Diversity, differentiation, and linkage disequilibrium: prospects for association mapping in the malaria vector anopheles arabiensis

Association mapping is a widely applied method for elucidating the genetic basis of phenotypic traits. However, factors such as linkage disequilibrium and levels of genetic diversity influence the power and resolution of this approach. Moreover, the presence of population subdivision among samples can result in spurious associations if not accounted for. As such, it is useful to have a detailed understanding of these factors before conducting association mapping experiments. Here we conducted whole-genome sequencing on 24 specimens of the malaria mosquito vector, Anopheles arabiensis, to further understanding of patterns of genetic diversity, population subdivision and linkage disequilibrium in this species. We found high levels of genetic diversity within the An. arabiensis genome, with ~800,000 high-confidence, single- nucleotide polymorphisms detected. However, levels of nucleotide diversity varied significantly both within and between chromosomes. We observed lower diversity on the X chromosome, within some inversions, and near centromeres. Population structure was absent at the local scale (Kilombero Valley, Tanzania) but detected between distant populations (Cameroon vs. Tanzania) where differentiation was largely restricted to certain autosomal chromosomal inversions such as 2Rb. Overall, linkage disequilibrium within An. arabiensis decayed very rapidly (within 200 bp) across all chromosomes. However, elevated linkage disequilibrium was observed within some inversions, suggesting that recombination is reduced in those regions. The overall low levels of linkage disequilibrium suggests that association studies in this taxon will be very challenging for all but variants of large effect, and will require large sample sizes

Joint Healthcare Infection Society (HIS) and Infection Prevention Society (IPS) guidelines for the prevention and control of meticillin-resistant Staphylococcus aureus (MRSA) in healthcare facilities

Meticillin-resistant Staphylococcus aureus (MRSA) infections remain a serious cause of healthcare-associated infection (HCAI) in many countries. MRSA is easily spread by multiple routes and can persist in the environment for long periods. In health and care settings, transmission via staff hands remains the most important route for patient MRSA acquisition. Infection prevention and control (IPC) measures and control of the use of antimicrobials are effective in reducing prevalence of MRSA. There have been many publications related to MRSA since the last guideline was published in 2006 and this update contains further measures that are clinically effective for preventing transmission when used by healthcare workers (Table I). Methods for systematic review were in accordance with National Institute for Health and Care Excellence (NICE) approved methodology and critical appraisal followed Scottish Intercollegiate Guidelines Network (SIGN) and other standard checklists. Articles published between 2004 and February 2021 were included. Questions for review were derived from a stakeholder meeting, which included patient representatives in accordance with the Population Intervention Comparison Outcome(PICO) framework. Recommendations are made in the following areas: screening, management of colonised healthcare staff, environmental screening and cleaning/disinfection, surveillance, IPC precautions (including isolation and movement of patients and equipment), and patient information

Grammatical meaning and the second language classroom : introduction

This special issue assembles empirical work on second language teaching and learning from a generative linguistic perspective. The focus is on properties that constitute grammar–meaning interaction, that differ in the native and target language grammars, and that have not been highlighted in the pedagogical literature so far. Common topics address whether and how learners acquire grammatical meanings in the second language, including difficult misalignments between native and target-language constructions and functional morphemes. We propose that teaching and learning a second language can be enhanced by focusing on the relationship between grammatical forms and their meanings, as elucidated by contemporary linguistic theory

Beyond paradigm : The ‘what’ and the ‘how’ of classroom research

This article reviews studies in second language classroom research from a cross-theoretic perspective, arguing that the classroom holds the potential for bringing together researchers from opposing theoretical orientations. It shows how generative and general cognitive approaches share a view of language that implicates both implicit and explicit knowledge, and that holds a bias towards implicit knowledge. Arguing that it is implicit knowledge that should be the object of research, it proposes that classroom research would benefit from incorporating insights from a generative understanding of language. Specifically, there is a need for a more nuanced view of the complexity of language in terms of linguistic domain, and the interaction between those domains. Generative second language acquisition research that shows developmental differences in terms of both linguistic domain and interface is reviewed. The core argument is a call for more attention to the ‘what’ of language development in classroom research and, by implication, teaching practice. As such, the language classroom is seen to offer potential for research that goes beyond paradigm to address both the ‘what’ and the ‘how’ of language development

The meaning of negation in the second language classroom: evidence from 'any'

This article brings together an experimental study involving L2 knowledge of negation in English and an analysis of how English language textbooks treat negation, in order to consider whether textbook explanations of negation could better exploit linguistic insights into negation. We focus on the English negative polarity item any, whose distribution is contingent on negation, whether through the explicit negator not or through lexical semantic negators (e.g. hardly). Our experiment compares Chinese-speaking learners with existing data from Arabic-speaking learners, finding lower accuracy on any with lexical semantic negators in both groups. Our textbook analysis reveals an approach to negation that is limited to form, focusing on the explicit negator not without explicit treatment of other types of negation. We propose that emphasizing the meaning of negation, with explicit treatment of the full range of negative forms could facilitate more complete acquisition across a range of grammatical properties where negation plays a role

Construction and analysis of a modular model of caspase activation in apoptosis

<p>Abstract</p> <p>Background</p> <p>A key physiological mechanism employed by multicellular organisms is apoptosis, or programmed cell death. Apoptosis is triggered by the activation of caspases in response to both extracellular (extrinsic) and intracellular (intrinsic) signals. The extrinsic and intrinsic pathways are characterized by the formation of the death-inducing signaling complex (DISC) and the apoptosome, respectively; both the DISC and the apoptosome are oligomers with complex formation dynamics. Additionally, the extrinsic and intrinsic pathways are coupled through the mitochondrial apoptosis-induced channel via the Bcl-2 family of proteins.</p> <p>Results</p> <p>A model of caspase activation is constructed and analyzed. The apoptosis signaling network is simplified through modularization methodologies and equilibrium abstractions for three functional modules. The mathematical model is composed of a system of ordinary differential equations which is numerically solved. Multiple linear regression analysis investigates the role of each module and reduced models are constructed to identify key contributions of the extrinsic and intrinsic pathways in triggering apoptosis for different cell lines.</p> <p>Conclusion</p> <p>Through linear regression techniques, we identified the feedbacks, dissociation of complexes, and negative regulators as the key components in apoptosis. The analysis and reduced models for our model formulation reveal that the chosen cell lines predominately exhibit strong extrinsic caspase, typical of type I cell, behavior. Furthermore, under the simplified model framework, the selected cells lines exhibit different modes by which caspase activation may occur. Finally the proposed modularized model of apoptosis may generalize behavior for additional cells and tissues, specifically identifying and predicting components responsible for the transition from type I to type II cell behavior.</p

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead