A Review of Sociological Issues in Fire Safety Regulation

This paper presents an overview of contemporary sociological issues in fire safety. The most obviously social aspects of fire safety—those that relate to the socioeconomic distribution of fire casualties and damage—are discussed first. The means that society uses to mitigate fire risks through regulation are treated next; focusing on the shift towards fire engineered solutions and the particular challenges this poses for the social distribution and communication of fire safety knowledge and expertise. Finally, the social construction of fire safety knowledge is discussed, raising questions about whether the confidence in the application of this knowledge by the full range of participants in the fire safety design and approvals process is always justified, given the specific assumptions involved in both the production of the knowledge and its extension to applications significantly removed from the original knowledge production; and the requisite competence that is therefore needed to apply this knowledge. The overarching objective is to argue that the fire safety professions ought to be more reflexive and informed about the nature of the knowledge and expertise that they develop and apply, and to suggest that fire safety scientists and engineers ought to actively collaborate with social scientists in research designed to study the way people interact with fire safety technology

The Primary Folding Defect and Rescue of ΔF508 CFTR Emerge during Translation of the Mutant Domain

In the vast majority of cystic fibrosis (CF) patients, deletion of residue F508 from CFTR is the cause of disease. F508 resides in the first nucleotide binding domain (NBD1) and its absence leads to CFTR misfolding and degradation. We show here that the primary folding defect arises during synthesis, as soon as NBD1 is translated. Introduction of either the I539T or G550E suppressor mutation in NBD1 partially rescues ΔF508 CFTR to the cell surface, but only I539T repaired ΔF508 NBD1. We demonstrated rescue of folding and stability of NBD1 from full-length ΔF508 CFTR expressed in cells to isolated purified domain. The co-translational rescue of ΔF508 NBD1 misfolding in CFTR by I539T advocates this domain as the most important drug target for cystic fibrosis

In Vivo RNAi Screening Identifies Regulators of Actin Dynamics as Key Determinants of Lymphoma Progression

April 1, 2010Mouse models have markedly improved our understanding of cancer development and tumor biology. However, these models have shown limited efficacy as tractable systems for unbiased genetic experimentation. Here, we report the adaptation of loss-of-function screening to mouse models of cancer. Specifically, we have been able to introduce a library of shRNAs into individual mice using transplantable Eμ-myc lymphoma cells. This approach has allowed us to screen nearly 1,000 genetic alterations in the context of a single tumor-bearing mouse. These experiments have identified a central role for regulators of actin dynamics and cell motility in lymphoma cell homeostasis in vivo. Validation experiments confirmed that these proteins represent bona fide lymphoma drug targets. Additionally, suppression of two of these targets, Rac2 and twinfilin, potentiated the action of the front-line chemotherapeutic vincristine, suggesting a critical relationship between cell motility and tumor relapse in hematopoietic malignancies.National Institutes of Health (U.S.) (RO1 CA128803-01)Massachusetts Institute of Technology. Dept. of Biology (Training Grant)Massachusetts Institute of Technology. Undergraduate Research Opportunities ProgramNational Cancer Institute (U.S.). Integrative Cancer Biology Program (Grant 1-U54-CA112967

Body mass index and annual increase of body mass index in long-term childhood cancer survivors; relationship to treatment

Evaluation of body mass index (BMI) at final height (FH) and annual BMI increase in adult childhood cancer survivors (CCS) after treatment with anthracyclines, platinum, and/or radiotherapy. BMI (weight/heightA(2)) was calculated retrospectively from diagnosis until FH. The prevalence of underweight (BMI < 18.5 kg/m(2)) and overweight (BMI a parts per thousand yenaEuro parts per thousand 25 kg/m(2))/obesity (BMI a parts per thousand yenaEuro parts per thousand 30 kg/m(2)) at FH was compared with age-matched controls. The association between underweight/overweight at FH and treatment was assessed by multivariate logistic regression. Annual BMI increase after treatment was assessed by multilevel analysis. Analyses were adjusted for age and underweight/overweight at diagnosis, and age at FH. At FH the prevalence of overweight had not increased, while CCS experienced more underweight as compared to controls (14% vs. 4%, P < 0.001). Overweight at FH was associated with cranial/craniospinal radiotherapy (CRT; OR, 2.23; 95% CI, 1.17-4.26) and underweight at FH with anthracyclines > 300 mg/m(2) (OR, 2.84; 95% CI, 1.33-6.06). Annual BMI increase was +0.47 (0.34-0.60) kg/m(2)/year. In CCS, the annual BMI increase was greater in those with CRT a parts per thousand yenaEuro parts per thousand 30 Gy as compared with those with less or no CRT (+0.15 kg/m(2)/year [0.04-0.25 kg/m(2)/year], P = 0.008) and smaller in those with a higher cumulative anthracycline dose (-0.03 kg/m(2)/year [-0.05 to -0.0005 kg/m(2)/year] per 100 mg/m(2), P = 0.046). After treatment with anthracyclines, platinum, and/or radiotherapy, CRT-treated survivors have more overweight at FH, and a greater annual BMI increase, while anthracycline-treated survivors have more underweight at FH and a lower annual BMI increase

A reporting format for leaf-level gas exchange data and metadata

Leaf-level gas exchange data support the mechanistic understanding of plant fluxes of carbon and water. These fluxes inform our understanding of ecosystem function, are an important constraint on parameterization of terrestrial biosphere models, are necessary to understand the response of plants to global environmental change, and are integral to efforts to improve crop production. Collection of these data using gas analyzers can be both technically challenging and time consuming, and individual studies generally focus on a small range of species, restricted time periods, or limited geographic regions. The high value of these data is exemplified by the many publications that reuse and synthesize gas exchange data, however the lack of metadata and data reporting conventions make full and efficient use of these data difficult. Here we propose a reporting format for leaf-level gas exchange data and metadata to provide guidance to data contributors on how to store data in repositories to maximize their discoverability, facilitate their efficient reuse, and add value to individual datasets. For data users, the reporting format will better allow data repositories to optimize data search and extraction, and more readily integrate similar data into harmonized synthesis products. The reporting format specifies data table variable naming and unit conventions, as well as metadata characterizing experimental conditions and protocols. For common data types that were the focus of this initial version of the reporting format, i.e., survey measurements, dark respiration, carbon dioxide and light response curves, and parameters derived from those measurements, we took a further step of defining required additional data and metadata that would maximize the potential reuse of those data types. To aid data contributors and the development of data ingest tools by data repositories we provided a translation table comparing the outputs of common gas exchange instruments. Extensive consultation with data collectors, data users, instrument manufacturers, and data scientists was undertaken in order to ensure that the reporting format met community needs. The reporting format presented here is intended to form a foundation for future development that will incorporate additional data types and variables as gas exchange systems and measurement approaches advance in the future. The reporting format is published in the U.S. Department of Energy's ESS-DIVE data repository, with documentation and future development efforts being maintained in a version control system

Transparent Meta-Analysis of Prospective Memory and Aging

Prospective memory (ProM) refers to our ability to become aware of a previously formed plan at the right time and place. After two decades of research on prospective memory and aging, narrative reviews and summaries have arrived at widely different conclusions. One view is that prospective memory shows large age declines, larger than age declines on retrospective memory (RetM). Another view is that prospective memory is an exception to age declines and remains invariant across the adult lifespan. The present meta-analysis of over twenty years of research settles this controversy. It shows that prospective memory declines with aging and that the magnitude of age decline varies by prospective memory subdomain (vigilance, prospective memory proper, habitual prospective memory) as well as test setting (laboratory, natural). Moreover, this meta-analysis demonstrates that previous claims of no age declines in prospective memory are artifacts of methodological and conceptual issues afflicting prior research including widespread ceiling effects, low statistical power, age confounds, and failure to distinguish between various subdomains of prospective memory (e.g., vigilance and prospective memory proper)

A genome-wide association study of blood cell morphology identifies cellular proteins implicated in disease aetiology

This is the final version. Available on open access from Nature Research via the DOI in this recordData availability; For ethical and legal reasons access to INTERVAL data are subject to controls. Bona fide scientists can seek access to relevant de-identified individual participant data—including genetic, haematology analyser and proteomic data—and a copy of the trial’s data dictionary by applying to the INTERVAL Data Access Committee using the email address [email protected]. The INTERVAL Data Access Committee (supplemented, when required, by expertise from additional external scientists) meets several times a year to review applications according to the usual academic criteria of scientific validity and feasibility. Following approval by the INTERVAL Data Access Committee, a material transfer or research collaboration agreement will be agreed and signed with the applicants. Applicants might be requested to provide reimbursement of data management or preparation costs, as the INTERVAL trial is no longer in receipt of funding. Applicants will be required to provide updates to the INTERVAL Data Access Committee on their use of the INTERVAL trial data, including provision of copies of any publications. Applicants will be required to adhere in publications with the INTERVAL trial’s policy for acknowledgment of the trial’s funders, stakeholders, and scientific or technical contributors. The GRCh37 genome reference build is available for download from https://grch37.ensembl.org/info/data/ftp/index.html. Genomewide summary statistics may be downloaded by anonymous ftp from ftp://ftp.sanger.ac.uk/pub/project/humgen/summary_statistics/sysmex_blood_cell_genetics. The data from Ulirsch et al.29 are available from https://github.com/caleblareau/singlecell_bloodtraits/, from the Gene Expression Omnibus (GEO) under accession GSE119453 and from the Sequence Read Archive (SRA) under accession PRJNA491478. Other MK epigenetic data were generated by the BLUEPRINT project and are available in the EGA dataset EGAD00001001871.Code availability: The R code used for the association analysis is available in the git repository: https://github.com/ParsaAkbari/UKBB500K-Conditional-Analysis.Blood cells contain functionally important intracellular structures, such as granules, critical to immunity and thrombosis. Quantitative variation in these structures has not been subjected previously to large-scale genetic analysis. We perform genome-wide association studies of 63 flow-cytometry derived cellular phenotypes-including cell-type specific measures of granularity, nucleic acid content and reactivity-in 41,515 participants in the INTERVAL study. We identify 2172 distinct variant-trait associations, including associations near genes coding for proteins in organelles implicated in inflammatory and thrombotic diseases. By integrating with epigenetic data we show that many intracellular structures are likely to be determined in immature precursor cells. By integrating with proteomic data we identify the transcription factor FOG2 as an early regulator of platelet formation and α-granularity. Finally, we show that colocalisation of our associations with disease risk signals can suggest aetiological cell-types-variants in IL2RA and ITGA4 respectively mirror the known effects of daclizumab in multiple sclerosis and vedolizumab in inflammatory bowel disease

De Novo Truncating Mutations in WASF1 Cause Intellectual Disability with Seizures.

Next-generation sequencing has been invaluable in the elucidation of the genetic etiology of many subtypes of intellectual disability in recent years. Here, using exome sequencing and whole-genome sequencing, we identified three de novo truncating mutations in WAS protein family member 1 (WASF1) in five unrelated individuals with moderate to profound intellectual disability with autistic features and seizures. WASF1, also known as WAVE1, is part of the WAVE complex and acts as a mediator between Rac-GTPase and actin to induce actin polymerization. The three mutations connected by Matchmaker Exchange were c.1516C>T (p.Arg506Ter), which occurs in three unrelated individuals, c.1558C>T (p.Gln520Ter), and c.1482delinsGCCAGG (p.Ile494MetfsTer23). All three variants are predicted to partially or fully disrupt the C-terminal actin-binding WCA domain. Functional studies using fibroblast cells from two affected individuals with the c.1516C>T mutation showed a truncated WASF1 and a defect in actin remodeling. This study provides evidence that de novo heterozygous mutations in WASF1 cause a rare form of intellectual disability