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Search Results: 1 - 10 of 328516 matches for " Gary S. Laco "
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Evaluation of Two Models for Human Topoisomerase I Interaction with dsDNA and Camptothecin Derivatives
Gary S. Laco
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0024314
Abstract: Human topoisomerase I (Top1) relaxes supercoiled DNA during cell division. Camptothecin stabilizes Top1/dsDNA covalent complexes which ultimately results in cell death, and this makes Top1 an anti-cancer target. There are two current models for how camptothecin and derivatives bind to Top1/dsDNA covalent complexes (Staker, et al., 2002, Proc Natl Acad Sci USA 99: 15387–15392; and Laco, et al., 2004, Bioorg Med Chem 12: 5225–5235). The interaction energies between bound camptothecin, and derivatives, and Top1/dsDNA in the two models were calculated. The published structure-activity-relationships for camptothecin and derivatives correlated with the interaction energies for camptothecin and derivatives in the Laco et al. model, however, this was not the case for several camptothecin derivatives in the Stacker et al. model. By defining the binding orientation of camptothecin and derivatives in the Top1/dsDNA active-site these results allow for the rational design of potentially more efficacious camptothecin derivatives.
Determinants of Vessel Targeting in Vasculitis
Gary S. Hoffman
Clinical and Developmental Immunology , 2004, DOI: 10.1080/17402520400001652
Abstract: Studies of autoimmune diseases have not yet elucidated why certain organs or vessels become the objects of injury while others are spared. This paper will explore the hypothesis that important differences exist in regions of the aorta that determine vulnerability to diseases, such as atherosclerosis, aortitis, giant cell arteritis and Takayasu's disease. The reader is invited to reassess; (1) whether the aorta is indeed a single homogeneous structure, and (2) whether the initial stage of aortitis (and indeed other diseases considered “autoimmune”) may be primarily due to acquired alterations of substrate, that influence unique immune profiles, which by themselves may not be pathogenic. Disease susceptibility and patterns are influenced by many factors that are inborn and acquired. Examples include genetic background, gender, ethnicity, aging, prior and concomitant illnesses, habits, diet, toxin and environmental exposures. Studies of vascular diseases must assess how such variables may affect regional differences in endothelial cells, subendothelial matrix, vascular smooth muscle and the response of each to a variety of stimuli.
The Influence of Bioactive Oxylipins from Marine Diatoms on Invertebrate Reproduction and Development
Gary S. Caldwell
Marine Drugs , 2009, DOI: 10.3390/md7030367
Abstract: Diatoms are one of the main primary producers in aquatic ecosystems and occupy a vital link in the transfer of photosynthetically-fixed carbon through aquatic food webs. Diatoms produce an array of biologically-active metabolites, many of which have been attributed as a form of chemical defence and may offer potential as candidate marine drugs. Of considerable interest are molecules belonging to the oxylipin family which are broadly disruptive to reproductive and developmental processes. The range of reproductive impacts includes; oocyte maturation; sperm motility; fertilization; embryogenesis and larval competence. Much of the observed bioactivity may be ascribed to disruption of intracellular calcium signalling, induction of cytoskeletal instability and promotion of apoptotic pathways. From an ecological perspective, the primary interest in diatom-oxylipins is in relation to the potential impact on energy flow in planktonic systems whereby the reproductive success of copepods (the main grazers of diatoms) is compromised. Much data exists providing evidence for and against diatom reproductive effects; however detailed knowledge of the physiological and molecular processes involved remains poor. This paper provides a review of the current state of knowledge of the mechanistic impacts of diatom-oxylipins on marine invertebrate reproduction and development.
