Discovery of a Redox Thiol Switch: Implications for Cellular Energy Metabolism

The redox-based modifications of cysteine residues in proteins regulate their function in many biological processes. The gas molecule H2S has been shown to persulfidate redox sensitive cysteine residues resulting in an H2S-modified proteome known as the sulfhydrome. Tandem Mass Tags (TMT) multiplexing strategies for large-scale proteomic analyses have become increasingly prevalent in detecting cysteine modifications. Here we developed a TMT-based proteomics approach for selectively trapping and tagging cysteine persulfides in the cellular proteomes. We revealed the natural protein sulfhydrome of two human cell lines, and identified insulin as a novel substrate in pancreatic beta cells. Moreover, we showed that under oxidative stress conditions, increased H2S can target enzymes involved in energy metabolism by switching specific cysteine modifications to persulfides. Specifically, we discovered a Redox Thiol Switch, from protein S-glutathioinylation to S-persulfidation (RTSGS). We propose that the RTSGS from S-glutathioinylation to S-persulfidation is a potential mechanism to fine tune cellular energy metabolism in response to different levels of oxidative stress

A novel small molecule inhibitor of human Drp1

Mitochondrial dynamin-related protein 1 (Drp1) is a large GTPase regulator of mitochondrial dynamics and is known to play an important role in numerous pathophysiological processes. Despite being the most widely used Drp1 inhibitor, the specificity of Mdivi-1 towards human Drp1 has not been definitively proven and there have been numerous issues reported with its use including off-target effects. In our hands Mdivi-1 showed varying binding affinities toward human Drp1, potentially impacted by compound aggregation. Herein, we sought to identify a novel small molecule inhibitor of Drp1. From an initial virtual screening, we identified DRP1i27 as a compound which directly bound to the human isoform 3 of Drp1 via surface plasmon resonance and microscale thermophoresis. Importantly, DRP1i27 was found to have a dose-dependent increase in the cellular networks of fused mitochondria but had no effect in Drp1 knock-out cells. Further analogues of this compound were identified and screened, though none displayed greater affinity to human Drp1 isoform 3 than DRP1i27. To date, this is the first small molecule inhibitor shown to directly bind to human Drp1

Crop Updates 2005 - Katanning

This session covers twenty five papers from different authors KEYNOTE How Farmers Can Work Together for a More Sustainable and Profitable Business, Brian McAlpine Farmer, Nuffield Scholar GENERAL 2005 Seasonal Outlook, David Stephens and Nicola Telcik, Department of Agriculture Essentials for cereal leaf disease management, K. Jayasena, R. Loughman, G. Thomas, C. Beard, and B. Paynter, Department of Agriculture Benefits to the grower of grain licensing, Colin Mann, Grain Licensing Authority SOIL & NUTRIENTS The effect of higher nitrogen fertiliser prices on rotation and fertiliser strategies in cropping systems, Ross Kingwell, Department of Agriculture Effect of stubble burning and seasonality on microbial processes and nutrient cycling, Francis Hoyle, University of Western Australia Soil Biology and Crop Production in Western Australian Farming Systems, D.V. Murphy, N. Milton, M. Osman, F.C. Hoyle, L.K Abbott, W.R. Cookson and S. Darmawanto, University of Western Australia Nutrient Management to get optimal production, Bill Bowden, Department of Agriculture OTHER CROPS Which malting barley variety and why? Blakely Paynter, Department of Agriculture KASPA AND OTHER NEW PULSE VARIETIES, 1. New Pulse varieties and where they fit in, K. Regan, P. White, Department of Agriculture & CLIMA, K. Siddique, CLIMA, K. Adhikari, Department of Agriculture & CLIMA, M. Harries, CLIMA Kaspa in the WA Grain Belt 2003-2004, Ian Pritchard, Department of Agriculture New annual pastures for Mediterranean farming systems, Angelo Loi, Phil Nichols, Clinton Revell & David Ferris, Department of Agriculture Challenging herbicide resistant ryegrass, Bill Roy, Agricultural Consulting & Research Services Pty.Ltd WEED MANAGEMENT Ingest, incinerate or invert? The pro’s and con’s of 3 weed seed removal tactics, Sally Peltzer1, Dave Minkey1 and Michael Walsh2 Department of Agriculture 1 and Western Australian Herbicide Resistance lnitiative2 A good use guide for pre-emergent herbicides, Alexandra Douglas, Department of Agriculture OTHER USEFUL INFORMATION 17.Growing season outlook, Meredith Fairbanks, Ian Foster, Geraldine Pasqual, David Stephens, Nicola Telcik, David Tennant, Department of Agriculture 18. Status Of Department Of Agriculture Western Australia Crop Varieties 19. Seed Licensee Details 20. Gene technology for growers. What is it? How does it Work? Belinda Barr, Australian Centre for Plant Functional Genomics, Dr Heather Bray, Molecular Plant Breeding Cooperative Research Centre. 21. Agronomic package for EGA Eagle Rock, Steve Penny, Department of Agriculture 22. Nutrient timing and requirements for increased crop yields in the high rainfall cropping zone, Narelle Hill, Ron McTaggart, Dr. Wal Anderson and Ray Tugwell Department of Agriculture 23. Insect contamination of cereal grain at harvest, Svetlana Micic and Phil Michael, Department of Agriculture 24. Crop leftovers: what’s in stubble for sheep? Roy Butler and Keith Croker, Department of Agriculture 25. Mandelup – Narrow-leafed lupi

