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Search Results: 1 - 10 of 468070 matches for " Gregory A. Ross "
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Affinity Crosslinking of Y1036 to Nerve Growth Factor Identifies Pharmacological Targeting Domain for Small Molecule Neurotrophin Antagonists  [PDF]
Joseph K. Eibl, Zouleika Abdallah, Allison E. Kennedy, John A. Scott, Gregory M. Ross
Neuroscience & Medicine (NM) , 2013, DOI: 10.4236/nm.2013.44043
Abstract:

Classically, small molecule antagonists have targeted membrane bound receptors and intracellular enzyme targets. While this drug discovery strategy is extremely successful, the number of new chemical entities in the pharmaceutical pipeline is diminishing and complementary strategies are in need. A particularly attractive therapeutic strategy is to neutralize soluble signalling proteins using small molecules. Small molecule-based technologies have the potential to sufficiently alter the molecular topology of a given ligand and inhibit ligand/receptor interactionseffectively neutralizing the ligand’s signalling capacity. Recent technical advances in the field of structural biology have enabled the elucidation of ligand/receptor complexes at atomic resolution enabling a detailed appreciation of the molecular interactions governing ligand-mediated receptor activation. Exploiting molecular modeling techniques to study these signalling complexes allows for a paradigm shift from receptorcentric to ligandcentric screening strategies. Nerve growth factor (NGF) is a prototypical protein signalling ligand, which binds two receptors, TrkA and p75NTR. We first explore the molecular landscape governing the ligand/receptor interactions of NGF/TrkA and NGF/p75 structures. Next, we use the recently reported NGF neutralizing small-molecule, Y1036, as an affinity probe to determine residues in proximity to the pharmacological targeting

Rapid and Accurate Prediction and Scoring of Water Molecules in Protein Binding Sites
Gregory A. Ross, Garrett M. Morris, Philip C. Biggin
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0032036
Abstract: Water plays a critical role in ligand-protein interactions. However, it is still challenging to predict accurately not only where water molecules prefer to bind, but also which of those water molecules might be displaceable. The latter is often seen as a route to optimizing affinity of potential drug candidates. Using a protocol we call WaterDock, we show that the freely available AutoDock Vina tool can be used to predict accurately the binding sites of water molecules. WaterDock was validated using data from X-ray crystallography, neutron diffraction and molecular dynamics simulations and correctly predicted 97% of the water molecules in the test set. In addition, we combined data-mining, heuristic and machine learning techniques to develop probabilistic water molecule classifiers. When applied to WaterDock predictions in the Astex Diverse Set of protein ligand complexes, we could identify whether a water molecule was conserved or displaced to an accuracy of 75%. A second model predicted whether water molecules were displaced by polar groups or by non-polar groups to an accuracy of 80%. These results should prove useful for anyone wishing to undertake rational design of new compounds where the displacement of water molecules is being considered as a route to improved affinity.
An analysis of lecture video utilization in undergraduate medical education: associations with performance in the courses
John A McNulty, Amy Hoyt, Gregory Gruener, Arcot Chandrasekhar, Baltazar Espiritu, Ron Price, Ross Naheedy
BMC Medical Education , 2009, DOI: 10.1186/1472-6920-9-6
Abstract: Streaming videos of lectures (n = 149) to first year and second year medical students (n = 284) were made available through a password-protected server. Server logs were analyzed over a 10-week period for both classes. For each lecture, the logs recorded time and location from which students accessed the file. A survey was administered at the end of the courses to obtain additional information about student use of the videos.There was a wide disparity in the level of use of lecture videos by medical students with the majority of students accessing the lecture videos sparingly (60% of the students viewed less than 10% of the available videos. The anonymous student survey revealed that students tended to view the videos by themselves from home during weekends and prior to exams. Students who accessed lecture videos more frequently had significantly (p < 0.002) lower exam scores.We conclude that