'Rac'-ing upstream to treat rheumatoid arthritis
Gary S Firestein
Arthritis Research & Therapy , 2010, DOI: 10.1186/ar2924
Abstract: Protein-based therapeutics for rheumatoid arthritis have limitations despite improved clinical outcomes. In addition to expense and the need for parenteral administration, a significant percentage of patients do not have robust responses. Intracellular signaling molecules, such as members of the Rho family [1], represent an attractive alternative because the compounds are often orally bioavailable and can block numerous proinflammatory mediators simultaneously.Targeting signal transduction, however, has been an exercise in frustration until recently. The p38 mitogen-activated protein kinase saga is emblematic of these problems [2]. Despite abundant preclinical data supporting the utility of p38 inhibitors, benefit has been marginal at best [3]. It is important to recognize that success in biologics also did not come with the first attempt. Numerous failures preceded the advent of TNF blockers, including anti-CD4, anti-CD5 and anti-CD52 antibodies, IL-2-diphtheria toxin fusion protein, IFNγ, IL-2, and several others. Clinical efficacy for JAK and Syk inhibitors demonstrated in recent years crossed the Rubicon for signaling-directed therapeutics [4,5]. The question now is not whether some of these agents can be effective; rather, it is whether the toxicity and side effects will be acceptable in a world where biologics have an advantageous therapeutic index.A distinguishing feature of the encouraging interventions (Syk, JAK, and perhaps c-Kit) compared with p38 inhibitors is that the former targets are proximal in the signaling cascade. Going upstream can be risky, since each enzyme casts a broader penumbra of effects than a downstream target. This increases the potential for both benefit and toxicity. Risk, however, can be managed; lack of efficacy cannot.This lesson is being exploited by going far upstream using therapeutics that inhibit the Rac proteins. These signaling enzymes, unlike the classical protein kinases that phosphorylate various transcription factors, a
Pathogenesis of rheumatoid arthritis: how early is early?
Gary S Firestein
Arthritis Research & Therapy , 2005, DOI: 10.1186/ar1780
Abstract: Development of hypotheses to explain the pathogenesis of chronic rheumatoid arthritis (RA), including the interesting new study by Raza and colleagues [1], has been a wondrous adventure. Virtually every immune cell type and inflammatory mediator has been implicated in the disease process at one time or another. Older, temporarily discarded hypotheses on B cells and immune complexes have enjoyed renewed energy with the advent of anti-B-cell therapies [2]. Now that T-cell-directed approaches, such as CTLA4-Ig [3], demonstrate efficacy, it appears that therapies targeting this cell lineage also are effective in a subpopulation of patients. Hence, chronic rheumatoid synovitis is marked by a complex interplay between multiple cell types, and individual patients display their own distinct hierarchy for the efficacy of therapeutic interventions [4].On the other hand, there is much less information on disease mechanisms in the earliest stages of RA. This is, in part, due to the changing definitions of 'early RA', with a cutoff that has gradually migrated from 2 years of symptoms to as little as 6 weeks. Even in the latter case, a prolonged preclinical period of immune hyper-reactivity and asymptomatic synovitis could exist before the disease becomes fully established. Many investigators believe that an appropriate genetic background in combination with stochastic events, such as activation of innate immunity, can serve as the trigger for RA. Subsequent perpetuation of the disease might involve entirely distinct adaptive immune mechanisms that are independent of the initiating events.Implicit in this assessment, an adaptive T-cell response might be required for full expression of RA. The nature of this response remains poorly defined, and studies of chronic rheumatoid synovitis have generally demonstrated blunted T-cell function and surprisingly limited cytokine production compared with other T-cell-mediated diseases. The lymphocyte cytokine profile in chronic RA synovium an
The Modern FPGA as Discriminator, TDC and ADC
Gary S. Varner
Physics , 2006, DOI: 10.1088/1748-0221/1/07/P07001
Abstract: Recent generations of Field Programmable Gate Arrays (FPGAs) have become indispensible tools for complex state machine control and signal processing, and now routinely incorporate CPU cores to allow execution of user software code. At the same time, their exceptional performance permits low-power implementation of functionality previously the exclusive domain of dedicated analog electronics. Specific examples presented here use FPGAs as discriminator, time-to-digital (TDC) and analog-to-digital converter (ADC). All three cases are examples of instrumentation for current or future astroparticle experiments.
