Formation and Function of the Rbl2p-beta-Tubulin Complex

The yeast protein Rbl2p suppresses the deleterious effects of excess beta-tubulin as efficiently as does alpha-tubulin. Both in vivo and in vitro, Rbl2p forms a complex with beta-tubulin that does not contain alpha-tubulin, thus defining a second pool of beta-tubulin in the cell. Formation of the complex depends upon the conformation of beta-tubulin. Newly synthesized beta-tubulin can bind to Rbl2p before it binds to alpha-tubulin. Rbl2p can also bind beta-tubulin from the alpha/beta-tubulin heterodimer, apparently by competing with alpha-tubulin. The Rbl2p-beta-tubulin complex has a half-life of ~2.5 h and is less stable than the alpha/beta-tubulin heterodimer. The results of our experiments explain both how excess Rbl2p can rescue cells overexpressing beta-tubulin and how it can be deleterious in a wild-type background. They also suggest that the Rbl2p-beta-tubulin complex is part of a cellular mechanism for regulating the levels and dimerization of tubulin chains

Rbl2p, a yeast protein that binds to β-tubulin and participates in microtubule function in vivo

AbstractGenetic configurations resulting in high ratios of β-tubulin to α-tubulin are toxic in S. cerevisiae, causing microtubule disassembly and cell death. We identified three non-tubulin yeast genes that, when overexpressed, rescue cells from excess β-tubulin. One, RBL2, rescues β-tubulin lethality as efficiently as does α-tubulin. Rbl2p binds to β-tubulin in vivo. Deficiencies or excesses of either RbI2p or α-tubulin affect microtubule-dependent functions in a parallel fashion. RbI2p has functional homology with murine cofactor A, a protein important for in vitro assays of β-tubulin folding. The results suggest that RbI2p participates in microtubule morphogenesis but not in the assembled polymer

Oral estradiol/micronized progesterone may be associated with lower risk of venous thromboembolism compared with conjugated equine estrogens/medroxyprogesterone acetate in real-world practice.

OBJECTIVES The Women's Health Initiative study reported an increased risk of venous thromboembolism among menopausal women treated with conjugated equine estrogens/medroxyprogesterone acetate (CEE/MPA) versus placebo. Newer hormone therapies may have a lower venous thromboembolism risk. The study compared the risk of venous thromboembolism between women treated with the combined oral product 17β-estradiol/micronized progesterone (E2/P4) and those treated with oral CEE/MPA regimens. STUDY DESIGN In a retrospective longitudinal study using real-world claims data from April 2019 to June 2021, women aged 40 years or more treated with oral E2/P4 or oral CEE/MPA who did not have a venous thromboembolism diagnosis before first dispensing claim of CEE/MPA or E2/P4 identified on or after May 1st 2019 (index date) were observed for 6 months or more after the index date. Oral E2/P4 and oral CEE/MPA had been prescribed by the treating physician in real-world practice and were observed through pharmacy dispensing records. MAIN OUTCOME MEASURES Venous thromboembolism risk was compared between women receiving oral E2/P4 versus oral CEE/MPA. RESULTS The study included 36,061 women treated with oral E2/P4 or oral CEE/MPA. In the analyses weighted by the inverse probability of treatment for control of potential confounding factors, the incidence of venous thromboembolism was significantly lower for oral E2/P4 compared with oral CEE/MPA (37/10,000 women-years for oral E2/P4 vs 53/10,000 women-years for oral CEE/MPA; incidence rate ratio 0.70, 95 % confidence interval: 0.53-0.92). CONCLUSIONS Real-world evidence suggests that the risk of venous thromboembolism is significantly lower among women treated with oral E2/P4 compared with oral CEE/MPA

Reduced Expression of Inflammatory Genes in Deceased Donor Kidneys Undergoing Pulsatile Pump Preservation

