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Search Results: 1 - 10 of 301608 matches for " Timothy J. Wells "
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An IP-10 (CXCL10)-Derived Peptide Inhibits Angiogenesis
Cecelia C. Yates-Binder, Margaret Rodgers, Jesse Jaynes, Alan Wells, Richard J. Bodnar, Timothy Turner
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0040812
Abstract: Angiogenesis plays a critical role in processes such as organ development, wound healing, and tumor growth. It requires well-orchestrated integration of soluble and matrix factors and timely recognition of such signals to regulate this process. Previous work has shown that newly forming vessels express the chemokine receptor CXC receptor 3 (CXCR3) and, activation by its ligand IP-10 (CXCL10), both inhibits development of new vasculature and causes regression of newly formed vessels. To identify and develop new therapeutic agents to limit or reverse pathological angiogenesis, we identified a 21 amino acid fragment of IP-10, spanning the α-helical domain residues 77–98, that mimic the actions of the whole IP-10 molecule on endothelial cells. Treatment of the endothelial cells with the 22 amino acid fragment referred to as IP-10p significantly inhibited VEGF-induced endothelial motility and tube formation in vitro, properties critical for angiogenesis. Using a Matrigel plug assay in vivo, we demonstrate that IP-10p both prevented vessel formation and induced involution of nascent vessels. CXCR3 neutralizing antibody was able to block the inhibitory effects of the IP-10p, demonstrating specificity of the peptide. Inhibition of endothelial function by IP-10p was similar to that described for IP-10, secondary to CXCR3-mediated increase in cAMP production, activation of PKA inhibiting cell migration, and inhibition of VEGF-mediated m-calpain activation. IP-10p provides a novel therapeutic agent that inhibits endothelial cell function thus, allowing for the modulation of angiogenesis.
Epistatic Genetic Effects among Alzheimer’s Candidate Genes
Timothy J. Hohman, Mary Ellen Koran, Tricia Thornton-Wells, for the Alzheimer's Neuroimaging Initiative
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0080839
Abstract: Background Novel risk variants for late-onset Alzheimer’s disease (AD) have been identified and replicated in genome-wide association studies. Recent work has begun to address the relationship between these risk variants and biomarkers of AD, though results have been mixed. The aim of the current study was to characterize single marker and epistatic genetic effects between the top candidate Single Nucleotide Polymorphisms (SNPs) in relation to amyloid deposition. Methods We used a combined dataset across ADNI-1 and ADNI-2, and looked within each dataset separately to validate identified genetic effects. Amyloid was quantified using data acquired by Positron Emission Tomography (PET) with 18F-AV-45. Results Two SNP-SNP interactions reached significance when correcting for multiple comparisons, BIN1 (rs7561528, rs744373) x PICALM (rs7851179). Carrying the minor allele in BIN1 was related to higher levels of amyloid deposition, however only in non-carriers of the protective PICALM minor allele. Conclusions Our results support previous research suggesting these candidate SNPs do not show single marker associations with amyloid pathology. However, we provide evidence for a novel interaction between PICALM and BIN1 in relation to amyloid deposition. Risk related to the BIN1 minor allele appears to be mitigated in the presence of the PICALM protective variant. In that way, variance in amyloid plaque burden can be better classified within the context of a complex genetic background. Efforts to model cumulative risk for AD should explicitly account for this epistatic effect, and future studies should explicitly test for such effects whenever statistically feasible.
Natural products as starting points for future anti-malarial therapies: going back to our roots?