力学进展 , 2007, DOI: 10.6052/1000-0992-2007-4-J2007-109
Abstract: 国土安全涉及到流体力学的广泛应用,并为其研究发展提供了诸多机遇.本评论选择列举了流体力学在反恐领域的各类课题,还建议了今后的研究方向.课题范围从防备、遏制策划中的恐怖袭击,一直到探测、应对和恢复.具体的内容则包括飞机加固,爆炸缓冲,传感器取样,爆炸物探测,微流控和芯片实验室,城市环境中化学羽流弥散以及建筑物通风等.此外,本文还讨论了蒸气羽流与远距探测,非致命武器,疾病空气传播,人员防护装备以及污染移除问题.涉及这类的应用,要求流体力学家跨越传统领域的边界,进行交叉学科研究,特别是要结合化学、生物学、气溶胶学与大气科学协同工作.
Adipose-derived stem cell therapy for severe muscle tears in working German shepherds: Two case reports  [PDF]
S. Gary Brown, Robert J. Harman, Linda L. Black
Stem Cell Discovery (SCD) , 2012, DOI: 10.4236/scd.2012.22007
Abstract: Injuries to muscle in the elite athlete are common and may be responsible for prolonged periods of loss of competitive activity. The implications for the athlete, his/her coach and team may be catastrophic if the injury occurs at a critical time in the athlete's diary. Imaging now plays a crucial role in diagnosis, prognostication and management of athletes with muscle injuries. This article discusses the methods available to clinicians and radiologists that are used to assess skeletal muscle injury. The spectrum of muscle injuries sustained in the elite athlete population is both discussed and illustrated.
The Volcanic Evolution of Cerro Uturuncu: A High-K, Composite Volcano in the Back-Arc of the Central Andes of SW Bolivia  [PDF]
Gary S. Michelfelder, Todd C. Feeley, Alicia D. Wilder
International Journal of Geosciences (IJG) , 2014, DOI: 10.4236/ijg.2014.511105
Abstract: Cerro Uturuncu, southwest Bolivia, is a high-K, calc-alkaline, composite volcano constructed upon extremely thick continental crust approximately 125 km behind the arc-front of the Andean Central Volcanic Zone (CVZ). Eruptive activity occurred between 890 - 271 ka in a single phase of volcanism lasting ~620,000 years. The edifice consists of a central cone and several flank vents where dacitic and andesitic lava flows and domes erupted. Volumes of individual eruptive units range from 0.1 to ~10 km3; the composite volume of Uturuncu is ~89 km3. In this paper, we present new field, petrographic, and geochemical data in an effort to understand the volcanic and magmatic evolution of Uturuncu. Lava flows and domes have a restricted range in whole rock compositions ranging from 61 wt% - 67 wt% SiO2; magmatic inclusions contained within these units have a larger range from 53 wt% - 64 wt% SiO2. Typical phenocryst assemblages are plagioclase > orthopyroxene > biotite >> quartz and Fe-Ti oxides. Pb isotope ratios are characteristic of the southern CVZ by containing high 207Pb/204Pb and 206Pb/204Pb and moderate to high 208Pb/204Pb. Sr and Nd isotope ratios indicate that Uturuncu magmas were modified by high 87Sr/86Sr and low 143Nd/144Nd felsic basement lithology during magma migration and differentiation. In all eruptive units, there is petrographic and geochemical evidence for magma mixing and mingling. In this regard, magma mixing and mingling is considered to be responsible for the small range in lava flow and dome compositions throughout the eruptive history of the center.
Inertial-range spectrum of whistler turbulence
Y. Narita,S. P. Gary
Annales Geophysicae (ANGEO) , 2010,
Abstract: We develop a theoretical model of an inertial-range energy spectrum for homogeneous whistler turbulence. The theory is a generalization of the Iroshnikov-Kraichnan concept of the inertial-range magnetohydrodynamic turbulence. In the model the dispersion relation is used to derive scaling laws for whistler waves at highly oblique propagation with respect to the mean magnetic field. The model predicts an energy spectrum for such whistler waves with a spectral index 2.5 in the perpendicular component of the wave vector and thus provides an interpretation about recent discoveries of the second inertial-range of magnetic energy spectra at high frequencies in the solar wind.
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