Background The use of expanded criteria donor kidneys (ECD) had been associated with worse outcomes. Whole gene expression of pre-implantation allograft biopsies from deceased donor kidneys (DDKs) was evaluated to compare the effect of pulsatile pump preservation (PPP) vs. cold storage preservation (CSP) on standard and ECD kidneys. Methodology/Principal Findings 99 pre-implantation DDK biopsies were studied using gene expression with GeneChips. Kidneys transplant recipients were followed post transplantation for 35.8 months (range = 24–62). The PPP group included 60 biopsies (cold ischemia time (CIT) = 1,367+/−509 minutes) and the CSP group included 39 biopsies (CIT = 1,022+/−485 minutes) (P Conclusions/Significance Inflammation was the most important up-regulated pattern associated with pre-implantation biopsies undergoing CSP even when the PPP group has a larger number of ECD kidneys. No significant difference was observed in delayed graft function incidence and graft function post-transplantation. These findings support the use of PPP in ECD donor kidneys

Crop Updates - 2003 Weeds

This session covers Thirty four papers from different authors INTRODUCTION INTEGRATED WEED MANAGEMENT IWM system studies/demonstration sites Six years of IWM investigation – what does it tell us? Bill Roy, Agricultural Consulting and Research Services Pty Ltd Long term herbicide resistance site, the final chapter, Peter Newman and Glen Adam, Department of Agriculture Management of skeleton weed (chondrilla juncea) in a cropping rotation in Western Australia, J. R. Peirce and B. J. Rayner, Department of Agriculture WEED BIOLOGY AND COMPETITION Annual ryegrass seedbanks: The good, the bad and the ugly, Kathryn J. Steadman1, Amanda J. Ellery2 and Sally C. Peltzer3 , 1WA Herbicide Resistance Initiative, UWA, 2CSIRO Plant Industry, 3 Department of Agriculture Annual ryegrass seeds after-ripen faster during a hot summer, Kathryn J. Steadman1, Gavin P. Bignell1 and Amanda J. Ellery2, 1WA Herbicide Resistance Initiative, UWA, 2CSIRO Plant Industry Predicting annual ryegrass dormancy from climatic variables, Amanda Ellery, Andrew Moore, Sandy Nedelkos, Ross Chapman, CSIRO Plant Industry Removing dormancy in annual ryegrass seeds for early herbicide resistance testing, Kathryn J. Steadman and Mechelle J. Owen, WA Herbicide Resistance Initiative, UWA Annual ryegrass germination responds to nitrogen, Amanda Ellery1, Simone Dudley1 and Robert Gallagher2, 1CSIRO Plant Industry, 2Washington State University The agro-ecology of Malva parviflora (small flowered mallow), Pippa J. Michael, Kathryn J. Steadman and Julie A. Plummer, Western Australia Herbicide Resistance Initiative, School of Plant Biology, University of Western Australia The looming threat of wild radish, Peter Newman, Department of Agriculture IWM TOOLS Double knock, how close can we go? Peter Newman and Glen Adam, Department of Agriculture Double knock herbicide effect on annual ryegrass, Catherine Borger, Abul Hashem and Nerys Wilkins, Department of Agriculture Tactical techniques for managing Annual Ryegrass, Sally Peltzer1, Alex Douglas1, Fran Hoyle1, Paul Matson1 and Michael Walsh2 Department of Agriculture and 2Western Australian Herbicide Resistance Initiative. Weed control through soil inversion, Sally Peltzer, Alex Douglas and Paul Matson, Department of Agriculture The burning issues of annual ryegrass seed control, Darren Chitty and Michael Walsh, Western Australian Herbicide Resistance Initiative, UWA No sign of chaff-cart resistant ryegrass! David Ferris, WA Herbicide Resistance Initiative UWA PACKAGES AND MODELLING Conserving glyphosate susceptibility – modelling past, present and future us. Paul Neve1, Art Diggle2, Patrick Smith3 and Stephen Powles1 ,1Western Australian Herbicide Resistance Initiative, School of Plant Biology, University of Western Australia, 2Department of Agriculture, 3CSIRO Sustainable Ecosystems WEEDEM: A program for predicting weed emergence in Western Australia, Michael Walsh,1 David Archer2, James Eklund2 and Frank Forcella2, 1Western Australia Herbicide Resistance Initiative, UWA, 2USDA-Agricultural Research Service, 803 Iowa Avenue, Morris, MN 56267, USA Weed and herbicide management for long term profit: A workshop, Alister Draper1 and Rick Llewellyn12, 1WA Herbicide Resistance Initiative, 2School of Agricultural and Resource Economics, University of Western Australia HERBICIDE RESISTANCE Alternative herbicides for control of triazine and diflufenican multiple resistant wild radish, Aik Cheam1, Siew Lee1, David Nicholson1 and Mike Clarke2 1Department of Agriculture, Western Australia, 2Bayer CropScience Resistance of wild mustard biotype to ALS-inhibiting herbicides in WA Wheatbelt, Abul Hashem, Department of Agriculture Glyphosate-resistant ryegrass biotypes in the WA wheatbelt, Abul Hashem, Catherine Borger and Nerys Wilkins, Department of Agriculture Implications of herbicide rates for resistance management, Paul Neve, Western Australian Herbicide Resistance Initiative, University of Western Australia Putting a price on herbicide resistance, Rick Llewellyn, School of Agricultural and Resource Economics/WA Herbicide Resistance Initiative, University of Western Australia Herbicide resistance from over the fence: Mobility and management, Debbie Allena, Rick Llewellynb, aUniversity of Western Australia, 4th year student, 2002. Mingenew-Irwin Group, bSchool of Agricultural and Resource Economics/Western Australia Herbicide Resistance Initiative, University of Western Australia HERBICIDE TOLERANCE Herbicide tolerance of new barley varieties, Harmohinder S. Dhammu and Terry Piper, Department of Agriculture Herbicide tolerance of new lupins, Harmohinder S. Dhammu, Terry Piper and David Nicholson, Department of Agriculture Herbicide tolerance of new field pea varieties, Harmohinder S. Dhammu, Terry Piper and David Nicholson, Department of Agriculture Herbicide tolerance of new lentil varieties, H.S. Dhammu, T.J. Piper and L.E. Young, Department of Agriculture HERBICIDES – NEW PRODUCTS/PRODUCT USES; USE Kill half leaf ryegrass with Spray.Seed® at night, Peter Newman and Glenn Adam, Department of Agriculture CLEARFIELD™ wheat to control hard-to-kill weeds, Abul Hashem, Catherine Borger and Nerys Wilkins, Department of Agriculture Diuron, a possible alternative to simazine pre-emergent in lupins, Peter Newman and Glenn Adam, Department of Agriculture Dual Gold® soft on barley, soft on weeds in dry conditions, Peter Newman and Glenn Adam, Department of Agriculture Dual Gold® soft on lupins, soft on ryegrass in dry conditions, Peter Newman and Glenn Adam, Department of Agricultur