Wells Timothy NC
Malaria Journal , 2011, DOI: 10.1186/1475-2875-10-s1-s3
Abstract: Background The discovery and development of new anti-malarials are at a crossroads. Fixed dose artemisinin combination therapy is now being used to treat a hundred million children each year, with a cost as low as 30 cents per child, with cure rates of over 95%. However, as with all anti-infective strategies, this triumph brings with it the seeds of its own downfall, the emergence of resistance. It takes ten years to develop a new medicine. New classes of medicines to combat malaria, as a result of infection by Plasmodium falciparum and Plasmodium vivax are urgently needed. Results Natural product scaffolds have been the basis of the majority of current anti-malarial medicines. Molecules such as quinine, lapachol and artemisinin were originally isolated from herbal medicinal products. After improvement with medicinal chemistry and formulation technologies, and combination with other active ingredients, they now make up the current armamentarium of medicines. In recent years advances in screening technologies have allowed testing of millions of compounds from pharmaceutical diversity for anti-malarial activity in cellular assays. These initiatives have resulted in thousands of new sub-micromolar active compounds – starting points for new drug discovery programmes. Against this backdrop, the paucity of potent natural products identified has been disappointing. Now is a good time to reflect on the current approach to screening herbal medicinal products and suggest revisions. Nearly sixty years ago, the Chinese doctor Chen Guofu, suggested natural products should be approached by dao-xing-ni-shi or ‘acting in the reversed order’, starting with observational clinical studies. Natural products based on herbal remedies are in use in the community, and have the potential unique advantage that clinical observational data exist, or can be generated. The first step should be the confirmation and definition of the clinical activity of herbal medicinal products already used by the community. This first step forms a solid basis of observations, before moving to in vivo pharmacological characterization and ultimately identifying the active ingredient. A large part of the population uses herbal medicinal products despite limited numbers of well-controlled clinical studies. Increased awareness by the regulators and public health bodies of the need for safety information on herbal medicinal products also lends support to obtaining more clinical data on such products. Conclusions The relative paucity of new herbal medicinal product scaffolds active against malaria results
Characterization of Atlantic Cod Spawning Habitat and Behavior in Icelandic Coastal Waters
Timothy B. Grabowski, Kevin M. Boswell, Bruce J. McAdam, R. J. David Wells, Gu?rún Marteinsdóttir
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0051321
Abstract: The physical habitat used during spawning may potentially be an important factor affecting reproductive output of broadcast spawning marine fishes, particularly for species with complex, substrate-oriented mating systems and behaviors, such as Atlantic cod Gadus morhua. We characterized the habitat use and behavior of spawning Atlantic cod at two locations off the coast of southwestern Iceland during a 2-d research cruise (15–16 April 2009). We simultaneously operated two different active hydroacoustic gear types, a split beam echosounder and a dual frequency imaging sonar (DIDSON), as well as a remotely operated underwater vehicle (ROV). A total of five fish species were identified through ROV surveys: including cusk Brosme brosme, Atlantic cod, haddock Melanogrammus aeglefinus, lemon sole Microstomus kitt, and Atlantic redfish Sebastes spp. Of the three habitats identified in the acoustic surveys, the transitional habitat between boulder/lava field and sand habitats was characterized by greater fish density and acoustic target strength compared to that of sand or boulder/lava field habitats independently. Atlantic cod were observed behaving in a manner consistent with published descriptions of spawning. Individuals were observed ascending 1–5 m into the water column from the bottom at an average vertical swimming speed of 0.20–0.25 m s?1 and maintained an average spacing of 1.0–1.4 m between individuals. Our results suggest that cod do not choose spawning locations indiscriminately despite the fact that it is a broadcast spawning fish with planktonic eggs that are released well above the seafloor.
Transcription Mapping of Embryonic Rat Brain Reveals EGR-1 Induction in SOX2+ Neural Progenitor Cells
Timothy Wells,David A. Carter
Frontiers in Molecular Neuroscience , 2011, DOI: 10.3389/fnmol.2011.00006
Abstract: Neuronal expression of the early growth response-1 (EGR-1; NGFI-A/Zif268) transcription factor has been extensively studied in the adult mammalian brain and linked to aspects of mature physiological/behavioral function. In contrast, this factor has not been studied in detail in the embryonic brain. Here, we used a fluorescent protein-encoding Egr-1 transgene to map the cellular distribution of Egr-1 transcription in embryonic rat brain. We identified a novel, widely distributed population of GFP+ cells, characterized as a precursor/stem cell phenotype by co-localization with SOX2/nestin/vimentin/S-100β and exclusion from other known cellular markers including DCX/BLBP/TBR2/NURR1. At both E18 and E20, these cells were located across the developing brain but concentrated in the subplate and intermediate zones. The transgene was also highly expressed in developing (NeuN+) striatal neurons. The authentic expression pattern that we observed for the rEgr-1 transgene sequence indicates that restriction to neuronal/precursor cells is largely driven by proximal 5′ sequence. Deletion of conserved Egr-1 silencer (neuron restrictive silencer factor) elements did not markedly alter transcriptional activity in transfected cells; this is consistent with a dominant role for positive factors in the control of cell-specific Egr-1 expression. Induction of Egr-1 in a population of SOX2+ cells indicates a co-incidence of extrinsic (EGR-1) and cell-intrinsic (SOX2) cellular signals that may form a novel level of progenitor cell regulation. The wide distribution of EGR-1 signaling in SOX2+ cells suggests an organizational role during late embryonic brain development.
