Heavy Hands, Magic, and Scene-Reading Traps

This is one of a series of articles in which I examine errors that philosophers of language may be led to make if already prone to exaggerating the rôle compositional semantics can play in explaining how we communicate, whether by expressing propositions with our words or by merely implying them. In the present article, I am concerned less with “pragmatic contributions” to the propositions we express—contributions some philosophers seem rather desperate to deny the existence or ubiquity of—than I am with certain types of traps that those who exaggerate the rôle of semantic convention and underestimate the rôle of pragmatic inference are apt to fall into

Positive regulation of meiotic DNA double-strand break formation by activation of the DNA damage checkpoint kinase Mec1(ATR)

During meiosis, formation and repair of programmed DNA double-strand breaks (DSBs) create genetic exchange between homologous chromosomes-a process that is critical for reductional meiotic chromosome segregation and the production of genetically diverse sexually reproducing populations. Meiotic DSB formation is a complex process, requiring numerous proteins, of which Spo11 is the evolutionarily conserved catalytic subunit. Precisely how Spo11 and its accessory proteins function or are regulated is unclear. Here, we use Saccharomyces cerevisiae to reveal that meiotic DSB formation is modulated by the Mec1(ATR) branch of the DNA damage signalling cascade, promoting DSB formation when Spo11-mediated catalysis is compromised. Activation of the positive feedback pathway correlates with the formation of single-stranded DNA (ssDNA) recombination intermediates and activation of the downstream kinase, Mek1. We show that the requirement for checkpoint activation can be rescued by prolonging meiotic prophase by deleting the NDT80 transcription factor, and that even transient prophase arrest caused by Ndt80 depletion is sufficient to restore meiotic spore viability in checkpoint mutants. Our observations are unexpected given recent reports that the complementary kinase pathway Tel1(ATM) acts to inhibit DSB formation. We propose that such antagonistic regulation of DSB formation by Mec1 and Tel1 creates a regulatory mechanism, where the absolute frequency of DSBs is maintained at a level optimal for genetic exchange and efficient chromosome segregation

Genome-wide association studies in ADHD

Attention-deficit/hyperactivity disorder, ADHD, is a common and highly heritable neuropsychiatric disorder that is seen in children and adults. Although heritability is estimated at around 76%, it has been hard to find genes underlying the disorder. ADHD is a multifactorial disorder, in which many genes, all with a small effect, are thought to cause the disorder in the presence of unfavorable environmental conditions. Whole genome linkage analyses have not yet lead to the identification of genes for ADHD, and results of candidate gene-based association studies have been able to explain only a tiny part of the genetic contribution to disease, either. A novel way of performing hypothesis-free analysis of the genome suitable for the identification of disease risk genes of considerably smaller effect is the genome-wide association study (GWAS). So far, five GWAS have been performed on the diagnosis of ADHD and related phenotypes. Four of these are based on a sample set of 958 parent–child trio’s collected as part of the International Multicentre ADHD Genetics (IMAGE) study and genotyped with funds from the Genetic Association Information Network (GAIN). The other is a pooled GWAS including adult patients with ADHD and controls. None of the papers reports any associations that are formally genome-wide significant after correction for multiple testing. There is also very limited overlap between studies, apart from an association with CDH13, which is reported in three of the studies. Little evidence supports an important role for the ‘classic’ ADHD genes, with possible exceptions for SLC9A9, NOS1 and CNR1. There is extensive overlap with findings from other psychiatric disorders. Though not genome-wide significant, findings from the individual studies converge to paint an interesting picture: whereas little evidence—as yet—points to a direct involvement of neurotransmitters (at least the classic dopaminergic, noradrenergic and serotonergic pathways) or regulators of neurotransmission, some suggestions are found for involvement of ‘new’ neurotransmission and cell–cell communication systems. A potential involvement of potassium channel subunits and regulators warrants further investigation. More basic processes also seem involved in ADHD, like cell division, adhesion (especially via cadherin and integrin systems), neuronal migration, and neuronal plasticity, as well as related transcription, cell polarity and extracellular matrix regulation, and cytoskeletal remodeling processes. In conclusion, the GWAS performed so far in ADHD, though far from conclusive, provide a first glimpse at genes for the disorder. Many more (much larger studies) will be needed. For this, collaboration between researchers as well as standardized protocols for phenotyping and DNA-collection will become increasingly important

The IMAGE project: methodological issues for the molecular genetic analysis of ADHD

The genetic mechanisms involved in attention deficit hyperactivity disorder (ADHD) are being studied with considerable success by several centres worldwide. These studies confirm prior hypotheses about the role of genetic variation within genes involved in the regulation of dopamine, norepinephrine and serotonin neurotransmission in susceptibility to ADHD. Despite the importance of these findings, uncertainties remain due to the very small effects sizes that are observed. We discuss possible reasons for why the true strength of the associations may have been underestimated in research to date, considering the effects of linkage disequilibrium, allelic heterogeneity, population differences and gene by environment interactions. With the identification of genes associated with ADHD, the goal of ADHD genetics is now shifting from gene discovery towards gene functionality – the study of intermediate phenotypes ('endophenotypes'). We discuss methodological issues relating to quantitative genetic data from twin and family studies on candidate endophenotypes and how such data can inform attempts to link molecular genetic data to cognitive, affective and motivational processes in ADHD. The International Multi-centre ADHD Gene (IMAGE) project exemplifies current collaborative research efforts on the genetics of ADHD. This European multi-site project is well placed to take advantage of the resources that are emerging following the sequencing of the human genome and the development of international resources for whole genome association analysis. As a result of IMAGE and other molecular genetic investigations of ADHD, we envisage a rapid increase in the number of identified genetic variants and the promise of identifying novel gene systems that we are not currently investigating, opening further doors in the study of gene functionality

Science in motion: integrating scientific knowledge into bushfire risk mitigation in southwest Victoria

Scientific knowledge and scientific uncertainties play a significant role in the mitigation of natural hazard risk. As such, the natural hazards sector is often represented as ‘science-led’ or ‘researchled’. However, in actuality, relationships between scientific research, policy and practice are neither simple nor linear, and there are presently few studies that focus on the layers of practitioners who find themselves mediating these relationships. In order to provide insight into the integration of scientific knowledge, this paper considers the findings of a case study of bushfire practitioners in the Barwon-Otway area of southwest Victoria. This region has recently been the site of multi-agency efforts to reduce the residual bushfire risk using the PHOENIX RapidFire bushfire simulator.The paper concludes by posing several questions relevant to this and other risk mitigation contexts

Planning for better animal health and welfare, Report from the 1st ANIPLAN project workshop, Hellevad, October 2007

’Minimising medicine use in organic dairy herds through animal health and welfare planning’, ANIPLAN, is a CORE-Organic project which was initiated in June 2007. The main aim of the project is to investigate active and well planned animal health and welfare promotion and disease prevention as a means of minimising medicine use in organic dairy herds. This aim will be met through the development of animal health and welfare planning principles for organic dairy farms under diverse conditions based on an evaluation of current experiences. This also includes application of animal health and welfare assessment across Europe. In order to bring this into practice the project also aims at developing guidelines for communication about animal health and welfare promotion in different settings, for example, as part of existing animal health advisory services or farmer groups such as the Danish Stable School system and the Dutch network programme. The project is divided into the following five work packages, four of which comprise research activities with the other focused on coordination and knowledge transfer, through meetings, workshops and publications. These proceedings represent our first results in terms of presented papers and discussions at our first project workshop in Hellevad Vandmølle as well as a review of Animal Health Planning in UK. The content of the workshop proceedings reflect the aim and starting points of all work packages, both in terms of analyses prior to the workshop, and developments during the workshop emanating from group work. Besides a general introduction to the project and the ideas of the project, Christoph Winckler provides an overview of the use of animal based parameters based on the results of the WelfareQuality project. Christopher Atkinson and Madeleine Neale presented concepts, principles and the practicalities of Animal Health Planning and Animal Health Plans based on UK experiences. Pip Nicholas from The University of Wales, Aberystwyth produced a report reviewing the current use of animal health and welfare planning. The entire document is included in these workshop proceedings. This was supplemented through presentations from all countries regarding animal health and welfare planning processes and research. These are summarised together with the concepts developed through dialogue at the workshop in the paper by Nicholas, Vaarst and Roderick. Finally, the Danish Stable School principles were presented by Mette Vaarst followed by discussion on different approaches of communication in farmer groups and at the individual level between farmers and advisors. One important outcome from this workshop is a set of preliminary principles for a good health planning process. We concluded through group discussions followed by a plenary session that a health planning process should aim at continuous development and improvement, and should incorporate health promotion and disease handling, based on a strategy where the current situation is evaluated and form basis for action, which is then reviewed in a new evaluation. It is important that any health plan is farm specific and based on farmer ownership, although an external person(s) should be involved, as well as external knowledge. The organic principles should form the framework for any action (meaning that a systems approach is needed), and the plan should be written. The good and positive aspects on each farm – things that other farmers potentially can learn from. The work and studies in dairy farms within the project will be based on these principles and comprise evaluation and review using animal based parameters as well as finding ways of communication with farmers about animal health and welfare

Determining the Quantitative Principles of T Cell Response to Antigenic Disparity in Stem Cell Transplantation

Alloreactivity compromising clinical outcomes in stem cell transplantation is observed despite HLA matching of donors and recipients. This has its origin in the variation between the exomes of the two, which provides the basis for minor histocompatibility antigens (mHA). The mHA presented on the HLA class I and II molecules and the ensuing T cell response to these antigens results in graft vs. host disease. In this paper, results of a whole exome sequencing study are presented, with resulting alloreactive polymorphic peptides and their HLA class I and HLA class II (DRB1) binding affinity quantified. Large libraries of potentially alloreactive recipient peptides binding both sets of molecules were identified, with HLA-DRB1 generally presenting a greater number of peptides. These results are used to develop a quantitative framework to understand the immunobiology of transplantation. A tensor-based approach is used to derive the equations needed to determine the alloreactive donor T cell response from the mHA-HLA binding affinity and protein expression data. This approach may be used in future studies to simulate the magnitude of expected donor T cell response and determine the risk for alloreactive complications in HLA matched or mismatched hematopoietic cell and solid organ transplantation

Workshop ANIPLAN - Payerbach Reichenau. Programme and presentations

Workshop ANIPLAN, May 11th-14th, 2009, Reichenau, Payerbach Reichenau, Austria. Programme and presentations

Dive, food and exercise effects on blood microparticles in Steller sea lions (Eumetopias jubatus) : exploring a biomarker for decompression sickness

Author Posting. © The Author(s), 2016. This is the author's version of the work. It is posted here by permission of American Physiological Society for personal use, not for redistribution. The definitive version was published in American Journal of Physiology - Regulatory, Integrative and Comparative Physiology 310 (2016): R596-R601, doi:10.1152/ajpregu.00512.2015.Recent studies of stranded marine mammals indicate that exposure to underwater military sonar may induce pathophysiological responses consistent with decompression sickness (DCS). However, DCS has been difficult to diagnose in marine mammals. We investigated whether blood microparticles (MPs, measured as number/μl plasma), which increase in response to decompression stress in terrestrial mammals, are a suitable biomarker for DCS in marine mammals. We obtained blood samples from trained Steller sea lions (Eumetopias jubatus, 4 adult females) wearing time-depth recorders that dove to predetermined depths (either 5 or 50 m). We hypothesized that MPs would be positively related to decompression stress (depth and duration underwater). We also tested the effect of feeding and exercise in isolation on MPs using the same blood sampling protocol. We found that feeding and exercise had no effect on blood MP levels, but that diving caused MPs to increase. However, blood MP levels did not correlate with diving depth, relative time underwater, and presumably decompression stress―possibly indicating acclimation following repeated exposure to depth.Funding for this project was provided by the Office of Naval Research to MM (ONR Award # N00014-12-10388) and SRT (ONR Award # N00014-13-10614). Additional support was provided by the National Oceanic and Atmospheric Administration through the North Pacific Marine Science Foundation and the North Pacific Universities Marine Mammal Research Consortium.2017-02-0

Recombinase-independent chromosomal rearrangements between dispersed inverted repeats in Saccharomyces cerevisiae meiosis

DNA double-strand break (DSB) repair by homologous recombination (HR) uses a DNA template with similar sequence to restore genetic identity. Allelic DNA repair templates can be found on the sister chromatid or homologous chromosome. During meiotic recombination, DSBs preferentially repair from the homologous chromosome, with a proportion of HR events generating crossovers. Nevertheless, regions of similar DNA sequence exist throughout the genome, providing potential DNA repair templates. When DSB repair occurs at these non-allelic loci (termed ectopic recombination), chromosomal duplications, deletions and rearrangements can arise. Here, we characterize in detail ectopic recombination arising between a dispersed pair of inverted repeats in wild-type Saccharomyces cerevisiae at both a local and a chromosomal scale– the latter identified via gross chromosomal acentric and dicentric chromosome rearrangements. Mutation of the DNA damage checkpoint clamp loader Rad24 and the RecQ helicase Sgs1 causes an increase in ectopic recombination. Unexpectedly, additional mutation of the RecA orthologues Rad51 and Dmc1 alters––but does not abolish––the type of ectopic recombinants generated, revealing a novel class of inverted chromosomal rearrangement driven by the single-strand annealing pathway. These data provide important insights into the role of key DNA repair proteins in regulating DNA repair pathway and template choice during meiosis