, presence of neurological abnormalities in early infancy, and duration of prenatal treatment. Completion rates for individual questions exceeded 92% except for child completed drawings of a man (70%), which were completed more by girls, older children, and in certain centres.
Conclusion:
Differences in response across European centres were predominantly related to the organisation of follow up and access to correct addresses. The questionnaire was acceptable in all six countries and offers a low cost tool for assessing development, behaviour, and parental concerns and anxiety, in multinational studies
Subclinical thyroid dysfunction and cognitive decline in old age
<p>Background: Subclinical thyroid dysfunction has been implicated as a risk factor for cognitive decline in old age, but results are inconsistent. We investigated the association between subclinical thyroid dysfunction and cognitive decline in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER).</p>
<p>Methods: Prospective longitudinal study of men and women aged 70–82 years with pre-existing vascular disease or more than one risk factor to develop this condition (N = 5,154). Participants taking antithyroid medications, thyroid hormone supplementation and/or amiodarone were excluded. Thyroid function was measured at baseline: subclinical hyper- and hypothyroidism were defined as thyroid stimulating hormones (TSH) <0.45 mU/L or >4.50 mU/L respectively, with normal levels of free thyroxine (FT4). Cognitive performance was tested at baseline and at four subsequent time points during a mean follow-up of 3 years, using five neuropsychological performance tests.</p>
<p>Results: Subclinical hyperthyroidism and hypothyroidism were found in 65 and 161 participants, respectively. We found no consistent association of subclinical hyper- or hypothyroidism with altered cognitive performance compared to euthyroid participants on the individual cognitive tests. Similarly, there was no association with rate of cognitive decline during follow-up.</p>
<p>Conclusion: We found no consistent evidence that subclinical hyper- or hypothyroidism contribute to cognitive impairment or decline in old age. Although our data are not in support of treatment of subclinical thyroid dysfunction to prevent cognitive dysfunction in later life, only large randomized controlled trials can provide definitive evidence.</p>
Subclinical thyroid dysfunction and cognitive decline in old age
<p>Background: Subclinical thyroid dysfunction has been implicated as a risk factor for cognitive decline in old age, but results are inconsistent. We investigated the association between subclinical thyroid dysfunction and cognitive decline in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER).</p>
<p>Methods: Prospective longitudinal study of men and women aged 70–82 years with pre-existing vascular disease or more than one risk factor to develop this condition (N = 5,154). Participants taking antithyroid medications, thyroid hormone supplementation and/or amiodarone were excluded. Thyroid function was measured at baseline: subclinical hyper- and hypothyroidism were defined as thyroid stimulating hormones (TSH) <0.45 mU/L or >4.50 mU/L respectively, with normal levels of free thyroxine (FT4). Cognitive performance was tested at baseline and at four subsequent time points during a mean follow-up of 3 years, using five neuropsychological performance tests.</p>
<p>Results: Subclinical hyperthyroidism and hypothyroidism were found in 65 and 161 participants, respectively. We found no consistent association of subclinical hyper- or hypothyroidism with altered cognitive performance compared to euthyroid participants on the individual cognitive tests. Similarly, there was no association with rate of cognitive decline during follow-up.</p>
<p>Conclusion: We found no consistent evidence that subclinical hyper- or hypothyroidism contribute to cognitive impairment or decline in old age. Although our data are not in support of treatment of subclinical thyroid dysfunction to prevent cognitive dysfunction in later life, only large randomized controlled trials can provide definitive evidence.</p>
The Role of Innate APOBEC3G and Adaptive AID Immune Responses in HLA-HIV/SIV Immunized SHIV Infected Macaques
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
The XMM cluster survey: Testing chameleon gravity using the profiles of clusters
The chameleon gravity model postulates the existence of a scalar field that couples with matter to mediate a fifth force. If it exists, this fifth force would influence the hot X-ray emitting gas filling the potential wells of galaxy clusters. However, it would not influence the clusters weak lensing signal. Therefore, by comparing X-ray and weak lensing profiles, one can place upper limits on the strength of a fifth force. This technique has been attempted before using a single, nearby cluster (Coma, z = 0.02). Here we apply the technique to the stacked profiles of 58 clusters at higher redshifts (0.1 R0| R0| on cosmological scales. We hope to improve this constraint in future by extending the study to hundreds of clusters using data from the Dark Energy Survey
Quasar Sightline and Galaxy Evolution (QSAGE) - III. The mass-metallicity and fundamental metallicity relation of z ≈ 2.2 galaxies
We present analysis of the mass-metallicity relation (MZR) for a sample of 67 [O iii]-selected star-forming (SF) galaxies at a redshift range of z = 1.99-2.32 (zmed = 2.16) using Hubble Space Telescope Wide Field Camera 3 grism spectroscopy from the Quasar Sightline and Galaxy Evolution survey. Metallicities were determined using empirical gas-phase metallicity calibrations based on the strong emission lines [O ii]3727, 3729, [O iii]4959, 5007 and Hβ. SF galaxies were identified, and distinguished from active-galactic nuclei, via Mass-Excitation diagrams. Using z ∼0 metallicity calibrations, we observe a negative offset in the z = 2.2 MZR of ≈-0.51 dex in metallicity when compared to locally derived relationships, in agreement with previous literature analysis. A similar offset of ≈-0.46 dex in metallicity is found when using empirical metallicity calibrations that are suitable out to z ∼5, though our z = 2.2 MZR, in this case, has a shallower slope. We find agreement between our MZR and those predicted from various galaxy evolution models and simulations. Additionally, we explore the extended fundamental metallicity relation (FMR) which includes an additional dependence on star formation rate. Our results consistently support the existence of the FMR, as well as revealing an offset of 0.28 ± 0.04 dex in metallicity compared to locally derived relationships, consistent with previous studies at similar redshifts. We interpret the negative correlation with SFR at fixed mass, inferred from an FMR existing for our sample, as being caused by the efficient accretion of metal-poor gas fuelling SFR at cosmic noon
SDSS-IV MaNGA: A serendipitous observation of a potential gas accretion event
The nature of warm, ionized gas outside of galaxies may illuminate several key galaxy evolutionary processes. A serendipitous observation by the MaNGA survey has revealed a large, asymmetric H complex with no optical counterpart that extends ≈8″ (≈6.3 kpc) beyond the effective radius of a dusty, starbursting galaxy. This H extension is approximately three times the effective radius of the host galaxy and displays a tail-like morphology. We analyze its gas-phase metallicities, gaseous kinematics, and emission-line ratios and discuss whether this H extension could be diffuse ionized gas, a gas accretion event, or something else. We find that this warm, ionized gas structure is most consistent with gas accretion through recycled wind material, which could be an important process that regulates the low-mass end of the galaxy stellar mass function.Funding for the Sloan Digital Sky Survey IV has been provided by the Alfred P. Sloan Foundation, the U.S. Department of Energy Office of Science, and the Participating Institutions. SDSS-IV acknowledges support and resources from the Center for High-Performance Computing at the University of Utah. SDSS-IV is managed by the Astrophysical Research Consortium for the Participating Institutions of the SDSS Collaboration. D.B. is supported by grant RSCF-14-22-00041. A.W. acknowledges support from a Leverhulme Early Career Fellowship. J.H.K. acknowledges financial support from the Spanish Ministry of Economy and Competitiveness (MINECO) under grant number AYA2013-41243-P and thanks the Astrophysics Research Institute of Liverpool John Moores University for their hospitality, and the Spanish Ministry of Education, Culture and Sports for financial support of his visit there, through grant number PR2015-00512
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