Proposal for gravitational-wave detection beyond the standard quantum limit through EPR entanglement

The Standard Quantum Limit in continuous monitoring of a system is given by the trade-off of shot noise and back-action noise. In gravitational-wave detectors, such as Advanced LIGO, both contributions can simultaneously be squeezed in a broad frequency band by injecting a spectrum of squeezed vacuum states with a frequency-dependent squeeze angle. This approach requires setting up an additional long base-line, low-loss filter cavity in a vacuum system at the detector's site. Here, we show that the need for such a filter cavity can be eliminated, by exploiting EPR-entangled signal and idler beams. By harnessing their mutual quantum correlations and the difference in the way each beam propagates in the interferometer, we can engineer the input signal beam to have the appropriate frequency dependent conditional squeezing once the out-going idler beam is detected. Our proposal is appropriate for all future gravitational-wave detectors for achieving sensitivities beyond the Standard Quantum Limit.Comment: 16 pages, 7 figure

Antimicrobials: a global alliance for optimizing their rational use in intra-abdominal infections (AGORA)

Intra-abdominal infections (IAI) are an important cause of morbidity and are frequently associated with poor prognosis, particularly in high-risk patients. The cornerstones in the management of complicated IAIs are timely effective source control with appropriate antimicrobial therapy. Empiric antimicrobial therapy is important in the management of intra-abdominal infections and must be broad enough to cover all likely organisms because inappropriate initial antimicrobial therapy is associated with poor patient outcomes and the development of bacterial resistance. The overuse of antimicrobials is widely accepted as a major driver of some emerging infections (such as C. difficile), the selection of resistant pathogens in individual patients, and for the continued development of antimicrobial resistance globally. The growing emergence of multi-drug resistant organisms and the limited development of new agents available to counteract them have caused an impending crisis with alarming implications, especially with regards to Gram-negative bacteria. An international task force from 79 different countries has joined this project by sharing a document on the rational use of antimicrobials for patients with IAIs. The project has been termed AGORA (Antimicrobials: A Global Alliance for Optimizing their Rational Use in Intra-Abdominal Infections). The authors hope that AGORA, involving many of the world's leading experts, can actively raise awareness in health workers and can improve prescribing behavior in treating IAIs

Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH): a stepped-wedge cluster-randomised trial

BACKGROUND: Emergency abdominal surgery is associated with poor patient outcomes. We studied the effectiveness of a national quality improvement (QI) programme to implement a care pathway to improve survival for these patients. METHODS: We did a stepped-wedge cluster-randomised trial of patients aged 40 years or older undergoing emergency open major abdominal surgery. Eligible UK National Health Service (NHS) hospitals (those that had an emergency general surgical service, a substantial volume of emergency abdominal surgery cases, and contributed data to the National Emergency Laparotomy Audit) were organised into 15 geographical clusters and commenced the QI programme in a random order, based on a computer-generated random sequence, over an 85-week period with one geographical cluster commencing the intervention every 5 weeks from the second to the 16th time period. Patients were masked to the study group, but it was not possible to mask hospital staff or investigators. The primary outcome measure was mortality within 90 days of surgery. Analyses were done on an intention-to-treat basis. This study is registered with the ISRCTN registry, number ISRCTN80682973. FINDINGS: Treatment took place between March 3, 2014, and Oct 19, 2015. 22 754 patients were assessed for elegibility. Of 15 873 eligible patients from 93 NHS hospitals, primary outcome data were analysed for 8482 patients in the usual care group and 7374 in the QI group. Eight patients in the usual care group and nine patients in the QI group were not included in the analysis because of missing primary outcome data. The primary outcome of 90-day mortality occurred in 1210 (16%) patients in the QI group compared with 1393 (16%) patients in the usual care group (HR 1·11, 0·96-1·28). INTERPRETATION: No survival benefit was observed from this QI programme to implement a care pathway for patients undergoing emergency abdominal surgery. Future QI programmes should ensure that teams have both the time and resources needed to improve patient care. FUNDING: National Institute for Health Research Health Services and Delivery Research Programme

Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH): a stepped-wedge cluster-randomised trial

Background: Emergency abdominal surgery is associated with poor patient outcomes. We studied the effectiveness of a national quality improvement (QI) programme to implement a care pathway to improve survival for these patients. Methods: We did a stepped-wedge cluster-randomised trial of patients aged 40 years or older undergoing emergency open major abdominal surgery. Eligible UK National Health Service (NHS) hospitals (those that had an emergency general surgical service, a substantial volume of emergency abdominal surgery cases, and contributed data to the National Emergency Laparotomy Audit) were organised into 15 geographical clusters and commenced the QI programme in a random order, based on a computer-generated random sequence, over an 85-week period with one geographical cluster commencing the intervention every 5 weeks from the second to the 16th time period. Patients were masked to the study group, but it was not possible to mask hospital staff or investigators. The primary outcome measure was mortality within 90 days of surgery. Analyses were done on an intention-to-treat basis. This study is registered with the ISRCTN registry, number ISRCTN80682973. Findings: Treatment took place between March 3, 2014, and Oct 19, 2015. 22 754 patients were assessed for elegibility. Of 15 873 eligible patients from 93 NHS hospitals, primary outcome data were analysed for 8482 patients in the usual care group and 7374 in the QI group. Eight patients in the usual care group and nine patients in the QI group were not included in the analysis because of missing primary outcome data. The primary outcome of 90-day mortality occurred in 1210 (16%) patients in the QI group compared with 1393 (16%) patients in the usual care group (HR 1·11, 0·96–1·28). Interpretation: No survival benefit was observed from this QI programme to implement a care pathway for patients undergoing emergency abdominal surgery. Future QI programmes should ensure that teams have both the time and resources needed to improve patient care. Funding: National Institute for Health Research Health Services and Delivery Research Programme

Synthesis of Substituted 4-(1H-indol-6-yl)-1H-indazoles as Potential PDK1 Inhibitors

The development of a preparative route to a series of novel 4-(1H-indol-6-yl)-1H-indazole compounds as potential PDK1 inhibitors is described. The synthetic strategy centres on the late-stage Suzuki crosscoupling of N-unprotected indazole and indole fragments. The use of a monoligated palladium catalyst system was found to be highly beneficial in the cross-coupling reaction. The indazole and indole fragments were constructed by diazotisation/cyclisation and SNAr/reductive cyclisation sequences, respectively