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Prime Targets (prime + target)
Selected AbstractsHuman Variation in Alcohol Response Is Influenced by Variation in Neuronal Signaling GenesALCOHOLISM, Issue 5 2010Geoff Joslyn Background:, Alcohol use disorders (AUD) exhibit the properties shared by common conditions and diseases classified as genetically complex. The etiology of AUDs is heterogeneous involving mostly unknown interactions of environmental and heritable factors. A person's level of response (LR) to alcohol is inversely correlated with a family history and the development of AUDs. As an AUD endophenotype, alcohol LR is hypothesized to be less genetically complex and closer to the primary etiology of AUDs. Methods:, A genome wide association study (GWAS) was performed on subjects characterized for alcohol LR phenotypes. Gene Set Enrichment Analysis (GSEA) of the GWAS data was performed to determine whether, as a group, genes that participate in a common biological function (a gene set) demonstrate greater genetic association than would be randomly expected. Results:, The GSEA analysis implicated variation in neuronal signaling genes, especially glutamate signaling, as being involved in alcohol LR variability in the human population. Conclusions:, These data, coupled with cell and animal model data implicating neuronal signaling in alcohol response, support the conclusion that neuronal signaling is mechanistically involved in alcohol's cellular and behavioral effects. Further, these data suggest that genetic variation in these signaling pathways contribute to human variation in alcohol response. Finally, this concordance of the cell, animal, and human findings supports neuronal signaling, particularly glutamate signaling, as a prime target for translational studies to understand and eventually modulate alcohol's effects. [source] Oxidized/misfolded superoxide dismutase-1: the cause of all amyotrophic lateral sclerosis?ANNALS OF NEUROLOGY, Issue 6 2007Edor Kabashi PhD The identification in 1993 of superoxide dismutase-1 (SOD1) mutations as the cause of 10 to 20% of familial amyotrophic lateral sclerosis cases, which represents 1 to 2% of all amyotrophic lateral sclerosis (ALS) cases, prompted a substantial amount of research into the mechanisms of SOD1-mediated toxicity. Recent experiments have demonstrated that oxidation of wild-type SOD1 leads to its misfolding, causing it to gain many of the same toxic properties as mutant SOD1. In vitro studies of oxidized/misfolded SOD1 and in vivo studies of misfolded SOD1 have indicated that these protein species are selectively toxic to motor neurons, suggesting that oxidized/misfolded SOD1 could lead to ALS even in individuals who do not carry an SOD1 mutation. It has also been reported that glial cells secrete oxidized/misfolded mutant SOD1 to the extracellular environment, where it can trigger the selective death of motor neurons, offering a possible explanation for the noncell autonomous nature of mutant SOD1 toxicity and the rapid progression of disease once the first symptoms develop. Therefore, considering that sporadic (SALS) and familial ALS (FALS) cases are clinically indistinguishable, the toxic properties of mutated SOD1 are similar to that of oxidized/misfolded wild-type SOD1 (wtSOD1), and secreted/extracellular misfolded SOD1 is selectively toxic to motor neurons, we propose that oxidized/misfolded SOD1 is the cause of most forms of classic ALS and should be a prime target for the design of ALS treatments. Ann Neurol 2007 [source] Combined in Silico and Experimental Approach for Drug Design: The Binding Mode of Peptidic and Non-Peptidic Inhibitors to Hsp90 N-Terminal DomainCHEMICAL BIOLOGY & DRUG DESIGN, Issue 5 2010Simona Tomaselli Heat shock protein 90 (Hsp90) is a prime target for antitumor therapies. The information obtained by molecular dynamics (MD) simulations is combined with NMR data to provide a cross-validated atomic resolution model of the complementary interactions of heat shock protein 90 with a peptidic (shepherdin) and a non-peptidic (5-aminoimidazole-4-carboxamide-1-,- d -ribofuranoside, AICAR) inhibitor, showing antiproliferative and proapoptotic activity in multiple tumor cell lines. This approach highlights the relevant role of imidazolic moiety in the interaction of both antagonist molecules. In 5-aminoimidazole-4-carboxamide-1-,- d -ribofuranoside bound state, one conformation of those present in solution is selected, where imidazolic, H4 and H5 protons have a key role in defining a non-polar region contacting heat shock protein 90 surface. The dynamic equilibrium between N-type and S-type puckered forms of 5-aminoimidazole-4-carboxamide-1-,- d -ribofuranoside moiety is shown to be functional to inhibitor binding. The first experimental structural data on these inhibitors are presented and discussed as hints for future design of improved molecules. [source] Optimization of Thienopyrrole-Based Finger-Loop Inhibitors of the Hepatitis,C Virus NS5B PolymeraseCHEMMEDCHEM, Issue 10 2009Hernando Dr., Ignacio Martin Abstract Infections caused by the hepatitis,C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The NS5B polymerase of HCV is responsible for the replication of viral RNA and has been a prime target in the search for novel treatment options. We had discovered allosteric finger-loop inhibitors based on a thieno[3,2- b]pyrrole scaffold as an alternative to the related indole inhibitors. Optimization of the thienopyrrole