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Search Results: 1 - 10 of 302875 matches for " Sarah J. Spencer "
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Perinatal programming of neuroendocrine mechanisms connecting feeding behavior and stress
Sarah J. Spencer
Frontiers in Neuroscience , 2013, DOI: 10.3389/fnins.2013.00109
Abstract: Feeding behavior is closely regulated by neuroendocrine mechanisms that can be influenced by stressful life events. However, the feeding response to stress varies among individuals with some increasing and others decreasing food intake after stress. In addition to the impact of acute lifestyle and genetic backgrounds, the early life environment can have a life-long influence on neuroendocrine mechanisms connecting stress to feeding behavior and may partially explain these opposing feeding responses to stress. In this review I will discuss the perinatal programming of adult hypothalamic stress and feeding circuitry. Specifically I will address how early life (prenatal and postnatal) nutrition, early life stress, and the early life hormonal profile can program the hypothalamic-pituitary-adrenal (HPA) axis, the endocrine arm of the body's response to stress long-term and how these changes can, in turn, influence the hypothalamic circuitry responsible for regulating feeding behavior. Thus, over- or under-feeding and/or stressful events during critical windows of early development can alter glucocorticoid (GC) regulation of the HPA axis, leading to changes in the GC influence on energy storage and changes in GC negative feedback on HPA axis-derived satiety signals such as corticotropin-releasing-hormone. Furthermore, peripheral hormones controlling satiety, such as leptin and insulin are altered by early life events, and can be influenced, in early life and adulthood, by stress. Importantly, these neuroendocrine signals act as trophic factors during development to stimulate connectivity throughout the hypothalamus. The interplay between these neuroendocrine signals, the perinatal environment, and activation of the stress circuitry in adulthood thus strongly influences feeding behavior and may explain why individuals have unique feeding responses to similar stressors.
Effects of Neonatal Overfeeding on Juvenile and Adult Feeding and Energy Expenditure in the Rat
Aneta Stefanidis, Sarah J. Spencer
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0052130
Abstract: Overfeeding during perinatal life leads to an overweight phenotype that persists throughout the juvenile stage and into adulthood, however, the mechanim(s) underlying this effect are poorly understood. We hypothesized that obesity due to neonatal overfeeding is maintained by changes in energy expenditure and that these changes differ between males and females. We investigated feeding, physical activity, hormonal and metabolic alterations that occur in adult rats made obese by having been nursed in small litters (SL) compared with those from control litters (CL). There were no differences in absolute food intake between the groups, and juvenile and adult SL rats ate less chow per gram body weight than the CL did in the dark (active) phase. Juvenile, but not adult SL rats did have reduced whole body energy expenditure, but there were no differences between the groups by the time they reached adulthood. Adult SL females (but not males) had reduced brown adipose tissue (BAT) temperatures compared with CL in the first half of the dark phase. Our results indicate a persistent overweight phenotype in rats overfed as neonates is not associated with hyperphagia at any stage, but is reflected in reduced energy expenditure into the juvenile phase. The reduced dark phase BAT activity in adult SL females is not sufficient to reduce total energy expenditure at this stage of life and there is an apparently compensatory effect that prevents SL and CL from continuing to diverge in weight that appears between the juvenile and adult stages.
The Role of Ghrelin in Neuroprotection after Ischemic Brain Injury
Sarah J. Spencer,Alyson A. Miller,Zane B. Andrews
Brain Sciences , 2013, DOI: 10.3390/brainsci3010344
Abstract: Ghrelin, a gastrointestinal peptide with a major role in regulating feeding and metabolism, has recently been investigated for its neuroprotective effects. In this review we discuss pre-clinical evidence suggesting ghrelin may be a useful therapeutic in protecting the brain against injury after ischemic stroke. Specifically, we will discuss evidence showing ghrelin administration can improve neuronal cell survival in animal models of focal cerebral ischemia, as well as rescue memory deficits. We will also discuss its proposed mechanisms of action, including anti-apoptotic and anti-inflammatory effects, and suggest ghrelin treatment may be a useful intervention after stroke in the clinic.
