Proposal for Numerical Benchmarking of Fluid-Structure Interaction in Cerebral Aneurysms

Computational fluid dynamics is intensively used to deepen the understanding of aneurysm growth and rupture in the attempt to support physicians during therapy planning. Numerous studies have assumed fully-rigid vessel walls in their simulations, whose sole hemodynamics may fail to provide a satisfactory criterion for rupture risk assessment. Moreover, direct in-vivo observations of intracranial aneurysm pulsation have been recently reported, encouraging the development of fluid-structure interaction for their modelling and for new assessments. In this work, we describe a new fluid-structure interaction benchmark setting for the careful evaluation of different aneurysm shapes. The studied configurations consist of three real aneurysm domes positioned on a toroidal channel. All geometric features, meshing characteristics, flow quantities, comparisons with a rigid-wall model and corresponding plots are provided. Reported results emphasize the alteration of flow patterns and hemodynamic descriptors when moving from the rigid-wall model to the complete fluid-structure interaction framework, thereby underlining the importance of the coupling between hemodynamics and the surrounding vessel tissue.Comment: 23 pages, 14 figure

Endoplasmic Reticulum Stress-Sensing Mechanism Is Activated in Entamoeba histolytica upon Treatment with Nitric Oxide

The Endoplasmic Reticulum stores calcium and is a site of protein synthesis and modification. Changes in ER homeostasis lead to stress responses with an activation of the unfolded protein response (UPR). The Entamoeba histolytica endomembrane system is simple compared to those of higher eukaryotes, as a canonical ER is not observed. During amoebiasis, an infection of the human intestine and liver by E. histolytica, nitric oxide (NO) triggers an apoptotic-like event preceded by an impairment of energy production and a loss of important parasite pathogenic features. We address the question of how this ancient eukaryote responds to stress induced by immune components (i.e. NO) and whether stress leads to ER changes and subsequently to an UPR. Gene expression analysis suggested that NO triggers stress responses marked by (i) dramatic up-regulation of hsp genes although a bona fide UPR is absent; (ii) induction of DNA repair and redox gene expression and iii) up-regulation of glycolysis-related gene expression. Enzymology approaches demonstrate that NO directly inhibits glycolysis and enhance cysteine synthase activity. Using live imaging and confocal microscopy we found that NO dramatically provokes extensive ER fragmentation. ER fission in E. histolytica appears as a protective response against stress, as it has been recently proposed for neuron self-defense during neurologic disorders. Chronic ER stress is also involved in metabolic diseases including diabetes, where NO production reduces ER calcium levels and activates cell death. Our data highlighted unique cellular responses of interest to understand the mechanisms of parasite death during amoebiasis

Quantification of stochastic noise of splicing and polyadenylation in Entamoeba histolytica

Alternative splicing and polyadenylation were observed pervasively in eukaryotic messenger RNAs. These alternative isoforms could either be consequences of physiological regulation or stochastic noise of RNA processing. To quantify the extent of stochastic noise in splicing and polyadenylation, we analyzed the alternative usage of splicing and polyadenylation sites in Entamoeba histolytica using RNA-Seq. First, we identified a large number of rarely spliced alternative junctions and then showed that the occurrence of these alternative splicing events is correlated with splicing site sequence, occurrence of constitutive splicing events and messenger RNA abundance. Our results implied the majority of these alternative splicing events are likely to be stochastic error of splicing machineries, and we estimated the corresponding error rates. Second, we observed extensive microheterogeneity of polyadenylation cleavage sites, and the extent of such microheterogeneity is correlated with the occurrence of constitutive cleavage events, suggesting most of such microheterogeneity is likely to be stochastic. Overall, we only observed a small fraction of alternative splicing and polyadenylation isoforms that are unlikely to be solely stochastic, implying the functional relevance of alternative splicing and polyadenylation in E. histolytica is limited. Lastly, we revised the gene models and annotated their 3′UTR in AmoebaDB, providing valuable resources to the community

Genome-wide analysis of butterfly bush in three uplands provides insights into biogeography, demography and speciation

Understanding processes that generate and maintain large disjunctions within plant species can provide valuable insights into plant diversity and speciation. The butterfly bush Buddleja alternifolia has an unusual disjunct distribution, occurring in the Himalaya, Hengduan Mountains (HDM) and the Loess Plateau (LP) in China. We generated a high-quality, chromosome-level genome assembly of B. alternifolia, the first within the family Scrophulariaceae. Whole-genome re-sequencing data from 48 populations plus morphological and petal colour reflectance data covering its full distribution range were collected. Three distinct genetic lineages of B. alternifolia were uncovered, corresponding to Himalayan, HDM and LP populations, with the last also differentiated morphologically and phenologically, indicating occurrence of allopatric speciation likely to be facilitated by geographic isolation and divergent adaptation to distinct ecological niches. Moreover, speciation with gene flow between populations from either side of a mountain barrier could be under way within LP. The current disjunctions within B. alternifolia might result from vicariance of a once widespread distribution, followed by several past contraction and expansion events, possibly linked to climate fluctuations promoted by the Kunlun-Yellow river tectonic movement. Several adaptive genes are likely to be either uniformly or diversely selected among regions, providing a footprint of local adaptations. These findings provide new insights into plant biogeography, adaptation and different processes of allopatric speciation