Genetic control of the innate immune response
Christine A Wells, Timothy Ravasi, Geoffrey J Faulkner, Piero Carninci, Yasushi Okazaki, Yoshihide Hayashizaki, Matthew Sweet, Brandon J Wainwright, David A Hume
BMC Immunology , 2003, DOI: 10.1186/1471-2172-4-5
Abstract: The mouse strains examined varied greatly in the number, amplitude and rate of induction of genes expressed in response to LPS. The response was attenuated in the C3H/HeJlpsd strain, which has a mutation in the LPS receptor Toll-like receptor 4 (TLR4). Variation between mouse strains allowed clustering into early (C57Bl/6J and DBA/2J) and delayed (BALB/c and C3H/ARC) transcriptional phenotypes. There was no clear correlation between gene induction patterns and variation at the Bcg locus (Slc11A1) or propensity to bias Th1 versus Th2 T cell activation responses.Macrophages from each strain responded to LPS with unique gene expression profiles. The variation apparent between genetic backgrounds provides insights into the breadth of possible inflammatory responses, and paradoxically, this divergence was used to identify a common transcriptional program that responds to TLR4 signalling, irrespective of genetic background. Our data indicates that many additional genetic loci control the nature and the extent of transcriptional responses promoted by a single pathogen-associated molecular pattern (PAMP), such as LPS.Susceptibility to infection is determined by the nature of the pathogen, and by the fitness of an individual to respond appropriately. The nature of the host response is controlled in part by the appropriate recognition of PAMPs by cells of the innate immune system [1,2]. Ineffective PAMP recognition, or an inappropriate response underlies clinical complications such as circulating bacterial load or septic shock. Lipopolysaccharide (LPS), a component of bacterial cell walls, is the predominant trigger of adverse clinical consequences of infection with gram-negative bacteria, including host procoagulant response and septic shock [3].Susceptibility to gram-negative bacteria in human populations has been associated with allelic variation at TLR4 [4,5], with consequences for infectious, inflammatory and cardiovascular disease [6]. Yet the complexity of the innate i
The relationship between serum sodium and intracranial pressure when using hypertonic saline to target mild hypernatremia in patients with head trauma
Diana L Wells, Joseph M Swanson, G Christopher Wood, Louis J Magnotti, Bradley A Boucher, Martin A Croce, Charles G Harrison, Michael S Muhlbauer, Timothy C Fabian
Critical Care , 2012, DOI: 10.1186/cc11678
Abstract: A retrospective review of patients who were admitted to the trauma ICU for TBI, had an ICP monitor placed, and received at least one dose of HTS between January 2006 and March 2011 was performed. Data were collected for up to 120 hours after ICP monitor placement. The primary outcome was the relationship between serum sodium and maximum ICP. Secondary outcomes were the relationship between serum sodium and the mean number of daily interventions for ICP control, and the acute effect of HTS on ICP during the 6 hours after each dose. Linear regression was used to analyze the primary outcome. Analysis of variance on ranks and repeated measures analysis of variance were used to evaluate the number of interventions and the acute effect of HTS on ICP, respectively.Eighty-one patients were enrolled with mean ± standard deviation age of 36 ± 15 years and median Glasgow Coma Scale score of 7 (interquartile range, 4 to 7). A total of 1,230 serum sodium values (range, 118 to174 mEq/l) and 7,483 ICP values (range, 0 to 159 mmHg) were collected. There was no correlation between serum sodium and maximum ICP (R2 = 0.0052). The overall mean ± standard deviation number of interventions for elevated ICP per day was 4.2 ± 2.9, 2.9 ± 2.0, and 2.6 ± 2.3 for patients with a mean serum sodium of < 145, 145 to 155, and > 155 mEq/l, respectively (P < 0.001). Regarding the acute effect of HTS on ICP, there was no statistical difference in mean ICP compared with baseline during hours 1 through 6 following HTS doses (baseline, 13.7 ± 8.4 mmHg; hour 1, 13.6 ± 8.3 mmHg; hour 2, 13.5 ± 8.8 mmHg; hour 3, 13.3 ± 8.7 mmHg; hour 4, 13.4 ± 8.7 mmHg; hour 5, 13.4 ± 8.3 mmHg; hour 6, 13.5 ± 8.3 mmHg; P = 0.84).Serum sodium concentrations did not correlate with ICP values. These results warrant further evaluation and possible reassessment of sodium goals for ICP management in patients with TBI.Traumatic brain injury (TBI) is the leading cause of morbidity and mortality in young adults [1]. When treating T
Health care utilization among complementary and alternative medicine users in a large military cohort
