X-ray irradiated cultures of mouse cortical neural stem/progenitor cells recover cell viability and proliferation with dose-dependent kinetics

Exposure of the developing or adult brain to ionizing radiation (IR) can cause cognitive impairment and/ or brain cancer, by targeting neural stem/progenitor cells (NSPCs). IR effects on NSPCs include transient cell cycle arrest, permanent cell cycle exit/differentiation, or cell death, depending on the experimental conditions. In vivo studies suggest that brain age influences NSPC response to IR, but whether this is due to intrinsic NSPC changes or to niche environment modifications remains unclear. Here, we describe the dose-dependent, time-dependent effects of X-ray IR in NSPC cultures derived from the mouse foetal cerebral cortex. We show that, although cortical NSPCs are resistant to low/moderate IR doses, high level IR exposure causes cell death, accumulation of DNA double-strand breaks, activation of p53- related molecular pathways and cell cycle alterations. Irradiated NSPC cultures transiently upregulate differentiation markers, but recover control levels of proliferation, viability and gene expression in the second week post-irradiation. These results are consistent with previously described in vivo effects of IR in the developing mouse cortex, and distinct from those observed in adult NSPC niches or in vitro adult NSPC cultures, suggesting that intrinsic differences in NSPCs of different origins might determine, at least in part, their response to IR

The care of older cancer patients in the United Kingdom

The ageing population poses new challenges globally. Cancer care for older patients is one of these challenges, and it has a significant impact on societies. In the United Kingdom (UK), as the number of older cancer patients increases, the management of this group has become part of daily practice for most oncology teams in every geographical area. Older cancer patients are at a higher risk of both under- and over-treatment. Therefore, the assessment of a patient’s biological age and effective organ functional reserve becomes paramount. This may then guide treatment decisions by better estimating a prognosis and the risk-to-benefit ratio of a given therapy to anticipate and mitigate against potential toxicities/difficulties. Moreover, older cancer patients are often affected by geriatric syndromes and other issues that impact their overall health, function and quality of life. Comprehensive geriatric assessments offer an opportunity to identify and address health problems which may then optimise one’s fitness and well-being. Whilst it is widely accepted that older cancer patients may benefit from such an approach, resources are often scarce, and access to dedicated services and research remains limited to specific centres across the UK. The aim of this project is to map the current services and projects in the UK to learn from each other and shape the future direction of care of older patients with cancer

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

A collaboratively derived environmental research agenda for Galapagos

Galápagos is one of the most pristine archipelagos in the world and its conservation relies upon research and sensible management. In recent decades both the interest in, and the needs of, the islands have increased, yet the funds and capacity for necessary research have remained limited. It has become, therefore, increasingly important to identify areas of priority research to assist decision-making in Galápagos conservation. This study identified 50 questions considered priorities for future research and management. The exercise involved the collaboration of policy makers, practitioners and researchers from more than 30 different organisations. Initially, 360 people were consulted to generate 781 questions. An established process of preworkshop voting and three rounds to reduce and reword the questions, followed by a two-day workshop, was used to produce the final 50 questions. The most common issues raised by this list of questions were human population growth, climate change and the impact of invasive alien species. These results have already been used by a range of organisations and politicians and are expected to provide the basis for future research on the islands so that its sustainability may be enhanced. </jats:p

The genetics of the mood disorder spectrum:genome-wide association analyses of over 185,000 cases and 439,000 controls

Background Mood disorders (including major depressive disorder and bipolar disorder) affect 10-20% of the population. They range from brief, mild episodes to severe, incapacitating conditions that markedly impact lives. Despite their diagnostic distinction, multiple approaches have shown considerable sharing of risk factors across the mood disorders. Methods To clarify their shared molecular genetic basis, and to highlight disorder-specific associations, we meta-analysed data from the latest Psychiatric Genomics Consortium (PGC) genome-wide association studies of major depression (including data from 23andMe) and bipolar disorder, and an additional major depressive disorder cohort from UK Biobank (total: 185,285 cases, 439,741 controls; non-overlapping N = 609,424). Results Seventy-three loci reached genome-wide significance in the meta-analysis, including 15 that are novel for mood disorders. More genome-wide significant loci from the PGC analysis of major depression than bipolar disorder reached genome-wide significance. Genetic correlations revealed that type 2 bipolar disorder correlates strongly with recurrent and single episode major depressive disorder. Systems biology analyses highlight both similarities and differences between the mood disorders, particularly in the mouse brain cell-types implicated by the expression patterns of associated genes. The mood disorders also differ in their genetic correlation with educational attainment – positive in bipolar disorder but negative in major depressive disorder. Conclusions The mood disorders share several genetic associations, and can be combined effectively to increase variant discovery. However, we demonstrate several differences between these disorders. Analysing subtypes of major depressive disorder and bipolar disorder provides evidence for a genetic mood disorders spectrum

Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders.

Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families (166 BD, 78 major depressive disorder, 151 unaffected) as well as 438 subjects from an independent, BD case/control cohort (161 unrelated BD, 277 unrelated controls) were analysed. Polygenic risk scores (PRS) for BD, schizophrenia (SCZ), and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had higher PRS for all three psychiatric disorders than the independent controls, with BD and SCZ being significant after correction for multiple testing, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and unrelated BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. However, the PRS explained only part of the observed phenotypic variance, and rare variants might have also contributed to disease development

JARID1B expression and its function in DNA damage repair are tightly regulated by miRNAs in breast cancer

JARID1B/KDM5B histone demethylase's mRNA is markedly overexpressed in breast cancer tissues and cell lines and the protein has been shown to have a prominent role in cancer cell proliferation and DNA repair. However, the mechanism of its post-transcriptional regulation in cancer cells remains elusive. We performed a computational analysis of transcriptomic data from a set of 103 breast cancer patients, which, along with JARID1B upregulation, showed a strong downregulation of 2 microRNAs (miRNAs), mir-381 and mir-486, potentially targeting its mRNA. We showed that both miRNAs can target JARID1B 3'UTR and reduce luciferase's activity in a complementarity-driven repression assay. Moreover, MCF7 breast cancer cells overexpressing JARID1B showed a strong protein reduction when transfected with mir-486. This protein's decrease is accompanied by accumulation of DNA damage, enhanced radiosensitivity and increase of BRCA1 mRNA, 3 features previously correlated with JARID1B silencing. These results enlighten an important role of a miRNA's circuit in regulating JARID1B's activity and suggest new perspectives for epigenetic therapies.Funding information: Sapienza Research Grant. Grant Number: RM11715C53A3F67

JARID1B expression and its function in DNA damage repair are tightly regulated by miRNAs in breast cancer

JARID1B/KDM5B histone demethylase's mRNA is markedly overexpressed in breast cancer tissues and cell lines and the protein has been shown to have a prominent role in cancer cell proliferation and DNA repair. However, the mechanism of its post-transcriptional regulation in cancer cells remains elusive. We performed a computational analysis of transcriptomic data from a set of 103 breast cancer patients, which, along with JARID1B upregulation, showed a strong downregulation of 2 microRNAs (miRNAs), mir-381 and mir-486, potentially targeting its mRNA. We showed that both miRNAs can target JARID1B 3'UTR and reduce luciferase's activity in a complementarity-driven repression assay. Moreover, MCF7 breast cancer cells overexpressing JARID1B showed a strong protein reduction when transfected with mir-486. This protein's decrease is accompanied by accumulation of DNA damage, enhanced radiosensitivity and increase of BRCA1 mRNA, 3 features previously correlated with JARID1B silencing. These results enlighten an important role of a miRNA's circuit in regulating JARID1B's activity and suggest new perspectives for epigenetic therapies.Funding information: Sapienza Research Grant. Grant Number: RM11715C53A3F67

Poster: "In vivo selection of JARID histone demethylases inhibitors and their use to enlighten the biological role of these enzymes in yeast and mammalian cells with focus on transcriptional regulation”

We recently discovered in S.cerevisiae an interesting conditional negative genetic interaction between the unique JARID histone demethylase Jhd2, responsible for H3K4 demethylation, and Not4, a protein which is involved in several different regulatory processes, including transcriptional regulation, RNA stability and Jhd2 degradation. The double deletion mutant Δjhd2/Δnot4 is hypersensitive to rapamycin and its sensitivity is promptly suppressed by episomal Jhd2 expression in the double deletion strain. While this genetic interaction could be useful for the understanding of the transcriptional role of Jhd2 in yeast, which is still elusive, it is also an ideal system for in vivo screening of inhibitors specific for JARID demethylases. In a pilot screening on 45 candidate small molecules, we identified a compound which specifically inhibits Jhd2 in vivo, leading to a consistent increase in trimethyl-H3K4. The compound inhibits human JARID 1B and 1D in vitro and shows a strong cytostatic effect, a mild cytotoxicity and a selective increase of trimethyl-H3K4 in HeLa cells. We better characterized the inhibitor’s effects in yeast and mammalian cells, with focus on transcriptional effects. The results in yeast enlighten a role of Jhd2 in regulating a set of genes transcriptionally induced upon diauxic shift