videos of lectures are used by relatively few medical students and that individual use of videos is associated with the degree to which students are having difficulty with the subject matter.Computer technologies have increasingly impacted medical education [1,2], most recently through the electronic distribution of videos, which are used extensively for a wide range of educational activities including demonstrating anatomical dissections [3], clinical procedures [4], assessments [4,5], providing access to online lectures [6] for use in asynchronous learning [6-10], as well as videoconferencing of patient scenarios [11]. In 2007, the Stritch School of Medicine instituted a policy that all lectures for the first two years of medical school would be provided online through secure networks using video streaming technology. The rationale for this policy was to provide additional asynchronous web-based resources for students to use for independent learning.Several studies have investigated student satisfaction of lecture videos [12], attendance issues [7,13,14], educational efficien
Polymorphisms in the Mitochondrial Ribosome Recycling Factor EF-G2mt/MEF2 Compromise Cell Respiratory Function and Increase Atorvastatin Toxicity
Sylvie Callegari,Philip A. Gregory,Matthew J. Sykes,Jennifer Bellon,Stuart Andrews,Ross A. McKinnon,Miguel A. de Barros Lopes
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1002755
Abstract: Mitochondrial translation, essential for synthesis of the electron transport chain complexes in the mitochondria, is governed by nuclear encoded genes. Polymorphisms within these genes are increasingly being implicated in disease and may also trigger adverse drug reactions. Statins, a class of HMG-CoA reductase inhibitors used to treat hypercholesterolemia, are among the most widely prescribed drugs in the world. However, a significant proportion of users suffer side effects of varying severity that commonly affect skeletal muscle. The mitochondria are one of the molecular targets of statins, and these drugs have been known to uncover otherwise silent mitochondrial mutations. Based on yeast genetic studies, we identify the mitochondrial translation factor MEF2 as a mediator of atorvastatin toxicity. The human ortholog of MEF2 is the Elongation Factor Gene (EF-G) 2, which has previously been shown to play a specific role in mitochondrial ribosome recycling. Using small interfering RNA (siRNA) silencing of expression in human cell lines, we demonstrate that the EF-G2mt gene is required for cell growth on galactose medium, signifying an essential role for this gene in aerobic respiration. Furthermore, EF-G2mt silenced cell lines have increased susceptibility to cell death in the presence of atorvastatin. Using yeast as a model, conserved amino acid variants, which arise from non-synonymous single nucleotide polymorphisms (SNPs) in the EF-G2mt gene, were generated in the yeast MEF2 gene. Although these mutations do not produce an obvious growth phenotype, three mutations reveal an atorvastatin-sensitive phenotype and further analysis uncovers a decreased respiratory capacity. These findings constitute the first reported phenotype associated with SNPs in the EF-G2mt gene and implicate the human EF-G2mt gene as a pharmacogenetic candidate gene for statin toxicity in humans.
AASB 141 Agriculture: A Deconstruction Using Foucauldian Constructs and Thematic Content Analysis
Gregory Kenneth Laing,Ross Kirkham
Asian Social Science , 2012, DOI: 10.5539/ass.v8n11p1
Abstract: The purpose of this paper is to explore the subtext of the accounting standard AASB 141 Agriculture. A hybrid method is employed in which Foucauldian constructs are examined by way of a thematic construct analysis and a deconstruction to derive an interpretation. The constructs of power are firmly established in the legal authority of the accounting standard with the terminology of the biological asset creating the mechanisim by which to desensitise the exercise of moral judgement. The notion of intellectual property as a legal principle is questioned in light of the view taken by the Courts in the USA and the scientific developments in regards to genetics and biological prodction of artifical life forms. Parallels are drawn between the nature and the context of the standard and the ethical and moral issues that were confronted by individuals during the Third Reich and more recent declines in terms of ethical and moral jusgements in society.
Characterization of an Oct1 orthologue in the channel catfish, Ictalurus punctatus: A negative regulator of immunoglobulin gene transcription?