Martin R White, Isabel G Jacobson, Besa Smith, Timothy S Wells, Gary D Gackstetter, Edward J Boyko, Tyler C Smith, Millennium Cohort Study Team
BMC Complementary and Alternative Medicine , 2011, DOI: 10.1186/1472-6882-11-27
Abstract: Inpatient and outpatient medical services were documented over a 12-month period for 44,287 participants from the Millennium Cohort Study. Equal access to medical services was available to anyone needing medical care during this study period. The number and types of medical visits were compared between CAM and non-CAM users. Chi square test and multivariable logistic regression was applied for the analysis.Of the 44,287 participants, 39% reported using at least one CAM therapy, and 61% reported not using any CAM therapies. Those individuals reporting CAM use accounted for 45.1% of outpatient care and 44.8% of inpatient care. Individuals reporting one or more health conditions were 15% more likely to report CAM use than non-CAM users and 19% more likely to report CAM use if reporting one or more health symptoms compared to non-CAM users. The unadjusted odds ratio for hospitalizations in CAM users compared to non-CAM users was 1.29 (95% CI: 1.16-1.43). The mean number of days receiving outpatient care for CAM users was 7.0 days and 5.9 days for non-CAM users (p < 0.001).Our study found those who report CAM use were requiring more physician-based medical services than users of conventional medicine. This appears to be primarily the result of an increase in the number of health conditions and symptoms reported by CAM users.Complementary and alternative medicine (CAM) is a term used to describe a wide variety of procedures, substances, and approaches for treating symptoms, illnesses, and injuries, as well as promoting good health. CAM therapies include a broad spectrum of ancient to new-age approaches that purport to prevent and/or treat numerous symptoms and medical conditions. Typically they are not considered part of conventional medicine, nor are they usually taught at U.S. medical schools [1]. In 2007, approximately 4 out of 10 adults in the United States reported using some form of CAM therapy in the past 12 months [2]. Similarly, in the United Kingdom and Australi
A generalised module for the selective extracellular accumulation of recombinant proteins
Yanina R Sevastsyanovich, Denisse L Leyton, Timothy J Wells, Catherine A Wardius, Karina Tveen-Jensen, Faye C Morris, Timothy J Knowles, Adam F Cunningham, Jeffrey A Cole, Ian R Henderson
Microbial Cell Factories , 2012, DOI: 10.1186/1475-2859-11-69
Abstract: Here, we report the development of a generalised module, based on an E. coli autotransporter secretion system, for the production of extracellular recombinant proteins. We demonstrate that a wide variety of structurally diverse proteins can be secreted as soluble proteins when linked to the autotransporter module. Yields were comparable to those achieved with other bacterial secretion systems.The advantage of this module is that it relies on a relatively simple and easily manipulated secretion system, exhibits no apparent limitation to the size of the secreted protein and can deliver proteins to the extracellular environment at levels of purity and yields sufficient for many biotechnological applications.
Mutational and Topological Analysis of the Escherichia coli BamA Protein
Douglas F. Browning, Sophie A. Matthews, Amanda E. Rossiter, Yanina R. Sevastsyanovich, Mark Jeeves, Jessica L. Mason, Timothy J. Wells, Catherine A. Wardius, Timothy J. Knowles, Adam F. Cunningham, Vassiliy N. Bavro, Michael Overduin, Ian R. Henderson
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0084512
Abstract: The multi-protein β-barrel assembly machine (BAM) of Escherichia coli is responsible for the folding and insertion of β-barrel containing integral outer membrane proteins (OMPs) into the bacterial outer membrane. An essential component of this complex is the BamA protein, which binds unfolded β-barrel precursors via the five polypeptide transport-associated (POTRA) domains in its N-terminus. The C-terminus of BamA contains a β-barrel domain, which tethers BamA to the outer membrane and is also thought to be involved in OMP insertion. Here we mutagenize BamA using linker scanning mutagenesis and demonstrate that all five POTRA domains are essential for BamA protein function in our experimental system. Furthermore, we generate a homology based model of the BamA β-barrel and test our model using insertion mutagenesis, deletion analysis and immunofluorescence to identify β-strands, periplasmic turns and extracellular loops. We show that the surface-exposed loops of the BamA β-barrel are essential.
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