Bioinformatics Methods for Learning Radiation-Induced Lung Inflammation from Heterogeneous Retrospective and Prospective Data
Sarah J. Spencer,Damian Almiron Bonnin,Joseph O. Deasy,Jeffrey D. Bradley,Issam El Naqa
Journal of Biomedicine and Biotechnology , 2009, DOI: 10.1155/2009/892863
Abstract: Radiotherapy outcomes are determined by complex interactions between physical and biological factors, reflecting both treatment conditions and underlying genetics. Recent advances in radiotherapy and biotechnology provide new opportunities and challenges for predicting radiation-induced toxicities, particularly radiation pneumonitis (RP), in lung cancer patients. In this work, we utilize datamining methods based on machine learning to build a predictive model of lung injury by retrospective analysis of treatment planning archives. In addition, biomarkers for this model are extracted from a prospective clinical trial that collects blood serum samples at multiple time points. We utilize a 3-way proteomics methodology to screen for differentially expressed proteins that are related to RP. Our preliminary results demonstrate that kernel methods can capture nonlinear dose-volume interactions, but fail to address missing biological factors. Our proteomics strategy yielded promising protein candidates, but their role in RP as well as their interactions with dose-volume metrics remain to be determined.
Recombination-Mediated Genetic Engineering of a Bacterial Artificial Chromosome Clone of Modified Vaccinia virus Ankara (MVA)
Matthew G. Cottingham, Rikke F. Andersen, Alexandra J. Spencer, Saroj Saurya, Julie Furze, Adrian V. S. Hill, Sarah C. Gilbert
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0001638
Abstract: The production, manipulation and rescue of a bacterial artificial chromosome clone of Vaccinia virus (VAC-BAC) in order to expedite construction of expression vectors and mutagenesis of the genome has been described (Domi & Moss, 2002, PNAS 99 12415–20). The genomic BAC clone was ‘rescued’ back to infectious virus using a Fowlpox virus helper to supply transcriptional machinery. We apply here a similar approach to the attenuated strain Modified Vaccinia virus Ankara (MVA), now widely used as a safe non-replicating recombinant vaccine vector in mammals, including humans. Four apparently full-length, rescuable clones were obtained, which had indistinguishable immunogenicity in mice. One clone was shotgun sequenced and found to be identical to the parent. We employed GalK recombination-mediated genetic engineering (recombineering) of MVA-BAC to delete five selected viral genes. Deletion of C12L, A44L, A46R or B7R did not significantly affect CD8+ T cell immunogenicity in BALB/c mice, but deletion of B15R enhanced specific CD8+ T cell responses to one of two endogenous viral epitopes (from the E2 and F2 proteins), in accordance with published work (Staib et al., 2005, J. Gen. Virol. 86, 1997–2006). In addition, we found a higher frequency of triple-positive IFN-γ, TNF-α and IL-2 secreting E3-specific CD8+ T-cells 8 weeks after vaccination with MVA lacking B15R. Furthermore, a recombinant vaccine capable of inducing CD8+ T cells against an epitope from Plasmodium berghei was created using GalK counterselection to insert an antigen expression cassette lacking a tandem marker gene into the traditional thymidine kinase locus of MVA-BAC. MVA continues to feature prominently in clinical trials of recombinant vaccines against diseases such as HIV-AIDS, malaria and tuberculosis. Here we demonstrate in proof-of-concept experiments that MVA-BAC recombineering is a viable route to more rapid and efficient generation of new candidate mutant and recombinant vaccines based on a clinically deployable viral vector.
A Novel Chimpanzee Adenovirus Vector with Low Human Seroprevalence: Improved Systems for Vector Derivation and Comparative Immunogenicity
Matthew D. J. Dicks, Alexandra J. Spencer, Nick J. Edwards, G?ran Wadell, Kalifa Bojang, Sarah C. Gilbert, Adrian V. S. Hill, Matthew G. Cottingham
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0040385
Abstract: Recombinant adenoviruses are among the most promising tools for vaccine antigen delivery. Recently, the development of new vectors has focused on serotypes to which the human population is less exposed in order to circumvent pre-existing anti vector immunity. This study describes the derivation of a new vaccine vector based on a chimpanzee adenovirus, Y25, together with a comparative assessment of its potential to elicit transgene product specific immune responses in mice. The vector was constructed in a bacterial artificial chromosome to facilitate genetic manipulation of genomic clones. In order to conduct a fair head-to-head immunological comparison of multiple adenoviral vectors, we optimised a method for accurate determination of infectious titre, since this parameter exhibits profound natural variability and can confound immunogenicity studies when doses are based on viral particle estimation. Cellular immunogenicity of recombinant E1 E3-deleted vector ChAdY25 was comparable to that of other species E derived chimpanzee adenovirus vectors including ChAd63, the first simian adenovirus vector to enter clinical trials in humans. Furthermore, the prevalence of virus neutralizing antibodies (titre >1:200) against ChAdY25 in serum samples collected from two human populations in the UK and Gambia was particularly low compared to published data for other chimpanzee adenoviruses. These findings support the continued development of new chimpanzee adenovirus vectors, including ChAdY25, for clinical use.
Toward an Integrated Model of Capsule Regulation in Cryptococcus neoformans
Brian C. Haynes,Michael L. Skowyra,Sarah J. Spencer,Stacey R. Gish,Matthew Williams,Elizabeth P. Held,Michael R. Brent,Tamara L. Doering
PLOS Pathogens , 2011, DOI: 10.1371/journal.ppat.1002411
Abstract: Cryptococcus neoformans is an opportunistic fungal pathogen that causes serious human disease in immunocompromised populations. Its polysaccharide capsule is a key virulence factor which is regulated in response to growth conditions, becoming enlarged in the context of infection. We used microarray analysis of cells stimulated to form capsule over a range of growth conditions to identify a transcriptional signature associated with capsule enlargement. The signature contains 880 genes, is enriched for genes encoding known capsule regulators, and includes many uncharacterized sequences. One uncharacterized sequence encodes a novel regulator of capsule and of fungal virulence. This factor is a homolog of the yeast protein Ada2, a member of the Spt-Ada-Gcn5 Acetyltransferase (SAGA) complex that regulates transcription of stress response genes via histone acetylation. Consistent with this homology, the C. neoformans null mutant exhibits reduced histone H3 lysine 9 acetylation. It is also defective in response to a variety of stress conditions, demonstrating phenotypes that overlap with, but are not identical to, those of other fungi with altered SAGA complexes. The mutant also exhibits significant defects in sexual development and virulence. To establish the role of Ada2 in the broader network of capsule regulation we performed RNA-Seq on strains lacking either Ada2 or one of two other capsule regulators: Cir1 and Nrg1. Analysis of the results suggested that Ada2 functions downstream of both Cir1 and Nrg1 via components of the high osmolarity glycerol (HOG) pathway. To identify direct targets of Ada2, we performed ChIP-Seq analysis of histone acetylation in the Ada2 null mutant. These studies supported the role of Ada2 in the direct regulation of capsule and mating responses and suggested that it may also play a direct role in regulating capsule-independent antiphagocytic virulence factors. These results validate our experimental approach to dissecting capsule regulation and provide multiple targets for future investigation.