series led to several N -acetamides with submicromolar potency in the cell-based replicon assay, but they lacked oral bioavailability in rats. By linking the N4-position to the ortho -position of the C5-aryl group, we were able to identify the tetracyclic thienopyrrole 40, which displayed a favorable pharmacokinetic profile in rats and dogs and is equipotent with recently disclosed finger-loop inhibitors based on an indole scaffold. [source] Induction of potent cellular immune response in mice by hepatitis C virus NS3 protein with double-stranded RNAIMMUNOLOGY, Issue 1 2007Bo Jin Summary Double-stranded RNA is produced during virus replication and, together with the viral antigen, is responsible for inducing host antivirus immunity. The hepatitis C virus (HCV) non-structural protein-3 (NS3) has been implicated in the immune evasion of HCV, and is one of the prime targets for inducing immunity against HCV infection. Mice were immunized with recombinant NS3 protein (rNS3) and poly (I:C) emulsified in Montanide ISA 720 (M720). Cytokine production was assayed by enzyme-linked immunospot assay, and CD4+ IFN-,+ T helper (Th) cells or CD8+ IFN-,+ cytotoxic T lymphocytes were detected by flow cytometry. Anti-NS3 titre and immunoglobulin G2a (IgG2a) and IgG1 levels were monitored by enzyme-linked immunosorbent assay. Administration of rNS3 formulated in poly (I:C) and M720 induced anti-NS3 titres with a predominantly IgG2a isotype comparable to those induced by rNS3 in CpG-ODN and M720. The cytokine profiles showed that this formulation induced a Th1-biased immune response with several-fold more interferon-, (IFN-,)-producing cells than interleukin-4-producing cells. In contrast, rNS3 in M720 induced a Th2-biased immune response. The frequency of IFN-,-producing CD4+ and CD8+ cells induced by rNS3 in poly (I:C) and M720 was significantly higher than that induced by rNS3, rNS3 in M720, or rNS3 in poly (I:C), and was comparable to that induced by rNS3 in CpG-ODN with M720. The antigen-specific CD8+ T-cell immune response persisted for up to 7 months after immunization. In conclusion, poly (I:C) with rNS3 in M720 can elicit a strong and persistent Th1-biased immune response and a cytotoxic T-lymphocyte response through cross-priming in mice. This study highlighted a promising formulation for inducing an efficient cellular immune response against HCV that has potential for HCV vaccine development. [source] The Militarization of Urban Marginality: Lessons from the Brazilian MetropolisINTERNATIONAL POLITICAL SOCIOLOGY, Issue 1 2008Loïc Wacquant This article examines the workings and effects of the penalization of poverty in urban Brazil at century's turn to uncover the deep logic of punitive containment as state strategy for the management of dispossessed and dishonored populations in the polarizing city in the age of triumphant neoliberalism. It shows how ramifying criminal violence (fed by extreme inequality and mass poverty), class and color discrimination in judicial processing, unchecked police brutality, and the catastrophic condition and chaotic operation of the carceral system combine to make the aggressive deployment of the penal apparatus in Brazil a surefire recipe for further disorder and disrespect for the law at the bottom of the urban hierarchy and steers the country into an institutional impasse. The policy of punitive containment pursued by political elites as a complement to the deregulation of the economy in the 1990s leads from the penalization to the militarization of urban marginality, under which residents of the declining favelas are treated as virtual enemies of the nation, tenuous trust in public institutions is undermined, and the spiral of violence accelerated. Brazil thus serves as a historical revelator of the full consequences of the penal disposal of the human detritus of a society swamped by social and physical insecurity. Drawing parallels between penal activity in the Brazilian and the U.S. metropolis further reveals that the neighborhoods of urban relegation wherein the marginal and stigmatized fractions of the postindustrial working class concentrate are the prime targets and proving ground upon which the neoliberal penal state is concretely being assembled, tried, and tested. Their study is therefore of urgent interest to analysts of international politics and state power at the dawn of the twenty-first century. [source] From JNK to Pay Dirt: Jun Kinases, their Biochemistry, Physiology and Clinical ImportanceIUBMB LIFE, Issue 4-5 2005Michael Karin Abstract The c-Jun N-terminal kinases (JNKs) were originally identified by their ability to phosphorylate c-Jun in response to UV-irradiation, but now are recognized as critical regulators of various aspects of mammalian physiology, including: cell proliferation, cell survival, cell death, DNA repair and metabolism. JNK-mediated phosphorylation enhances the ability of c-Jun, a component of the AP-1 transcription factor, to activate transcription, in response to a plethora of extracellular stimuli. The JNK activation leads to induction of AP-1-dependent target genes involved in cell proliferation, cell death, inflammation, and DNA repair. The JNKs, which are encoded by three different Jnk loci, are now known to be regulated by many other stimuli, from pro-inflammatory cytokines to obesity, in addition to UV-irradiation. Targeted disruption of the Jnk loci in mice has proved to be a critical tool in better understanding their physiological functions. Such studies revealed that the JNKs play important roles in numerous cellular processes, including: programmed cell death, T cell differentiation, negative regulation of insulin signaling, control of fat deposition, and epithelial sheet migration. Importantly, the JNKs have become prime targets for drug development in several important clinical areas, including: inflammation, diabetes, and cancer. IUBMB Life, 57: 283-295, 2005 [source] Emerging Role of Epigenetics in the Actions of AlcoholALCOHOLISM, Issue 9 2008Shivendra D. Shukla This review deals with the recent developments on the epigenetic effects of ethanol. A large body of data have come from studies in liver and in neuronal systems and involve post-translational modifications in histones and methylations in DNA. Ethanol causes site selective acetylation, methylation, and phosphorylation in histone. With respect to methylations the methyl group donating system involving S-adenosyl methionine appears to play a central role. There is contrasting effect of acetylation versus methylation on the same site of histone, as it relates to the transcriptional activation. Epigenetic memory also appears to correlate with liver pathology and Mallory body formation. Experimental evidence supports transcriptional regulation of genes in the CNS by DNA methylations. These studies are contributing towards a better understanding of a novel epigenetic regulation of gene expression in the context of alcohol. The critical steps and the enzymes (e.g., histone acetyltransferase, histone deacetylase, DNA methyltransferase) responsible for the epigenetic modifications are prime targets for intense investigation. The emerging data are also beginning to offer novel insight towards defining the molecular actions of ethanol and may contribute to potential therapeutic targets at the nucleosomal level. These epigenetic studies have opened up a new avenue of investigation in the alcohol field. [source] Mitochondria-targeted disruptors and inhibitors of cytochrome c/cardiolipin peroxidase complexes: A new strategy in anti-apoptotic drug discoveryMOLECULAR NUTRITION & FOOD RESEARCH (FORMERLY NAHRUNG/FOOD), Issue 1 2009Valerian E. Kagan Abstract Thre critical role of mitochondria in programmed cell death leads to the design of mitochondriotropic agents as a strategy in regulating apoptosis. For anticancer therapy, stimulation of proapoptotic mitochondrial events in tumor cells and their suppression in surrounding normal cells represents a promising paradigm for new therapies. Different approaches targeting regulation of components of mitochondrial antioxidant system such as Mn-SOD demonstrated significant antitumor efficiency, particularly in combination therapy. This review is focused on a newly discovered early stage of mitochondria-dependent apoptosis , oxidative lipid signaling involving a mitochondria-specific phospholipid cardiolipin (CL). Cytochrome c (cyt c) acts as a CL-specific peroxidase very early in apoptosis. At this stage, the hostile events are still secluded within the mitochondria and do not reach the cytosolic targets. CL oxidation process is required for the release of pro-apoptotic factors into the cytosol. Manipulation of cyt c interactions with CL, inhibition of peroxidase activity, and prevention of CL peroxidation are prime targets for the discovery of anti-apoptotic drugs acting before the "point-of-no-return" in the fulfillment of the cell death program. Therefore, mitochondria-targeted disruptors and inhibitors of cyt c/CL peroxidase complexes and suppression of CL peroxidation represent new strategies in anti-apoptotic drug discovery. [source] Technology Advances and Tanker Spill PreventionNAVAL ENGINEERS JOURNAL, Issue 4 2001Cdr. G. Rodgers USCGR (Ret.) ABSTRACT Goals to alert the bridge watch for imminent grounding or collision with shallow underwater dangers, have long been stymied by lags in active sonar technology. Thus "lower hemisphere" designs for shallow underwater search have been unable to exploit solutions useful topside for the "upper hemisphere" guarded by radar and other technology. While the radar environment normally exhibits single path, direct line-of-sight conditions for prime targets, the shallow water sonar environment is cluttered by a mix of echoes and multipath returns for identical ranges. Thus we first must accommodate to a quirky hydroacoustic environment as a major design subsystem for any shallow water navigational sonar. Secondly, for large carriers found in the world tanker fleet, there is recognition that some simple backfit solution is needed for any electroacoustic interface, the sonar transducer. Commercial carriers have not been designed or built with special hull considerations such as sonar domes and recesses; therefore, this second vital subsystem requires particular design attention for projecting hydro-acoustic energy and receiving return echoes. Several recent patents are on file which apply to this problem. Thirdly, signal processing considerations provide a set of design-critical factors. High speed digital signal processors (DSPs) of recent "parallel" design offer opportunities to search at high speed and to unravel the confusing mix of acoustic energy found in shallow water returns. Past hurdles are endemic for these three critical subsystems: hydroacoustic environment, electroacoustic transducer design, and signal processing, but now these seem most amenable to technology transfer. [source] | |||||||||||||