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  • 1
    Publication Date: 2012-06-05
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Svensson, Robert U -- Shaw, Reuben J -- England -- Nature. 2012 May 31;485(7400):590-1. doi: 10.1038/485590a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22660317" target="_blank"〉PubMed〈/a〉
    Keywords: AMP-Activated Protein Kinases/*metabolism ; Animals ; *Energy Metabolism ; Female ; *Homeostasis ; Male ; NADP/*metabolism ; Neoplasms/*metabolism/*pathology ; *Oxidative Stress
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2014-07-22
    Description: During the blood stages of malaria, several hundred parasite-encoded proteins are exported beyond the double-membrane barrier that separates the parasite from the host cell cytosol. These proteins have a variety of roles that are essential to virulence or parasite growth. There is keen interest in understanding how proteins are exported and whether common machineries are involved in trafficking the different classes of exported proteins. One potential trafficking machine is a protein complex known as the Plasmodium translocon of exported proteins (PTEX). Although PTEX has been linked to the export of one class of exported proteins, there has been no direct evidence for its role and scope in protein translocation. Here we show, through the generation of two parasite lines defective for essential PTEX components (HSP101 or PTEX150), and analysis of a line lacking the non-essential component TRX2 (ref. 12), greatly reduced trafficking of all classes of exported proteins beyond the double membrane barrier enveloping the parasite. This includes proteins containing the PEXEL motif (RxLxE/Q/D) and PEXEL-negative exported proteins (PNEPs). Moreover, the export of proteins destined for expression on the infected erythrocyte surface, including the major virulence factor PfEMP1 in Plasmodium falciparum, was significantly reduced in PTEX knockdown parasites. PTEX function was also essential for blood-stage growth, because even a modest knockdown of PTEX components had a strong effect on the parasite's capacity to complete the erythrocytic cycle both in vitro and in vivo. Hence, as the only known nexus for protein export in Plasmodium parasites, and an essential enzymic machine, PTEX is a prime drug target.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Elsworth, Brendan -- Matthews, Kathryn -- Nie, Catherine Q -- Kalanon, Ming -- Charnaud, Sarah C -- Sanders, Paul R -- Chisholm, Scott A -- Counihan, Natalie A -- Shaw, Philip J -- Pino, Paco -- Chan, Jo-Anne -- Azevedo, Mauro F -- Rogerson, Stephen J -- Beeson, James G -- Crabb, Brendan S -- Gilson, Paul R -- de Koning-Ward, Tania F -- England -- Nature. 2014 Jul 31;511(7511):587-91. doi: 10.1038/nature13555. Epub 2014 Jul 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, 3004, Australia [2] Monash University, Clayton, Victoria, 3800, Australia [3]. ; 1] Deakin University, Waurn Ponds, 3216, Australia [2]. ; Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, 3004, Australia. ; Deakin University, Waurn Ponds, 3216, Australia. ; 1] Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, 3004, Australia [2] Monash University, Clayton, Victoria, 3800, Australia. ; National Center for Genetic Engineering and Biotechnology (BIOTEC), Pathum Thani 12120, Thailand. ; The University of Geneva, 1211 Geneva 4, Switzerland. ; The University of Melbourne, Parkville, Victoria, 3010 Australia. ; 1] Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, 3004, Australia [2] Monash University, Clayton, Victoria, 3800, Australia [3] The University of Melbourne, Parkville, Victoria, 3010 Australia. ; 1] Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, 3004, Australia [2] Monash University, Clayton, Victoria, 3800, Australia [3] The University of Melbourne, Parkville, Victoria, 3010 Australia [4].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043043" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Erythrocytes/metabolism/parasitology ; Heat-Shock Proteins/genetics/*metabolism ; Humans ; Life Cycle Stages/physiology ; Malaria/*parasitology ; Multiprotein Complexes/metabolism ; Plasmodium falciparum/*genetics/*metabolism ; Protein Transport/genetics ; Protozoan Proteins/genetics/*metabolism ; Vacuoles/metabolism/parasitology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
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    Nature Publishing Group (NPG)
    Publication Date: 2018-06-26
    Description: GNAS shifts metabolism in pancreatic cancer GNAS shifts metabolism in pancreatic cancer, Published online: 25 June 2018; doi:10.1038/s41556-018-0120-5 Specific combinations of mutations cause unique signalling and metabolic requirements. Concurrent G-protein αs (GNAS) and KRAS mutations in a subset of pancreatic tumours are now shown to inhibit SIK kinases through aberrant cAMP–PKA activation, triggering a metabolic program defined by lipid metabolism and fatty acid oxidation.