Identification of a Novel Human Polyomavirus in Organs of the Gastrointestinal Tract
Sarah Korup, Janita Rietscher, Sébastien Calvignac-Spencer, Franziska Trusch, J?rg Hofmann, Ugo Moens, Igor Sauer, Sebastian Voigt, Rosa Schmuck, Bernhard Ehlers
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0058021
Abstract: Polyomaviruses are small, non-enveloped viruses with a circular double-stranded DNA genome. Using a generic polyomavirus PCR targeting the VP1 major structural protein gene, a novel polyomavirus was initially identified in resected human liver tissue and provisionally named Human Polyomavirus 12 (HPyV12). Its 5033 bp genome is predicted to encode large and small T antigens and the 3 structural proteins VP1, VP2 and VP3. Phylogenetic analyses did not reveal a close relationship to any known human or animal polyomavirus. Investigation of organs, body fluids and excretions of diseased individuals and healthy subjects with both HPyV12-specific nested PCR and quantitative real-time PCR revealed additional virus-positive samples of resected liver, cecum and rectum tissues and a positive fecal sample. A capsomer-based IgG ELISA was established using the major capsid protein VP1 of HPyV12. Seroprevalences of 23% and 17%, respectively, were determined in sera from healthy adults and adolescents and a pediatric group of children. These data indicate that the virus naturally infects humans and that primary infection may already occur in childhood.
A Survey of Satellite Galaxies around NGC 4258
Meghin Spencer,Sarah Loebman,Peter Yoachim
Physics , 2014, DOI: 10.1088/0004-637X/788/2/146
Abstract: We conduct a survey of satellite galaxies around the nearby spiral NGC 4258 by combining spectroscopic observations from the Apache Point Observatory 3.5-meter telescope with SDSS spectra. New spectroscopy is obtained for 15 galaxies. Of the 47 observed objects, we categorize 8 of them as probable satellites, 8 as possible satellites, and 17 as unlikely to be satellites. We do not speculate on the membership of the remaining 14 galaxies due to a lack of velocity and distance information. Radially integrating our best fit NFW profile for NGC 4258 yields a total mass of 1.8e12 Msun within 200 kpc. We find that the angular distribution of the satellites appears to be random, and not preferentially aligned with the disk of NGC 4258. In addition, many of the probable satellite galaxies have blue u-r colors and appear to be star-forming irregulars in SDSS images; this stands in contrast to the low number of blue satellites in the Milky Way and M31 systems at comparable distances.
A T Cell-Inducing Influenza Vaccine for the Elderly: Safety and Immunogenicity of MVA-NP+M1 in Adults Aged over 50 Years
Richard D. Antrobus, Patrick J. Lillie, Tamara K. Berthoud, Alexandra J. Spencer, James E. McLaren, Kristin Ladell, Teresa Lambe, Anita Milicic, David A. Price, Adrian V. S. Hill, Sarah C. Gilbert
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0048322
Abstract: Background Current influenza vaccines have reduced immunogenicity and are of uncertain efficacy in older adults. We assessed the safety and immunogenicity of MVA-NP+M1, a viral-vectored influenza vaccine designed to boost memory T cell responses, in a group of older adults. Methods Thirty volunteers (aged 50–85) received a single intramuscular injection of MVA-NP+M1 at a dose of 1·5×108 plaque forming units (pfu). Safety and immunogenicity were assessed over a period of one year. The frequency of T cells specific for nucleoprotein (NP) and matrix protein 1 (M1) was determined by interferon-gamma (IFN-γ) ELISpot, and their phenotypic and functional properties were characterized by polychromatic flow cytometry. In a subset of M1-specific CD8+ T cells, T cell receptor (TCR) gene expression was evaluated using an unbiased molecular approach. Results Vaccination with MVA-NP+M1 was well tolerated. ELISpot responses were boosted significantly above baseline following vaccination. Increases were detected in both CD4+ and CD8+ T cell subsets. Clonality studies indicated that MVA-NP+M1 expanded pre-existing memory CD8+ T cells, which displayed a predominant CD27+CD45RO+CD57?CCR7? phenotype both before and after vaccination. Conclusions MVA-NP+M1 is safe and immunogenic in older adults. Unlike seasonal influenza vaccination, the immune responses generated by MVA-NP+M1 are similar between younger and older individuals. A T cell-inducing vaccine such as MVA-NP+M1 may therefore provide a way to circumvent the immunosenescence that impairs routine influenza vaccination. Trial Registration ClinicalTrials.gov NCT00942071
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