Mara L Lennard, Jun-ichi Hikima, David A Ross, Corine P Kruiswijk, Melanie R Wilson, Norman W Miller, Gregory W Warr
BMC Molecular Biology , 2007, DOI: 10.1186/1471-2199-8-8
Abstract: An orthologue of Oct1, a POU family transcription factor, was cloned from a catfish macrophage cDNA library. The inferred amino acid sequence of the catfish Oct1, when aligned with other vertebrate Oct1 sequences, revealed clear conservation of structure, with the POU specific subdomain of catfish Oct1 showing 96% identity to that of mouse Oct1. Expression of Oct1 was observed in clonal T and B cell lines and in all tissues examined. Catfish Oct1, when transfected into both mammalian (mouse) and catfish B cell lines, unexpectedly failed to drive transcription from three different octamer-containing reporter constructs. These contained a trimer of octamer motifs, a fish VH promoter, and the core region of the catfish Eμ3' IGH enhancer, respectively. This failure of catfish Oct1 to drive transcription was not rescued by human BOB.1, a co-activator of Oct transcription factors that stimulates transcription driven by catfish Oct2. When co-transfected with catfish Oct2, Oct1 reduced Oct2 driven transcriptional activation. Electrophoretic mobility shift assays showed that catfish Oct1 (native or expressed in vitro) bound both consensus and variant octamer motifs. Putative N- and C-terminal activation domains of Oct1, when fused to a Gal4 DNA binding domain and co-transfected with Gal4-dependent reporter constructs were transcriptionally inactive, which may be due in part to a lack of residues associated with activation domain function.An orthologue to mammalian Oct1 has been found in the catfish. It is similar to mammalian Oct1 in structure and expression. However, these results indicate that the physiological functions of catfish Oct1 differ from those of mammalian Oct1 and include negative regulation of transcription.The octamer motif (ATGCAAAT) and its reverse complement [1] are important cis-regulatory elements found in transcriptional control regions of ubiquitously expressed genes, such as histone H2B and small nuclear RNAs (U1, U2, and U6), as well as cell-type spe
Genetic Background Can Result in a Marked or Minimal Effect of Gene Knockout (GPR55 and CB2 Receptor) in Experimental Autoimmune Encephalomyelitis Models of Multiple Sclerosis
Sofia Sisay, Gareth Pryce, Samuel J. Jackson, Carolyn Tanner, Ruth A. Ross, Gregory J. Michael, David L. Selwood, Gavin Giovannoni, David Baker
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0076907
Abstract: Endocannabinoids and some phytocannabinoids bind to CB1 and CB2 cannabinoid receptors, transient receptor potential vanilloid one (TRPV1) receptor and the orphan G protein receptor fifty-five (GPR55). Studies using C57BL/10 and C57BL/6 (Cnr2tm1Zim) CB2 cannabinoid receptor knockout mice have demonstrated an immune-augmenting effect in experimental autoimmune encephalomyelitis (EAE) models of multiple sclerosis. However, other EAE studies in Biozzi ABH mice often failed to show any treatment effect of either CB2 receptor agonism or antagonism on inhibition of T cell autoimmunity. The influence of genetic background on the induction of EAE in endocannabinoid system-related gene knockout mice was examined. It was found that C57BL/6.GPR55 knockout mice developed less severe disease, notably in female mice, following active induction with myelin oligodendrocyte glycoprotein 35-55 peptide. In contrast C57BL/6.CB2 (Cnr2Dgen) receptor knockout mice developed augmented severity of disease consistent with the genetically and pharmacologically-distinct, Cnr2tm1Zim mice. However, when the knockout gene was bred into the ABH mouse background and EAE induced with spinal cord autoantigens the immune-enhancing effect of CB2 receptor deletion was lost. Likewise CB1 receptor and transient receptor potential vanilloid one knockout mice on the ABH background demonstrated no alteration in immune-susceptibility, in terms of disease incidence and severity of EAE, in contrast to that reported in some C57BL/6 mouse studies. Furthermore the immune-modulating influence of GPR55 was marginal on the ABH mouse background. Whilst sedative doses of tetrahydrocannabinol could induce immunosuppression, this was associated with a CB1 receptor rather than a CB2 receptor-mediated effect. These data support the fact that non-psychoactive doses of medicinal cannabis have a marginal influence on the immune response in MS. Importantly, it adds a note of caution for the translational value of some transgenic/gene knockout and other studies on low-EAE susceptibility backgrounds with inconsistent disease course and susceptibility.
HTSstation: A Web Application and Open-Access Libraries for High-Throughput Sequencing Data Analysis
Fabrice P. A. David, Julien Delafontaine, Solenne Carat, Frederick J. Ross, Gregory Lefebvre, Yohan Jarosz, Lucas Sinclair, Daan Noordermeer, Jacques Rougemont, Marion Leleu
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0085879
Abstract: The HTSstation analysis portal is a suite of simple web forms coupled to modular analysis pipelines for various applications of High-Throughput Sequencing including ChIP-seq, RNA-seq, 4C-seq and re-sequencing. HTSstation offers biologists the possibility to rapidly investigate their HTS data using an intuitive web application with heuristically pre-defined parameters. A number of open-source software components have been implemented and can be used to build, configure and run HTS analysis pipelines reactively. Besides, our programming framework empowers developers with the possibility to design their own workflows and integrate additional third-party software. The HTSstation web application is accessible at http://htsstation.epfl.ch.
Radical Resection of Adult Low Grade Oligodendroglioma without Adjuvant Therapy: Results of a Prospective Treatment Protocol—Surgical Treatment of Low-Grade Oligodendroglioma  [PDF]
Donald A. Ross, Lynda Yang, Oren Sagher, Amy M. Ross
Journal of Cancer Therapy (JCT) , 2011, DOI: 10.4236/jct.2011.22030
Abstract: The goal of this work was to demonstrate prospectively that maximal surgical resection of low grade oligodendrogliomas without adjuvant therapy does not reduce life expectancy over that of historical controls. All patients with surgically accessible grade II oligodendrogliomas underwent maximal resection using stereotactic guidance and/or cortical mapping and were followed with serial MRI scans without adjuvant therapy until either progression or spread into brain regions deemed not surgically resectable. Nineteen patients were treated between 1993 and 2006. Ten patients required reoperation an average of 55 months after their first surgery. Nine patients progressed to anaplastic tumors an average of 42 months after their first surgery: six patients died from their tumors an average of 73 months after diagnosis, two are still alive 76 and 18 months after progression, and one was lost to follow up. Ten patients are alive and progression-free an average of 116 months after diagnosis, one of whom was lost to follow up at 106 months from diagnosis. Four patients are alive and event-free an average of 125 months after diagnosis. All are male and three had tumors in the superior frontal gyrus. The event-free survival, progression-free survival, and overall survival of our patients are not worse than those of patients treated with postoperative adjuvant therapy. Withholding adjuvant therapy at diagnosis appears to be safe. It will be important to establish the molecular differences between the patients who did very well and those who progressed so that adjuvant therapy could be offered to the latter.
Lobar Distribution of Low Grade Oligodendroglioma: Distribution, Molecular Characteristics, and Survival Based upon Location  [PDF]
Donald A. Ross, Shao Tao, Sakir Gultekin, Amy M. Ross
Journal of Cancer Therapy (JCT) , 2014, DOI: 10.4236/jct.2014.513126
Abstract:

Grade II oligodendrogliomas are rare and slow growing tumors, making long-term follow up difficult, but necessary for better understanding. In this retrospective study a review of all grade II oligodendrogliomas encountered in the last 20 years at one institution, was undertaken to determine if specific tumor location and immunohistochemical analysis had any impact on recurrence rate, progression free survival, or life expectancy. Eighty-nine grade II oligodendroglioms cases were reviewed (38 females and 51 males; mean age was 40.3 ± 13.8 years). Tumor location was: frontal lobe (44, 49.4%) and superior frontal gyrus (30, 33.7%). 1p19q data were available in 49 patients. Twenty-nine cases were co-deleted (59.2%). There was no significant difference in the incidence of 1p19q co-deletion between superior frontal gyrus tumors vs. other frontal tumors or extra-frontal tumors (p= 0.45). Follow up of at least 3 months after diagnosis was available in 79 patients (mean follow up: 93.2 months). In recurrence analysis, recurrence by 1p19q status and recurrence by location revealed no significant differences. In analysis of progression, progression by 1p19q status and progression by location revealed no significant differences. An analysis of deaths for the sample, deaths by 1p19q status and deaths by location revealed no significant differences. There was a higher death rate among patients >50 years of age, however this, too, was not significant.There did not appear to be any advantage in recurrence rate, progression free survival, or life expectancy for tumors located in the frontal lobe or superior frontal gyrus. 1p19q co-deletion did not appear to confer an advantage as measured by time to recurrence, time to progression, or overall survival. Other than age, eloquent location, Karnofsky status, and overall tumor size as reported by others, tumor location and 1p19q status in low grade oligodendrogliomas are not currently predictive of survival.

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