Exercises in applied phonics for grade two

Thesis (Ed.M.)--Boston Universit

The state of the art—psoriatic arthritis outcome assessment in clinical trials and daily practice

Psoriatic arthritis is a heterogeneous condition with substantial challenges in optimising outcome measures for both clinical trials and daily practice. As with other inflammatory arthritides, there is no gold standard instrument for measuring disease activity or impact, both of which are key to evaluate therapeutic approaches in trials and monitor disease in daily practice. A wide range of domains have been highlighted in the Outcome Measures in Rheumatology (OMERACT) core domain set for psoriatic arthritis; reflecting the disease involvement in multiple tissues (joints, tendons, skin, and spine) and the heterogenous impact of the disease on individuals. This Review summarises the current evidence around outcome measure selection, considering factors such as unidimensional versus multidimensional outcomes, continuous versus binary measures, and the feasibility of these approaches in trials compared with clinical practice

Coordinated nuclease activities counteract Ku at single-ended DNA double-strand breaks.

Repair of single-ended DNA double-strand breaks (seDSBs) by homologous recombination (HR) requires the generation of a 3' single-strand DNA overhang by exonuclease activities in a process called DNA resection. However, it is anticipated that the highly abundant DNA end-binding protein Ku sequesters seDSBs and shields them from exonuclease activities. Despite pioneering works in yeast, it is unclear how mammalian cells counteract Ku at seDSBs to allow HR to proceed. Here we show that in human cells, ATM-dependent phosphorylation of CtIP and the epistatic and coordinated actions of MRE11 and CtIP nuclease activities are required to limit the stable loading of Ku on seDSBs. We also provide evidence for a hitherto unsuspected additional mechanism that contributes to prevent Ku accumulation at seDSBs, acting downstream of MRE11 endonuclease activity and in parallel with MRE11 exonuclease activity. Finally, we show that Ku persistence at seDSBs compromises Rad51 focus assembly but not DNA resection.EMBO (long-term fellowship (ALTF 93-2010)), Cancer Research UK (Grant IDs: C6/A11224, C6/A18796, C6946/A14492), La Ligue Nationale Contre le Cancer (senior post-doctoral fellowship, Equipe Labellisée 2013), Wellcome Trust (WT092096), University of Cambridge, INSERMThis is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms1288

Anthropogenic Subsidies Affect Common Raven Nesting, Space-Use, and Movement

Common raven (Corvus corax) number shave increased drastically throughout the Great Basin. Anthropogenic resources provide subsidies for growing raven populations with potential negative impacts on prey species including species of conservation concern such as greater sage-grouse (Centrocercus urophasianus).Our objective was to identify the effects of anthropogenic subsidies on raven nesting, space-use, and movement in sage-grouse habitat. We captured and radio-tagged 67 ravens between 2015 and 2018 and identified 70 nests during the 2018 breeding season. We found the majority of nests were built on anthropogenic structures. We also examined raven use of anthropogenic subsidies including highways, railroads, landfills, and agricultural fields. Finally, we examined movement behavior in terms of hourly step-length in relation to anthropogenic subsidies. Our results illustrate how ravens benefit from anthropogenic subsidies in sage-grouse habitat and the importance of subsidy management in controlling raven populations

Inter- and Intra-annual Effects of Lethal Removal on Common Raven Abundance in Nevada and California, USA

