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bsp is a bridging model between abstract execution and concrete parallel systems. Structure and abstraction brought by bsp allow to have portable parallel programs with scalable performance predictions, without dealing with low-level details of architectures. In the past, we designed bsml for programming bsp algorithms in ml . However, the simplicity of the bsp model does not fit the complexity of today’s hierarchical architectures such as clusters of machines with multiple multi-core processors. The multi-bsp model is an extension of the bsp model which brings a tree-based view of nested components of hierarchical architectures. To program multi-bsp algorithms in ml , we propose the multi-ml language as an extension of bsml where a specific kind of recursion is used to go through a hierarchy of computing nodes. We define a formal semantics of the language and present preliminary experiments which show performance improvements with respect to bsml .

In genome editing with CRISPR–Cas9, transgene integration often remains challenging. Here, we present an approach for increasing the efficiency of transgene integration by homology-dependent repair (HDR). CtIP, a key protein in early steps of homologous recombination, is fused to Cas9 and stimulates transgene integration by HDR at the human AAVS1 safe harbor locus. A minimal N-terminal fragment of CtIP, designated HE for HDR enhancer, is sufficient to stimulate HDR and this depends on CDK phosphorylation sites and the multimerization domain essential for CtIP activity in homologous recombination. HDR stimulation by Cas9–HE, however, depends on the guide RNA used, a limitation that may be overcome by testing multiple guides to the locus of interest. The Cas9–HE fusion is simple to use and allows obtaining twofold or more efficient transgene integration than that with Cas9 in several experimental systems, including human cell lines, iPS cells, and rat zygotes. The integration of exogenous DNA into the genome using CRISPR–Cas9 often presents a challenge to researchers. Here the authors fuse CtIP to Cas9 to stimulate recombination at target loci.

Whatever their size and the ecosystem they live in, all organisms may disperse at some stage of their life cycle. Dispersal dynamics are to a varying extent dependent on organismal size, life history, ecological niche, survival capacities and phylogeny. Moves towards a synthesis in dispersal ecology have focused primarily on vertebrates and higher plants, yet recent studies suggest that the dispersal of microorganisms and macroorganisms has much more in common than previously assumed. The dispersal of one organism enables co-dispersal for many others, smaller in size. There is an increasing need for a more integrated approach to study dispersal within the context of organismal interactions and their environments. Such an approach is facilitated by recent developments of powerful indirect techniques that enable tracking of microorganisms and macroorganisms over multiple spatial and temporal scales. Likewise, dispersal modelling and theoretical models of the consequences of dispersal can inspire empirical studies across the entire size spectrum. Simultaneously studying the relationships between dispersal of microorganisms and macroorganisms, and accounting for dispersal through time and space, will allow us to better understand the functioning and dynamics of communities and ecosystems, and to make better predictions of future dispersal patterns, changes in biodiversity and connectivity.

The histone methyltransferase EZH2 has an essential role in the development of follicular lymphoma (FL). Recurrent gain-of-function mutations in EZH2 have been described in 25% of FL patients and induce aberrant methylation of histone H3 lysine 27 (H3K27). We evaluated the role of EZH2 genomic gains in FL biology. Using RNA sequencing, Sanger sequencing and SNP-arrays, the mutation status, copy-number and gene-expression profiles of EZH2 were assessed in a cohort of 159 FL patients from the PRIMA trial. Immunohistochemical (IHC) EZH2 expression ( n =55) and H3K27 methylation ( n =63) profiles were also evaluated. In total, 37% of patients (59/159) harbored an alteration in the EZH2 gene (mutation n =46, gain n =23). Both types of alterations were associated with highly similar transcriptional changes, with increased proliferation programs. An H3K27me3/me2 IHC score fully distinguished mutated from wild-type samples, showing its applicability as surrogate for EZH2 mutation analysis. However, this score did not predict the presence of gains at the EZH2 locus. The presence of an EZH2 genetic alteration was an independent factor associated with a longer progression-free survival (hazard ratio 0.58, 95% confidence interval 0.36–0.93, P =0.025). We propose that the copy-number status of EZH2 should also be considered when evaluating patient stratification and selecting patients for EZH2 inhibitor-targeted therapies.

PurposeConquerFear is an efficacious intervention for fear of cancer recurrence (FCR) that demonstrated greater improvements than an attention control (relaxation training) in a randomized controlled trial. This study aimed to determine mediators and moderators of the relative treatment efficacy of ConquerFear versus relaxation.MethodsOne hundred and fifty-two cancer survivors completed 5 therapy sessions and outcome measures before and after intervention and at 6 months’ follow-up. We examined theoretically relevant variables as potential mediators and moderators of treatment outcome. We hypothesized that metacognitions and intrusions would moderate and mediate the relationship between treatment group and FCR level at follow-up.ResultsOnly total FCR score at baseline moderated treatment outcome. Participants with higher levels of FCR benefited more from ConquerFear relative to relaxation on the primary outcome. Changes in metacognitions and intrusive thoughts about cancer during treatment partially mediated the relationship between treatment group and FCR.ConclusionsThese results show that ConquerFear is relatively more effective than relaxation for those with overall higher levels of FCR. The mediation analyses confirmed that the most likely mechanism of treatment efficacy was the reduction in unhelpful metacognitions and intrusive thoughts during treatment, consistent with the theoretical framework underpinning ConquerFear.Implications for Cancer SurvivorsConquerFear is a brief, effective treatment for FCR in cancer survivors with early-stage disease. The treatment works by reducing intrusive thoughts about cancer and changing beliefs about worry and is particularly helpful for people with moderate to severe FCR.

In 4 of 15 patients with idiopathic atrial fibrillation, four novel, heterozygous mutations in GJA5 — the gene for the gap-junction protein connexin 40 — were identified. These supplement the list of mutations that cause atrial fibrillation and will improve our understanding of the molecular basis of atrial fibrillation. In 4 of 15 patients with idiopathic atrial fibrillation, four novel, heterozygous mutations in GJA5 — the gene for the gap-junction protein connexin 40 — were identified. Atrial fibrillation is characterized by rapid, erratic electrical activation of the atrial myocardium, resulting in the loss of effective contractility, an increased likelihood of clot formation, and an increased risk of stroke. 1 The rapid atrial activity may be conducted to the ventricles, resulting in the deterioration of heart function. In addition to causing substantial morbidity, atrial fibrillation confers an increased risk of mortality that is independent of coexisting risk factors. 2 In the United States, more than 2 million adults have atrial fibrillation, with the prevalence increasing with age (5.9 percent among those older than 65 years). 3 Thus, the socioeconomic burden . . .

Diatoms are known for their intricate, silicified cell walls (frustules). Silica polymerization occurs in a compartment called the silica deposition vesicle (SDV) and it was proposed that the cytoskeleton influences silica patterning through the SDV membrane (silicalemma) via interactions with transmembrane proteins. In this work we identify a family of proteins associated with the silicalemma, named SAPs for Silicalemma Associated Proteins. The T . pseudonana SAPs (TpSAPs) are characterized by their motif organization; each contains a transmembrane domain, serine rich region and a conserved cytoplasmic domain. Fluorescent tagging demonstrated that two of the TpSAPs were localized to the silicalemma and that the intralumenal region of TpSAP3 remained embedded in the silica while the cytoplasmic region was cleaved. Knockdown lines of TpSAP1 and 3 displayed malformed valves; which confirmed their roles in frustule morphogenesis. This study provides the first demonstration of altering silica structure through manipulation of a single gene.

Dispersal barriers have demographic, evolutionary, and ecosystem‐wide consequences. With ongoing changes in the environment, some dispersal barriers will likely disappear while new ones will appear, and it is crucial to understand these dynamics to forecast species' distributions and adaptive potential. Here we review recent literature on the ecological and evolutionary aspects of dispersal to highlight key dynamics of dispersal barriers in the face of global change. After defining dispersal barriers, we explain that a better understanding of their dynamics requires identifying the barrier types that are most susceptible to change and predicting species' responses. This knowledge is a prerequisite for designing management strategies to increase or reduce connectivity, and maintain adaptive potential. Our intent is to motivate researchers to explicitly consider dispersal barriers in order to better forecast the dynamics of species and ecosystems subject to global change.

Parkinson's disease is a progressive neurodegenerative disorder with multifactorial causes, among which genetic risk factors play a part. The RAB GTPases are regulators and substrates of LRRK2, and variants in the LRRK2 gene are important risk factors for Parkinson's disease. We aimed to explore genetic variability in RAB GTPases within cases of familial Parkinson's disease. We did whole-exome sequencing in probands from families in Canada and Tunisia with Parkinson's disease without a genetic cause, who were recruited from the Centre for Applied Neurogenetics (Vancouver, BC, Canada), an international consortium that includes people with Parkinson's disease from 36 sites in 24 countries. 61 RAB GTPases were genetically screened, and candidate variants were genotyped in relatives of the probands to assess disease segregation by linkage analysis. Genotyping was also done to assess variant frequencies in individuals with idiopathic Parkinson's disease and controls, matched for age and sex, who were also from the Centre for Applied Neurogenetics but unrelated to the probands or each other. All participants were aged 18 years or older. The sequencing and genotyping findings were validated by case–control association analyses using bioinformatic data obtained from publicly available clinicogenomic databases (AMP-PD, GP2, and 100 000 Genomes Project) and a private German clinical diagnostic database (University of Tübingen). Clinical and pathological findings were summarised and haplotypes were determined. In-vitro studies were done to investigate protein interactions and enzyme activities. Between June 1, 2010, and May 31, 2017, 130 probands from Canada and Tunisia (47 [36%] female and 83 [64%] male; mean age 72·7 years [SD 11·7; range 38–96]; 109 White European ancestry, 18 north African, two east Asian, and one Hispanic] underwent whole-exome sequencing. 15 variants in RAB GTPase genes were identified, of which the RAB32 variant c.213C>G (Ser71Arg) cosegregated with autosomal dominant Parkinson's disease in three families (nine affected individuals; non-parametric linkage Z score=1·95; p=0·03). 2604 unrelated individuals with Parkinson's disease and 344 matched controls were additionally genotyped, and five more people originating from five countries (Canada, Italy, Poland, Turkey, and Tunisia) were identified with the RAB32 variant. From the database searches, in which 6043 individuals with Parkinson's disease and 62 549 controls were included, another eight individuals were identified with the RAB32 variant from four countries (Canada, Germany, UK, and USA). Overall, the association of RAB32 c.213C>G (Ser71Arg) with Parkinson's disease was significant (odds ratio [OR] 13·17, 95% CI 2·15–87·23; p=0·0055; I2=99·96%). In the people who had the variant, Parkinson's disease presented at age 54·6 years (SD 12·75, range 31–81, n=16), and two-thirds had a family history of parkinsonism. RAB32 Ser71Arg heterozygotes shared a common haplotype, although penetrance was incomplete. Findings in one individual at autopsy showed sparse neurofibrillary tangle pathology in the midbrain and thalamus, without Lewy body pathology. In functional studies, RAB32 Arg71 activated LRRK2 kinase to a level greater than RAB32 Ser71. RAB32 Ser71Arg is a novel genetic risk factor for Parkinson's disease, with reduced penetrance. The variant was found in individuals with Parkinson's disease from multiple ethnic groups, with the same haplotype. In-vitro assays show that RAB32 Arg71 activates LRRK2 kinase, which indicates that genetically distinct causes of familial parkinsonism share the same mechanism. The discovery of RAB32 Ser71Arg also suggests several genetically inherited causes of Parkinson's disease originated to control intracellular immunity. This shared aetiology should be considered in future translational research, while the global epidemiology of RAB32 Ser71Arg needs to be assessed to inform genetic counselling. National Institutes of Health, the Canada Excellence Research Chairs program, Aligning Science Across Parkinson's, the Michael J Fox Foundation for Parkinson's Research, and the UK Medical Research Council.