    Print ISSN: 1465-7392
    Electronic ISSN: 1476-4679
    Topics: Biology , Medicine
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  • 4
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2012-05-19
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shaw, Reuben J -- Cantley, Lewis C -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2012 May 18;336(6083):813-4. doi: 10.1126/science.1223140.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA. shaw@salk.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22605741" target="_blank"〉PubMed〈/a〉
    Keywords: AMP-Activated Protein Kinases/*metabolism ; Animals ; Humans ; Salicylates/*metabolism/*pharmacology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 5
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2013-06-01
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shaw, Reuben J -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2013 May 31;340(6136):1056-7. doi: 10.1126/science.1240315.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular and Cell Biology Laboratory, Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA. shaw@salk.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23723225" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acids/*metabolism ; Carrier Proteins/*metabolism ; Humans ; Lysosomes/*enzymology ; Monomeric GTP-Binding Proteins/*metabolism ; Multiprotein Complexes ; Neoplasms/*enzymology ; Proteins/*metabolism ; TOR Serine-Threonine Kinases ; Tumor Suppressor Proteins/*metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2018-04-27
    Description: Mycobacterium tuberculosis and the fast-growing species Mycobacterium abscessus are two important human pathogens causing persistent pulmonary infections that are difficult to cure and require long treatment times. The emergence of drug-resistant M. tuberculosis strains and the high level of intrinsic resistance of M. abscessus call for novel drug scaffolds that effectively target both pathogens. In this study, we evaluated the activity of bis(pyrrolide-imine) gold(III) macrocycles and chelates, originally designed as DNA intercalators capable of targeting human topoisomerase types I and II (Topo1 and Topo2), against M. abscessus and M. tuberculosis . We identified a total of 5 noncytotoxic compounds active against both mycobacterial pathogens under replicating in vitro conditions. We chose one of these hits, compound 14, for detailed analysis due to its potent bactericidal mode of inhibition and scalable synthesis. The clinical relevance of this compound was demonstrated by its ability to inhibit a panel of diverse M. tuberculosis and M. abscessus clinical isolates. Prompted by previous data suggesting that compound 14 may target topoisomerase/gyrase enzymes, we demonstrated that it lacked cross-resistance with fluoroquinolones, which target the M. tuberculosis gyrase. In vitro enzyme assays confirmed the potent activity of compound 14 against bacterial topoisomerase 1A (Topo1) enzymes but not gyrase. Novel scaffolds like compound 14 with potent, selective bactericidal activity against M. tuberculosis and M. abscessus that act on validated but underexploited targets like Topo1 represent a promising starting point for the development of novel therapeutics for infections by pathogenic mycobacteria.
    Print ISSN: 0066-4804
    Electronic ISSN: 1098-6596
    Topics: Biology , Medicine
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  • 7
    Publication Date: 2018-05-16
    Description: Purpose: The purpose of this study is to investigate the potential interplay between opioid analgesia and tumor metastasis through modulation of μ-opioid receptor (MOR), Toll-like receptor 4 (TLR4) activation, and matrix degradation potential. Experimental Design: Plasma samples were collected from 60 patients undergoing elective lower limb joint replacement preoperatively and at 3, 6, and 24 hours after surgery; pain scores were documented at the same time points. Opioid administration was recorded and converted into morphine IV equivalents. Plasma samples were also collected from 10 healthy volunteers. Alphascreen cyclic AMP assay and MOR-overexpressing cells were employed to quantify MOR activation. HEK-Blue hTLR4 were utilized to measure TLR4 activation. Circulating matrix metalloprotease and tissue inhibitor of matrix protease activities were assessed by gelatin zymography and reverse zymography, respectively. Results: Postoperative plasma samples displayed the ability to activate MOR and to inhibit lipopolysaccharide (LPS)-induced TLR4 activation. Linear mixed model analysis revealed that MOR activation had a significant effect on inhibition of LPS-induced TLR4 activation. Furthermore, TLR4 had a significant effect to explain pain scores. Postoperative samples also displayed altered circulating matrix-degrading enzymes activity potential, but this was correlated neither to opioid administration nor to MOR activation potential. Conclusions: Our results show for the first time that (i) opioids administered to surgery patients result in modulation of ligand-induced TLR4 activation and (ii) postoperative pain is associated with increased circulating TLR4 activation potential. Our study further promotes the use of MOR activation potential rather than opioid intake in clinical studies measuring opioid exposure at a given time point. Clin Cancer Res; 24(10); 2319–27. ©2018 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 8
    Publication Date: 2018-06-16
    Description: With the increasing availability of genomics, routine analysis of advanced cancers is now feasible. Treatment selection is frequently guided by the molecular characteristics of a patient's tumor, and an increasing number of trials are genomically selected. Furthermore, multiple studies have demonstrated the benefit of therapies that are chosen based upon the molecular profile of a tumor. However, the rapid evolution of genomic testing platforms and emergence of new technologies make interpreting molecular testing reports more challenging. More sophisticated precision oncology decision support services are essential. This review outlines existing tools available for health care providers and precision oncology teams and highlights strategies for optimizing decision support. Specific attention is given to the assays currently available for molecular testing, as well as considerations for interpreting alteration information. This article also discusses strategies for identifying and matching patients to clinical trials, current challenges, and proposals for future development of precision oncology decision support. Clin Cancer Res; 24(12); 2719–31. ©2018 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 9
    Publication Date: 2018-07-24
    Description: Recent studies suggest that autism is often associated with dysregulated immune responses and altered microbiota composition. This has led to growing speculation about potential roles for hyperactive immune responses and the microbiome in autism. Yet how microbiome–immune cross-talk contributes to neurodevelopmental disorders currently remains poorly understood. In this study, we report critical roles for prenatal microbiota composition in the development of behavioral abnormalities in a murine maternal immune activation (MIA) model of autism that is driven by the viral mimetic polyinosinic-polycytidylic acid. We show that preconception microbiota transplantation can transfer susceptibility to MIA-associated neurodevelopmental disease and that this is associated with modulation of the maternal immune response. Furthermore, we find that ablation of IL-17a signaling provides protection against the development of neurodevelopmental abnormalities in MIA offspring. Our findings suggest that microbiota landscape can influence MIA-induced neurodevelopmental disease pathogenesis and that this occurs as a result of microflora-associated calibration of gestational IL-17a responses.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
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  • 10
    Publication Date: 2011-02-19
    Description: 〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237313/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237313/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Birnbaum, Morris J -- Shaw, Reuben J -- P01 CA120964/CA/NCI NIH HHS/ -- P01 DK049210/DK/NIDDK NIH HHS/ -- P30 CA014195/CA/NCI NIH HHS/ -- R01 DK056886/DK/NIDDK NIH HHS/ -- R01 DK080425/DK/NIDDK NIH HHS/ -- England -- Nature. 2011 Feb 17;470(7334):338-9. doi: 10.1038/470338a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21331030" target="_blank"〉PubMed〈/a〉
    Keywords: Adenylate Kinase/metabolism ; Animals ; Ataxia Telangiectasia Mutated Proteins ; Blood Glucose/analysis/biosynthesis ; Cell Cycle Proteins/antagonists & inhibitors/*genetics/*metabolism ; DNA-Binding Proteins/antagonists & inhibitors/*genetics/*metabolism ; Diabetes Mellitus, Type 2/complications/*drug therapy/*genetics ; Energy Intake ; Enzyme Activation/drug effects ; Female ; Genome-Wide Association Study ; Humans ; Hypoglycemic Agents/*pharmacology ; Metformin/*pharmacology ; Neoplasms/drug therapy/*genetics/pathology ; Pharmacogenetics ; Polycystic Ovary Syndrome/complications ; Protein-Serine-Threonine Kinases/antagonists & inhibitors/*genetics/*metabolism ; Tumor Suppressor Proteins/antagonists & inhibitors/*genetics/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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