The everchanging epidemiology of meningococcal disease worldwide and the potential for prevention through vaccination.

Neisseria meningitidis is a major cause of bacterial meningitis and septicaemia worldwide and is associated with high case fatality rates and serious life-long complications among survivors. Twelve serogroups are recognised, of which six (A, B, C, W, X and Y) are responsible for nearly all cases of invasive meningococcal disease (IMD). The incidence of IMD and responsible serogroups vary widely both geographically and over time. For the first time, effective vaccines against all these serogroups are available or nearing licensure. Over the past two decades, IMD incidence has been declining across most parts of the world through a combination of successful meningococcal immunisation programmes and secular trends. The introduction of meningococcal C conjugate vaccines in the early 2000s was associated with rapid declines in meningococcal C disease, whilst implementation of a meningococcal A conjugate vaccine across the African meningitis belt led to near-elimination of meningococcal A disease. Consequently, other serogroups have become more important causes of IMD. In particular, the emergence of a hypervirulent meningococcal group W clone has led many countries to shift from monovalent meningococcal C to quadrivalent ACWY conjugate vaccines in their national immunisation programmes. Additionally, the recent licensure of two protein-based, broad-spectrum meningococcal B vaccines finally provides protection against the most common group responsible for childhood IMD across Europe and Australia. This review describes global IMD epidemiology across each continent and trends over time, the serogroups responsible for IMD, the impact of meningococcal immunisation programmes and future needs to eliminate this devastating disease

Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly