Evolution of asexual and sexual reproduction in the aspergilli

Aspergillus nidulans has long-been used as a model organism to gain insights into the genetic basis of asexual and sexual developmental processes both in other members of the genus Aspergillus, and filamentous fungi in general. Paradigms have been established concerning the regulatory mechanisms of conidial development. However, recent studies have shown considerable genome divergence in the fungal kingdom, questioning the general applicability of findings from Aspergillus, and certain longstanding evolutionary theories have been questioned. The phylogenetic distribution of key regulatory elements of asexual reproduction in A. nidulans was investigated in a broad taxonomic range of fungi. This revealed that some proteins were well conserved in the Pezizomycotina (e.g. AbaA, FlbA, FluG, NsdD, MedA, and some velvet proteins), suggesting similar developmental roles. However, other elements (e.g. BrlA) had a more restricted distribution solely in the Eurotiomycetes, and it appears that the genetic control of sporulation seems to be more complex in the aspergilli than in some other taxonomic groups of the Pezizomycotina. The evolution of the velvet protein family is discussed based on the history of expansion and contraction events in the early divergent fungi. Heterologous expression of the A. nidulans abaA gene in Monascus ruber failed to induce development of complete conidiophores as seen in the aspergilli, but did result in increased conidial production. The absence of many components of the asexual developmental pathway from members of the Saccharomycotina supports the hypothesis that differences in the complexity of their spore formation is due in part to the increased diversity of the sporulation machinery evident in the Pezizomycotina. Investigations were also made into the evolution of sex and sexuality in the aspergilli. MAT loci were identified from the heterothallic Aspergillus (Emericella) heterothallicus and Aspergillus (Neosartorya) fennelliae and the homothallic Aspergillus pseudoglaucus (=Eurotium repens). A consistent architecture of the MAT locus was seen in these and other heterothallic aspergilli whereas much variation was seen in the arrangement of MAT loci in homothallic aspergilli. This suggested that it is most likely that the common ancestor of the aspergilli exhibited a heterothallic breeding system. Finally, the supposed prevalence of asexuality in the aspergilli was examined. Investigations were made using A. clavatus as a representative ‘asexual’ species. It was possible to induce a sexual cycle in A. clavatus given the correct MAT1-1 and MAT1-2 partners and environmental conditions, with recombination confirmed utilising molecular markers. This indicated that sexual reproduction might be possible in many supposedly asexual aspergilli and beyond, providing general insights into the nature of asexuality in fungi.National Natural Science Foundation of China 31601446National Research Foundation of Korea 2016010945Intelligent Synthetic Biology Center of Global Frontier Projects 2015M3A6A8065838Biotechnology and Biological Sciences Research CouncilGovernment of IraqMinisterio de Economía y Competitividad BIO2015-67148-

Radial asymptotics of Lemaitre-Tolman-Bondi dust models

We examine the radial asymptotic behavior of spherically symmetric Lemaitre-Tolman-Bondi dust models by looking at their covariant scalars along radial rays, which are spacelike geodesics parametrized by proper length $\ell$, orthogonal to the 4-velocity and to the orbits of SO(3). By introducing quasi-local scalars defined as integral functions along the rays, we obtain a complete and covariant representation of the models, leading to an initial value parametrization in which all scalars can be given by scaling laws depending on two metric scale factors and two basic initial value functions. Considering regular "open" LTB models whose space slices allow for a diverging $\ell$, we provide the conditions on the radial coordinate so that its asymptotic limit corresponds to the limit as $\ell\to\infty$. The "asymptotic state" is then defined as this limit, together with asymptotic series expansion around it, evaluated for all metric functions, covariant scalars (local and quasi-local) and their fluctuations. By looking at different sets of initial conditions, we examine and classify the asymptotic states of parabolic, hyperbolic and open elliptic models admitting a symmetry center. We show that in the radial direction the models can be asymptotic to any one of the following spacetimes: FLRW dust cosmologies with zero or negative spatial curvature, sections of Minkowski flat space (including Milne's space), sections of the Schwarzschild--Kruskal manifold or self--similar dust solutions.Comment: 44 pages (including a long appendix), 3 figures, IOP LaTeX style. Typos corrected and an important reference added. Accepted for publication in General Relativity and Gravitatio

Dark energy as a mirage

Motivated by the observed cosmic matter distribution, we present the following conjecture: due to the formation of voids and opaque structures, the average matter density on the path of the light from the well-observed objects changes from Omega_M ~ 1 in the homogeneous early universe to Omega_M ~ 0 in the clumpy late universe, so that the average expansion rate increases along our line of sight from EdS expansion Ht ~ 2/3 at high redshifts to free expansion Ht ~ 1 at low redshifts. To calculate the modified observable distance-redshift relations, we introduce a generalized Dyer-Roeder method that allows for two crucial physical properties of the universe: inhomogeneities in the expansion rate and the growth of the nonlinear structures. By treating the transition redshift to the void-dominated era as a free parameter, we find a phenomenological fit to the observations from the CMB anisotropy, the position of the baryon oscillation peak, the magnitude-redshift relations of type Ia supernovae, the local Hubble flow and the nucleosynthesis, resulting in a concordant model of the universe with 90% dark matter, 10% baryons, no dark energy, 15 Gyr as the age of the universe and a natural value for the transition redshift z_0=0.35. Unlike a large local void, the model respects the cosmological principle, further offering an explanation for the late onset of the perceived acceleration as a consequence of the forming nonlinear structures. Additional tests, such as quantitative predictions for angular deviations due to an anisotropic void distribution and a theoretical derivation of the model, can vindicate or falsify the interpretation that light propagation in voids is responsible for the perceived acceleration.Comment: 33 pages, 2 figs; v2: minor clarifications, results unchanged; v3: matches the version published in General Relativity and Gravitatio

A new strategy for enhancing imputation quality of rare variants from next-generation sequencing data via combining SNP and exome chip data

Background: Rare variants have gathered increasing attention as a possible alternative source of missing heritability. Since next generation sequencing technology is not yet cost-effective for large-scale genomic studies, a widely used alternative approach is imputation. However, the imputation approach may be limited by the low accuracy of the imputed rare variants. To improve imputation accuracy of rare variants, various approaches have been suggested, including increasing the sample size of the reference panel, using sequencing data from study-specific samples (i.e., specific populations), and using local reference panels by genotyping or sequencing a subset of study samples. While these approaches mainly utilize reference panels, imputation accuracy of rare variants can also be increased by using exome chips containing rare variants. The exome chip contains 250 K rare variants selected from the discovered variants of about 12,000 sequenced samples. If exome chip data are available for previously genotyped samples, the combined approach using a genotype panel of merged data, including exome chips and SNP chips, should increase the imputation accuracy of rare variants. Results: In this study, we describe a combined imputation which uses both exome chip and SNP chip data simultaneously as a genotype panel. The effectiveness and performance of the combined approach was demonstrated using a reference panel of 848 samples constructed using exome sequencing data from the T2D-GENES consortium and 5,349 sample genotype panels consisting of an exome chip and SNP chip. As a result, the combined approach increased imputation quality up to 11 %, and genomic coverage for rare variants up to 117.7 % (MAF < 1 %), compared to imputation using the SNP chip alone. Also, we investigated the systematic effect of reference panels on imputation quality using five reference panels and three genotype panels. The best performing approach was the combination of the study specific reference panel and the genotype panel of combined data. Conclusions: Our study demonstrates that combined datasets, including SNP chips and exome chips, enhances both the imputation quality and genomic coverage of rare variants

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

Evaluating the contribution of rare variants to type 2 diabetes and related traits using pedigrees

A major challenge in evaluating the contribution of rare variants to complex disease is identifying enough copies of the rare alleles to permit informative statistical analysis. To investigate the contribution of rare variants to the risk of type 2 diabetes (T2D) and related traits, we performed deep whole-genome analysis of 1,034 members of 20 large Mexican-American families with high prevalence of T2D. If rare variants of large effect accounted for much of the diabetes risk in these families, our experiment was powered to detect association. Using gene expression data on 21,677 transcripts for 643 pedigree members, we identified evidence for large-effect rare-variant cis-expression quantitative trait loci that could not be detected in population studies, validating our approach. However, we did not identify any rare variants of large effect associated with T2D, or the related traits of fasting glucose and insulin, suggesting that large-effect rare variants account for only a modest fraction of the genetic risk of these traits in this sample of families. Reliable identification of large-effect rare variants will require larger samples of extended pedigrees or different study designs that further enrich for such variants

Dipeptidyl peptidase-1 inhibition in patients hospitalised with COVID-19: a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial

Background Neutrophil serine proteases are involved in the pathogenesis of COVID-19 and increased serine protease activity has been reported in severe and fatal infection. We investigated whether brensocatib, an inhibitor of dipeptidyl peptidase-1 (DPP-1; an enzyme responsible for the activation of neutrophil serine proteases), would improve outcomes in patients hospitalised with COVID-19. Methods In a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial, across 14 hospitals in the UK, patients aged 16 years and older who were hospitalised with COVID-19 and had at least one risk factor for severe disease were randomly assigned 1:1, within 96 h of hospital admission, to once-daily brensocatib 25 mg or placebo orally for 28 days. Patients were randomly assigned via a central web-based randomisation system (TruST). Randomisation was stratified by site and age (65 years or ≥65 years), and within each stratum, blocks were of random sizes of two, four, or six patients. Participants in both groups continued to receive other therapies required to manage their condition. Participants, study staff, and investigators were masked to the study assignment. The primary outcome was the 7-point WHO ordinal scale for clinical status at day 29 after random assignment. The intention-to-treat population included all patients who were randomly assigned and met the enrolment criteria. The safety population included all participants who received at least one dose of study medication. This study was registered with the ISRCTN registry, ISRCTN30564012. Findings Between June 5, 2020, and Jan 25, 2021, 406 patients were randomly assigned to brensocatib or placebo; 192 (47·3%) to the brensocatib group and 214 (52·7%) to the placebo group. Two participants were excluded after being randomly assigned in the brensocatib group (214 patients included in the placebo group and 190 included in the brensocatib group in the intention-to-treat population). Primary outcome data was unavailable for six patients (three in the brensocatib group and three in the placebo group). Patients in the brensocatib group had worse clinical status at day 29 after being randomly assigned than those in the placebo group (adjusted odds ratio 0·72 [95% CI 0·57–0·92]). Prespecified subgroup analyses of the primary outcome supported the primary results. 185 participants reported at least one adverse event; 99 (46%) in the placebo group and 86 (45%) in the brensocatib group. The most common adverse events were gastrointestinal disorders and infections. One death in the placebo group was judged as possibly related to study drug. Interpretation Brensocatib treatment did not improve clinical status at day 29 in patients hospitalised with COVID-19

Chapter 13 The Nature of the Entrepreneurial Process: Causation, Effectuation, and Pragmatism

This chapter is an appreciation of and a critical reflection on Sarasvathy's work on the causation and effectuation models of entrepreneurship. While Sarasvathy has made significant contributions to the field, it is suggested that more fruitful results can be achieved if two modifications are made. First, it is argued that the six dimensions on which the two models differ are independent and therefore it is more fruitful to focus on the dimensions rather than on the two models. Second, it is argued that a pragmatic view of entrepreneurship is most fruitful when it is not applied at the level of the entrepreneurial process, but at the level of underlying human actions