Populations of common ravens (Corvus corax; ravens) have increased rapidly within sagebrush (Artemisia spp.) ecosystems between 1960 and 2020. Although ravens are native to North America, their population densities have expanded to levels that negatively influence the population dynamics of other wildlife species of conservation concern, such as greater sage-grouse (Centrocercus urophasianus) and desert tortoises (Gopherus agassizii). For this reason, lethal removal, such as the application of the avicide DRC-1339, has been used to manage raven numbers at local scales and under certain circumstances. Because the relative effectiveness of DRC-1339 in reducing raven populations densities is not thoroughly understood, we completed 2 case studies using a before-after-control-impact experimental design of density estimates generated from point count data within a Bayesian hierarchical distance sampling framework. Specifically, we analyzed \u3e16,000 point count surveys collected during 2009–2019 and split into 2 study designs covering multiple field sites within the Great Basin region. The first experiment evaluated intra-annual changes in density by comparing before and after treatment time periods within a single breeding season for multiple treatment regions compared to 2 control regions. The other experiment focused on inter-annual differences by comparing time periods across years before and after the onset of annual avicide application for a single treatment region compared to multiple control regions. Our models estimated a 100% probability of decline in density relative to control sites for both the intra- and inter-annual model designs. At treatment sites, expected densities of ravens varied but were reduced by 43% (95% CRI: 33–49%) and 54% (95% CRI: 24–71%) according to intra- and inter-annual analyses, respectively, whereas densities increased by 42% (95% CRI: 27–60%) and 15% (95% CRI: -17 to 58%) at control sites. Although population densities were reduced with treatments, trends indicated that sustained effort would likely be needed to maintain densities at acceptable levels within regions of interest. Effectively reducing the adverse effects of raven populations on other native species likely will depend on a variety of targeted management actions such as improving habitat quality for prey species, possibly reducing ravens’ population density, and treating the cause of increased raven abundance to reduce future carrying capacity and prevent rebounds

Brazilian Adolescents Infected by HIV: Epidemiologic Characteristics and Adherence to Treatment

Over the last 3 decades since the first AIDS cases appeared, we have witnessed great progress in therapeutic methodologies that have transformed the evolution of the disease from debilitating and fatal, into chronic and controllable. HIV-infected children are arriving at adolescence and bringing specific challenges, not only to themselves, but also to their families and caregivers. This retrospective study sets forth epidemiological and treatment characteristics of 46 HIV-infected adolescents followed in a specialized university service relating said characteristics to therapy adherence assessed through a combination of three indirect methods. Therapy adherence did not reveal any association with either epidemiologic characteristics regarding age, sex, school level, household composition, age at diagnosis, mode of infection, knowledge of diagnosis, treatment time, or initial antiretroviral scheme. Patients with good therapy adherence presented lower viral load and used a smaller number of antiretroviral schemes

Detection of functional protein domains by unbiased genome-wide forward genetic screening

Genetic and chemo-genetic interactions have played key roles in elucidating the molecular mechanisms by which certain chemicals perturb cellular functions. Many studies have employed gene knockout collections or gene disruption/depletion strategies to identify routes for evolving resistance to chemical agents. By contrast, searching for point-mutational genetic suppressors that can identify separation- or gain-of-function mutations, has been limited even in simpler, genetically amenable organisms such as yeast, and has not until recently been possible in mammalian cell culture systems. Here, by demonstrating its utility in identifying suppressors of cellular sensitivity to the drugs camptothecin or olaparib, we describe an approach allowing systematic, large-scale detection of spontaneous or chemically-induced suppressor mutations in yeast and in haploid mouse embryonic stem cells in a short timeframe, and with potential applications in essentially any other haploid system. In addition to its utility for molecular biology research, this protocol can be used to identify drug targets and to predict mechanisms leading to drug resistance. Mapping suppressor mutations on the primary sequence or three-dimensional structures of protein suppressor hits provides insights into functionally relevant protein domains, advancing our molecular understanding of protein functions, and potentially helping to improve drug design and applicability

Beliefs, benefits, barriers, attitude, intake and knowledge about peanuts and tree nuts among WIC participants in eastern North Carolina

The objective of this study was to assess beliefs (e.g. advantages, disadvantages, benefits, barriers) and knowledge about eating peanuts and tree nuts. Personal interviews based on the Theory of Planned Behavior were conducted to elicit beliefs about eating nuts. Then, a cross-sectional survey was administered to WIC participants from one county in North Carolina. One-hundred-twenty-four WIC participants (mean (SD) age=28.39 (8.09) completed the study. Most were Caucasian (51.6%) females (96%). About one third believed that eating nuts may help to lower cholesterol level. However, only about one forth believed that nuts can lower a risk of a heart attack or diabetes. More than one third believed that eating nuts will cause weight gain. The knowledge of respondents' about nutrient content of nuts was low with correct answers to most questions about 20% or below. The mean (SD) positive attitude, negative attitude, benefits and barriers scores, based on a range from 1 to 5, were 2.53 (0.91), 3.25 (0.89), 2.97 (0.85) and 2.90 (0.76), respectively. WIC participants' beliefs regarding the health effects of nuts are inconsistent with the most recent research findings. They are in a need to education about benefits of eating nuts

DNA repair. PAXX, a paralog of XRCC4 and XLF, interacts with Ku to promote DNA double-strand break repair.

XRCC4 and XLF are two structurally related proteins that function in DNA double-strand break (DSB) repair. Here, we identify human PAXX (PAralog of XRCC4 and XLF, also called C9orf142) as a new XRCC4 superfamily member and show that its crystal structure resembles that of XRCC4. PAXX interacts directly with the DSB-repair protein Ku and is recruited to DNA-damage sites in cells. Using RNA interference and CRISPR-Cas9 to generate PAXX(-/-) cells, we demonstrate that PAXX functions with XRCC4 and XLF to mediate DSB repair and cell survival in response to DSB-inducing agents. Finally, we reveal that PAXX promotes Ku-dependent DNA ligation in vitro and assembly of core nonhomologous end-joining (NHEJ) factors on damaged chromatin in cells. These findings identify PAXX as a new component of the NHEJ machinery.T.O. and T.L.B. are supported by the Wellcome Trust. The Jackson lab is funded by Cancer Research UK (CRUK) program grant C6/A11224, the European Research Council and the European Community Seventh Framework Programme grant agreement no. HEALTH-F2-2010- 259893 (DDResponse). Core infrastructure funding to the Jackson lab is provided by CRUK (C6946/A14492) and the Wellcome Trust (WT092096). S.P.J. receives his salary from the University of Cambridge, supplemented by CRUK. V.M.D. is a CRUK Career Development Fellow. The Draviam lab is funded by a CRUK CDA (C28598/A9787).This is the accepted manuscript version. The final version is available from AAAS at http://www.sciencemag.org/content/347/6218/185.full

Small Molecule Inhibition of UBE2T/FANCL-mediated Ubiquitylation in the Fanconi Anemia Pathway

The Fanconi anemia pathway orchestrates the repair of DNA inter-strand crosslinks and stalled replication forks. A key step in this pathway is UBE2T and FANCL dependent monoubiquitylation of the FANCD2-FANCI complex. The Fanconi anemia pathway represents an attractive therapeutic target because activation of this pathway has been linked to chemotherapy resistance in several cancers. However, very few selective inhibitors of ubiquitin conjugation pathways are known to date. By using a high-throughput screen compatible assay, we have identified a small molecule inhibitor of UBE2T/FANCL-mediated FANCD2 monoubiquitylation that sensitizes cells to the DNA cross-linking agent, carboplatin.M.J.C was funded through the Cambridge PhD Training Programme in Chemical Biology and Molecular Medicine. Y.G is funded by Cancer Research UK, C6/A18796 and a Wellcome Trust Investigator Award to S.P.J. 206388/Z/17/Z. Research in the Jackson lab is funded by CRUK (C6/A18796) and the Wellcome Trust (206388/Z/17/Z), with core infrastructure funding from the Wellcome Trust (203144) and CRUK (C6946/A24843). Work in the CRUK Manchester Institute Drug Discovery Unit was funded by CRUK (Grant numbers C480/A1141 and C309/A8274)