RNA Sequencing Reveals Widespread Transcription of Natural Antisense RNAs in Entamoeba Species.

Entamoeba is a genus of Amoebozoa that includes the intestine-colonizing pathogenic species Entamoeba histolytica. To understand the basis of gene regulation in E. histolytica from an evolutionary perspective, we have profiled the transcriptomes of its closely related species E. dispar, E. moshkovskii and E. invadens. Genome-wide identification of transcription start sites (TSS) and polyadenylation sites (PAS) revealed the similarities and differences of their gene regulatory sequences. In particular, we found the widespread initiation of antisense transcription from within the gene coding sequences is a common feature among all Entamoeba species. Interestingly, we observed the enrichment of antisense transcription in genes involved in several processes that are common to species infecting the human intestine, e.g., the metabolism of phospholipids. These results suggest a potentially conserved and compact gene regulatory system in Entamoeba

Genome-wide analysis of butterfly bush (Buddleja alternifolia) in three uplands provides insights into biogeography, demography and speciation

Understanding processes that generate and maintain large disjunctions within plant species can provide valuable insights into plant diversity and speciation. The butterfly bush Buddleja alternifolia has an unusual disjunct distribution, occurring in the Himalaya, Hengduan Mountains (HDM) and the Loess Plateau (LP) in China. We generated a high-quality, chromosome-level genome assembly of B. alternifolia, the first within the family Scrophulariaceae. Whole-genome re-sequencing data from 48 populations plus morphological and petal colour reflectance data covering its full distribution range were collected. Three distinct genetic lineages of B. alternifolia were uncovered, corresponding to Himalayan, HDM and LP populations, with the last also differentiated morphologically and phenologically, indicating occurrence of allopatric speciation likely to be facilitated by geographic isolation and divergent adaptation to distinct ecological niches. Moreover, speciation with gene flow between populations from either side of a mountain barrier could be under way within LP. The current disjunctions within B. alternifolia might result from vicariance of a once widespread distribution, followed by several past contraction and expansion events, possibly linked to climate fluctuations promoted by the Kunlun–Yellow river tectonic movement. Several adaptive genes are likely to be either uniformly or diversely selected among regions, providing a footprint of local adaptations. These findings provide new insights into plant biogeography, adaptation and different processes of allopatric speciation.Supplementary Material 1: Dataset S1 Morphological measurement and floral colour reflectance data for populations of Buddleja alternifola. Fig. S1 Phylogenetic trees inferred by ASTRAL- and ML-based approaches. Fig. S2 Patterns of linkage disequilibrium (LD). Fig. S3 Models 1–3, during the process of divergence among the three linkages, no gene flows with no changes in effective population size and (Model 1); with changes in effective population sizes starting from the divergence of TB (TDIV1), as well as SC and HT (TDIV2, Model 2); with changes in effective population sizes starting from TDIV1. Fig. S4 The phylogenomic tree used for time assignment of divergence for ancestral area reconstruction using representative samples of B. alternifolia and three species in the genus are currently available with re-sequencing data. Fig. S5 Cross-validation (CV) error and marginal likelihood values for different model K. Fig. S6 Reconstructing the phylogenomic relationships for 46 species of Buddleja using single-copy genes. Methods S1 Site ancestral state estimation. Methods S2 Estimating mutation rate of B. alternifolia. Methods S3 Reconstructing the phylogenomic relationships for 46 species of Buddleja using single-copy genes.Supplementary Material 2: Notes S1 Reproducibility of analyses for BEAST and r8s files.Supplementary Material 3: Table S1 Statistics of all assemblies. Table S2 Basic information with regards to genomes of 17 plants that were used to gene family analysis and the phylogenetic tree construction. Table S3 A matrix information on geographic distances among populations. Table S4 Environmental parameters used for assessment of ecological niche differentiation in B. alternifolia. Table S5 Geographical coordinate of B. alternifolia. Table S6 WGS-PacBio sequencing statistics. Table S7 WGS Illumina sequencing statistics. Table S8 HiC sequencing statistics. Table S9 Repeat annotations of the Buddleja alternifolia genome assembly. Table S10 Gene annotation statistics of the Buddleja alternifolia assembly. Table S11 Functional annotation of predicted genes in the Buddleja alternifolia genome. Table S12 Summary of the gene family analyses. Table S13 Basic information on location and genome mapping characteristics of all sampled individuals. Table S14 Summary of SNP annotations. Table S15 Global pairwise Fst between areas at the whole-genome level. Table S16 Pairwise Fst between areas in the divided nine subgroups of the whole genome, that is, eight in the gene region and one in the intergene region. Table S17 Results of nine models used in the fastsimocal analysis. Table S18 Basic parameters of three models compared in BioGeoBears, that is, Dec and Divalike based on dispersal-vicariance analysis, and Bayarea based on Bayesian inference of historical biogeography for discrete areas, with and without the founder-event speciation ‘J’ parameter. Table S19 Results of IBD and IBA analysis using simple and partial Mantel tests. Table S20 Shared genes detected by both approaches, red colour font indicating the shared genes of a significant overrepresentation with a specific GO term (P < 0.05). Table S21 Annotation of genes with significant GO terms (P < 0.05) detected by both approaches. Please note: Wiley Blackwell are not responsible for the content or functionality of any Supporting Information supplied by the authors. Any queries (other than missing material) should be directed to the New Phytologist Central Office.National Natural Science Foundation of China; Second Tibetan Plateau Scientific Expedition and Research Programme; Yunnan Science and Technology Innovation Team Programme for PSESP Conservation and Utilisation; Youth Innovation Promotion Association, Chinese Academy of Sciences.https://nph.onlinelibrary.wiley.com/journal/14698137am2022BiochemistryGeneticsMicrobiology and Plant Patholog

Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor

Cellular senescence suppresses cancer by arresting cell proliferation, essentially permanently, in response to oncogenic stimuli, including genotoxic stress. We modified the use of antibody arrays to provide a quantitative assessment of factors secreted by senescent cells. We show that human cells induced to senesce by genotoxic stress secrete myriad factors associated with inflammation and malignancy. This senescence-associated secretory phenotype (SASP) developed slowly over several days and only after DNA damage of sufficient magnitude to induce senescence. Remarkably similar SASPs developed in normal fibroblasts, normal epithelial cells, and epithelial tumor cells after genotoxic stress in culture, and in epithelial tumor cells in vivo after treatment of prostate cancer patients with DNA-damaging chemotherapy. In cultured premalignant epithelial cells, SASPs induced an epithelial–mesenchyme transition and invasiveness, hallmarks of malignancy, by a paracrine mechanism that depended largely on the SASP factors interleukin (IL)-6 and IL-8. Strikingly, two manipulations markedly amplified, and accelerated development of, the SASPs: oncogenic RAS expression, which causes genotoxic stress and senescence in normal cells, and functional loss of the p53 tumor suppressor protein. Both loss of p53 and gain of oncogenic RAS also exacerbated the promalignant paracrine activities of the SASPs. Our findings define a central feature of genotoxic stress-induced senescence. Moreover, they suggest a cell-nonautonomous mechanism by which p53 can restrain, and oncogenic RAS can promote, the development of age-related cancer by altering the tissue microenvironment

Analysis of the Genome and Transcriptome of Cryptococcus neoformans var. grubii Reveals Complex RNA Expression and Microevolution Leading to Virulence Attenuation

Cryptococcus neoformans is a pathogenic basidiomycetous yeast responsible for more than 600,000 deaths each year. It occurs as two serotypes (A and D) representing two varieties (i.e. grubii and neoformans, respectively). Here, we sequenced the genome and performed an RNA-Seq-based analysis of the C. neoformans var. grubii transcriptome structure. We determined the chromosomal locations, analyzed the sequence/structural features of the centromeres, and identified origins of replication. The genome was annotated based on automated and manual curation. More than 40,000 introns populating more than 99% of the expressed genes were identified. Although most of these introns are located in the coding DNA sequences (CDS), over 2,000 introns in the untranslated regions (UTRs) were also identified. Poly(A)-containing reads were employed to locate the polyadenylation sites of more than 80% of the genes. Examination of the sequences around these sites revealed a new poly(A)-site-associated motif (AUGHAH). In addition, 1,197 miscRNAs were identified. These miscRNAs can be spliced and/or polyadenylated, but do not appear to have obvious coding capacities. Finally, this genome sequence enabled a comparative analysis of strain H99 variants obtained after laboratory passage. The spectrum of mutations identified provides insights into the genetics underlying the micro-evolution of a laboratory strain, and identifies mutations involved in stress responses, mating efficiency, and virulence

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements