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This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/8138346. In this manuscript, Deevy and colleagues investigate the molecular impacts of EZH2 variants found in individuals with Weaver syndrome.EZH2 is a catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) responsible for depositing histone 3 lysine 27 (H3K27) mono(me1), di (me2) and trimethylation (me3). Heterozygous mutations in EZH2 are associated with Weaver syndrome and are inherited in an autosomal dominant manner. To model Weaver syndrome, the authors express human EZH2 with and without Weaver-associated variants in mouse embryonic stem cells heterozygous for Ezh2, where one allele is catalytically inactivated. Weaver syndrome extremely rare, and generating models from each patient is intractable and would introduce confounding genetic variability. Here, by creating a parental Ezh2 heterozygous line and overexpressing human EZH2 variants enables the team to model changes in H3K27 methylation and gene expression in a well-controlled system.The authors employ a combination of Western Blotting, quantitative ChIP-seq, and STORM to demonstrate Weaver-associated EHZ2 variants generally decrease global levels of H3K27me2/3 as well as chromatin compaction. Further, RNA-seq analysis uncovered a shared set of 18 genes that are ectopically upregulated in 4/5 Weaver-syndrome variants tested, in association with a loss of H3K27me3, PRC2 and PRC1 at their promoter sequences. Importantly, the authors note that 6/18 genes are implicated in human growth phenotypes.Another EZH2 variant, A733T, is associated with human growth restriction. Of note, most of the 18 upregulated genes in Weaver models are downregulated in cells reconstituted with A733T, coincident with a gain of H3K27me3, PRC2 and PRC1 levels at their promoters. Such reciprocal effects strongly suggests that modulating EZH2 activity has important consequences on human growth, perhaps through the regulation of this shared set of growth-related genes.The authors also describe significant restriction of intergenic H3K27me2 levels in Weaver-associated mutants, and reciprocal H3K27me3 expansion in A733T and lymphoma-related Y641F mutants. However, the transcriptional consequence of changes in intergenic H3K27 methylation is less obvious and was not assessed.The number and range of variants associated with Weaver syndrome assayed, as well as those associated with lymphoma and growth restriction, greatly helped contextualize the effect of all these variants.Altogether, this is a compelling set of experiments that characterize reciprocal H3K27me2/3 and gene expression dynamics that likely contribute to human overgrowth and undergrowth phenotypes. The manuscript is well written, and the figures are clear and support their observations and conclusions.Major commentsThe authors mention Weaver syndrome-associated variants are classically considered hypomorphs because EZH2 has lower histone methylation activity in vitro, leading to the conclusion that haploinsufficiency underlies Weaver syndrome. Indeed, OMIM currently lists Weaver syndrome inheritance as autosomal dominant. However, the authors' literature search did not uncover cases of "full" heterozygotes, where one allele is genetically ablated, suggesting Weaver syndrome variants are dominant negative. The molecular assays carried out lend support to this claim and is consistent with an autosomal dominant form of inheritance.It remains unclear to me what impact the heterozygous deletion of the Ezh2 SET domain has on cells. Since there are no reported cases of "full" heterozygous Ezh2 Weaver syndrome (where one allele is fully inactivated, like in a SET domain mutant), it is odd to me that the parental Ezh2 het line shares many molecular signatures with the Weaver-associated EZH2 expressing variants:· WB quantification and spike-in normalized ChIP shows global H3K27me3 levels are lower in hets compared to WT, at a similar level (albeit higher) compared to the 10 Weaver syndrome variants (with the exception of A677T).· STORM imaging reveals hets have decompacted chromatin compared to WT, like in the Weaver variant cells.· At least 9 genes are significantly upregulated in Ezh2 het cells; are any shared with those upregulated in Weaver syndrome variants?· It would be interesting to include the quantitative H3K27me3 ChIP data generated from het cells in the meta-analysis over intergenic DNA (Fig. 4b)· Essentially, what I'm asking is: is what respect are Ezh2 het cells unlike Weaver syndrome variant expressing cells? Is it possible that hets impart a modest dominant negative effect, and expressing a Weaver variant in these cells pushes these (potentially sensitized) cells further toward PRC2 dysfunction in a dominant negative manner?It is unclear whether the Weaver variants overlap conserved residues between mouse and human. An amino acid alignment of (at least) human and mouse EZH2, highlighting the position of Weaver variants, would be nice.Can the authors expand on their speculation in the Discussion regarding why these Weaver mutants have a dominant negative effect? Specifically, why is Weaver-variant EZH2 able to methylate H3K27 (Extended data 1e), but when expressed in a het context reduce global H3K27me3 and restrict intergenic H3K27me3?From the Introduction: "Furthermore, we previously proposed that the potential disruption of intergenic H3K27me2/3 could contribute to the aetiology of Weaver syndrome5, and we now speculate it may also be central to the aetiology of EZH2-associated growth restriction."Can the authors speculate on the relevance of disrupting intergenic H3K27me2/3 levels? Expression analysis focused solely on PcG target gene promoters. Is non-genic transcription disrupted in Weaver variant EZH2 expression cells?From the Introduction: "This broad deposition profile of H3K27me2 prompted us to propose it could function as a repressive "blanket" to counter H3K27ac accumulation and/or to restrict the inappropriate activation of enhancers of alternative lineages."Does H3K27me2 restriction in Weaver variant EZH2 expressing mESCs result in H3K27ac gain at alternative lineage enhancers? Or is it believed to be a cell-type specific effect?Minor commentsIn the Discussion the authors state "Here, we characterize the Weaver syndrome- associated EZH2-A677T variant and find that it acts similarly to 'gain-of-function' EZH2 variants causative of B- cell lymphoma [ref 30]". Repeating (as it was mentioned in the Introduction) the fact that the mutant in ref 30 (A677G) is at the same residue would stress the overlap between Weaver syndrome mutations and cancer-associated mutations at EZH2. Can the authors speculate why the Y641F mutant results in the increase of both global H3K27me3 and H3K27ac? Different scales?WB loading controls used: ACTIN and GAPDH. In a perfect world pan-H3 would have been used.Figure 1a is extremely helpful in understanding the variants presented. It would be nice to add all the mutants studied, including gain-of-function lymphoma-related ones like Y641F. Or do as in 3b and 5a and show the schema again. I believe only Y641F is missing.Figure 3d: Seems unnecessary to present WT vs A677T data as overlapping tracks. It's clear from the tracks above that A677T increases H3K27me3 at the region shown.I don't think I interpret Figure 2a correctly. Is it showing K27me3 at intergenic regions? I thought K27me2 should be enriched at these regions.The introduction mentions p.A738T is a missense mutation associated with growth restriction. But the missense mutation studied was labeled A733T. Differences in human vs mouse amino acid position counting?Sup 1 d is labelled cY677G typo – should be A677G Competing interests The author declares that they have no competing interests.

This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/7529495. In this manuscript, Taglini and colleagues explore the role of de novo DNA methyltransferase DNMT3B in human heterochromatin methylation. Using a human colorectal cancer cell line lacking DNMT3B, the authors demonstrate a specific loss of DNA methylation over pericentromeric DNA and constitutive heterochromatin, which are normally characterized by intermediate levels of DNA methylation and high H3K9 methylation. This model is consistent with previous studies that link DNMT3B loss of function mutations with pericentromeric DNA demethylation, genome instability and ICF-1 syndrome. The authors then reconstituted DNMT3B-less cells with DNMT3B variants that carry a series of clinically relevant mutations, including the previously described S270P mutation in the PWWP domain, which was hypothesized to be the domain required for DNMT3B targeting to pericentromeric DNA. The authors also generated DNMT3B variants carrying PWWP domain mutations at paralogous amino acids to those that cause Heyn-Sproul-Jackson Syndrome (HESJAS) syndrome when mutated in DNMT3A (W263A and D266A) which result in methylation of DNA methylation valleys normally marked by H3K27me3. Unexpectedly, using two types of protein stability assays and Western blotting, the S270P mutation was shown to result in protein destabilization, conferring a loss of function mutation. Further characterization of pericentromeric DNA in revealed that S270P leads to loss of DNMT3B at heterochromatin hypomethylated pericentromeric DNA, likely due to protein activity loss. On the other hand, WGBS, southern blotting and bisulphite-PCR of W263A and D266A mutants show that both lead to an increase in pericentromeric and heterochromatin DNA methylation. Thus, while DNMT3B normally targets transcribed gene bodies and heterochromatin, mutations that alter PWWP function shift the balance of DNMT3B localization from genic regions to heterochromatin regions. Surprisingly, complete abrogation the PWWP domain does not result in DNMT3B redistribution, suggesting the W263A and D266A are gain of function mutations. Finally, the authors demonstrate that the uncharacterized N terminal of DNMT3B is required for heterochromatin targeting, but is dispensable in a W263A mutant context. Overall, this is an excellently conducted and well written study. The authors employ orthogonal technologies to conclude DNMT3B's role in the methylation of pericentromeric and constitutive heterochromatin DNA. While evidence already suggested DNMT3B associates with pericentromeric DNA in mouse via HP1a and Suv39h proteins (Lehnertz et al., 2003 Current Biology), Taglini and colleagues widened the scope of this interaction to generalize the association between DNMT3B and constitutive heterochromatin genome-wide. Furthermore, the integration of disease-relevant mutations deconvoluted a standing mystery in clinically observed DNMT3B mutation in ICF-1 syndrome. Major comments I wonder whether DNMT3A can compensate for the lack of DNMT3B in the 'parental' DNMT3B KO cell line. Both at gene bodies (which seems to be the case) and over heterochromatin. The authors could do a Southern on Satellite II DNA to check methylation levels in the DNMT3A/B double KO to confirm. During my reading on the Results section it was unclear the extent of overlap between pericentromeric regions and H3K9me3 domains. If possible, the authors could include pericentromeric DNA annotations (if these exist) or the location of Satellite II DNA (again, assuming reliable annotations exist). Does the ΔPWWP mutation change the stability of DNMT3B? Do the H3K9me3 domains correspond to LADs? Could mine data from (van Schaik et al., 2020 EMBO Reports). Minor comments Rescue with DNMT3A instead of DNMT3B showed little gain of DNAme at H3K9me3 domains, revealing a difference in targeting of the DNMTs. However, if the cells normally express DNMT3A, this is an overexpression experiment, which could be discussed. Could the authors speculate about the many isoforms of DNMT3B and how they may encode proteins with variable N terminal domains or missing PWWP? Such isoforms were discussed in a 2016 paper using the HCT116 cell line (Duymich et al., 2016 Nature Communications). P5. "They also significantly overlapped heterochromatic regions resistant to nuclease digestion identified using Protect-seq in the same cells (Jaccard=0.623, p=2.11x10-30, Fisher's test) (Spracklin and Pradhan, 2020)" has no associated figure, though I'm not sure one is required. Maybe a supplemental table? What is the overlap of K9me3 domains in DNMT3B WT & KO cells? The title of Fig 2c (right) could be improved as it's not JUST W263A cells, but also 3BWT cells. I think Figure 7 model is a tad ambiguous about K9me3/K27me3 marked regions and omits interesting biology, namely, that H3K27me3 is redistributed over K9me3-marked regions in DNMT3B KO cells. Further, different "PWWP mutations" have different effects on DNMT3B targeting. Boxplot Fig 1c,e: Would be nice to know the absolute levels of DNAme instead of just the delta (maybe as a supplement). Would also be nice to display the p-value between "other domains" and "H3K27me3 only domains" in Fig 1c. Are the DNMT3B W263A and 266A mutations found in human diseases? Are major satellite II / pericentromeric DNA regions transcribed in the various cell lines? Similarly, how come H3K27me3 colocalizes with H3K9me3 in the absence of DNAme? See (Saksouk et al., 2014 Molecular Cell). Could the authors speculate? It would be interesting to test whether any of the mutations generated and tested here modify the cooperative binding of DNMT3B with other proteins frequently mutated in human ICF, such as ZBTB24 (ICF-2), CDCA7 (ICF-3) or HELLS (ICF-4). Competing interests The author declares that they have no competing interests.

In mammals, only the zygote and blastomeres of the early embryo are fully totipotent. This totipotency is mirrored in vitro by mouse "2-cell-like cells" (2CLCs), which appear at low frequency in cultures of Embryonic Stem cells (ESCs). Because totipotency is incompletely understood, we carried out a genome-wide CRISPR KO screen in mouse ESCs, searching for mutants that reactivate the expression of Dazl, a robust 2-cell-like marker. Using secondary screens, we identify four mutants that reactivate not just Dazl, but also a broader 2-cell-like signature: the E3 ubiquitin ligase adaptor SPOP, the Zinc Finger transcription factor ZBTB14, MCM3AP, a component of the RNA processing complex TREX-2, and the lysine demethylase KDM5C. Functional experiments show how these factors link to known players of the 2 cell-like state. These results extend our knowledge of totipotency, a key phase of organismal life.

The hallmarks of the alveolar subclass of rhabdomyosarcoma are chromosomal translocations that generate chimeric PAX3-FOXO1 or PAX7-FOXO1 transcription factors. Both PAX-FOXO1s result in related cell transformation in animal models, but both mutations are associated with distinct pathological manifestations in patients. To assess the mechanisms underlying these differences, we generated isogenic fibroblast lines expressing either PAX-FOXO1 paralog. Mapping of their genomic recruitment using CUT&Tag revealed that the two chimeric proteins have distinct DNA binding preferences. In addition, PAX7-FOXO1 causes stronger de novo transactivation of its bound regions than PAX3-FOXO1, resulting in greater transcriptomic dynamics involving genes regulating cell shape and cycle. Consistently, PAX3-FOXO1 accentuates fibroblast cellular traits associated with contractility and surface adhesion and limits entry into M phase. In contrast, PAX7-FOXO1 drives cells to adopt an amoeboid shape, reduces entry into S phase, and causes more genomic instabilities. Altogether, our results argue that the diversity of rhabdomyosarcoma manifestation arises, in part, from the divergence between the transcriptional activities of PAX3-FOXO1 and PAX7-FOXO1. Furthermore, the identified pronounced deleterious effects of PAX7-FOXO1 provide an explanation for the low frequency of the translocation generating this factor in patients with rhabdomyosarcoma.

International audience; Polycomb-group proteins assemble into two primary complexes-Polycomb repressive complex (PRC) 1 and 2-that safeguard cell fate by repressing gene transcription. Two new studies explore the PRC1 landscape during the transition from gametes to embryos in mice, thus providing insight into the intergenerational transmission of epigenetic information and gene regulation dynamics as embryos prepare for gastrulation.

The seismic provisions of the Canadian CSA S16-14 standard for steel structures for heavy industrial steel structures are reviewed and applied for a 65.4 m tall concentrically braced frames (CBFs) for an industrial application in Vancouver, BC. Two approaches are examined: a capacity design method in accordance with CSA S16 Annex M and a simpler, non-capacity design approach for the structures of the Conventional Construction (Type CC) category. Nonlinear response history analyses are performed to examine and compare the seismic response of the structures. Modifications are proposed to mobilize higher brace inelastic response, mitigate storey drift concentrations, and ensure that the columns can safely resist the seismic induced axial and flexural demands. The modified provisions are validated for additional structures having heights varying from 43 to 80 m and two different vertical distribution of the seismic weights. The robustness of the structures against excessive storey drifts and column buckling limit states is verified through incremental dynamic analysis. Both Annex M and Type CC design approaches, as modified in this study, represent two practical options to achieve cost-effective designs resulting in satisfactory seismic response. Three-dimensional nonlinear response history analysis is used to compare the 100%–100% and 100%–30% combination rules to predict the axial load demand on columns part of two orthogonal CBFs. For the structure studied, the results showed that the latter would give more realistic force estimates.

De novo DNA methylation (DNAme) during mammalian spermatogenesis yields a densely methylated genome, with the exception of CpG islands (CGIs), which are hypomethylated in sperm. Following fertilization, the paternal genome undergoes widespread DNAme loss before the first S-phase. Paradoxically, recent mass spectrometry analysis revealed that a low level of de novo DNAme occurs exclusively on the zygotic paternal genome. However, the loci involved and impact on genic transcription was not addressed. Here, we employ allele-specific analysis of wholegenome bisulphite sequencing (WGBS) data and show that a number of genomic regions, including several dozen CGI promoters, are de novo methylated on the paternal genome in 2-cell embryos. A subset of these promoters maintains DNAme through development to the blastocyst stage. Consistent with zygotic paternal DNAme acquisition (PDA), many of these loci are hypermethylated in androgenetic blastocysts but hypomethylated in parthenogenetic blastocysts. Strikingly, PDA is lost following maternal deletion ofDnmt3a. Furthermore, a subset of promoters showing PDA which are normally transcribed from the paternal allele in blastocysts show premature transcription at the 4-cell stage in maternalDnmt3aknockout embryos. These observations uncover an unexpected role for maternal DNMT3A activity in postfertilization epigenetic reprogramming and transcriptional silencing of the paternal genome.

Cell size is a complex trait that responds to developmental and environmental cues. Quantitative size analysis of mutant strain collections disrupted for protein kinases and transcriptional regulators in the pathogenic yeast Candida albicans uncovered 66 genes that altered cell size, few of which overlapped with known size genes in the budding yeast Saccharomyces cerevisiae. A potent size regulator specific to C. albicans was the conserved p38/HOG MAPK module that mediates the osmostress response. Basal HOG activity inhibited the SBF G1/S transcription factor complex in a stress-independent fashion to delay the G1/S transition. The HOG network also governed ribosome biogenesis through the master transcriptional regulator Sfp1. Hog1 bound to the promoters and cognate transcription factors for ribosome biogenesis regulons and interacted genetically with the SBF G1/S machinery, and thereby directly linked cell growth and division. These results illuminate the evolutionary plasticity of size control and identify the HOG module as a nexus of cell cycle and growth regulation.

De novo DNA methylation (DNAme) during mouse oogenesis occurs within transcribed regions enriched for H3K36me3. As many oocyte transcripts originate in long terminal repeats (LTRs), which are heterogeneous even between closely related mammals, we examined whether species-specific LTR-initiated transcription units (LITs) shape the oocyte methylome. Here we identify thousands of syntenic regions in mouse, rat, and human that show divergent DNAme associated with private LITs, many of which initiate in lineage-specific LTR retrotransposons. Furthermore, CpG island (CGI) promoters methylated in mouse and/or rat, but not human oocytes, are embedded within rodent-specific LITs and vice versa. Notably, at a subset of such CGI promoters, DNAme persists on the maternal genome in fertilized and parthenogenetic mouse blastocysts or in human placenta, indicative of species-specific epigenetic inheritance. Polymorphic LITs are also responsible for disparate DNAme at promoter CGIs in distantly related mouse strains, revealing that LITs also promote intra-species divergence in CGI DNAme., De novo DNA methylation during mouse oogenesis occurs within transcribed regions. Here the authors investigate the role of species-specific long terminal repeats (LTRs)-initiated transcription units in regulating the oocyte methylome, identifying syntenic regions in mouse, rat and human with divergent DNA methylation associated with private LITs.

Cell size is a complex trait that responds to developmental and environmental cues. Quantitative analysis of the size phenome in the pathogenic yeastCandida albicansuncovered 195 genes that markedly altered cell size, few of which overlapped with known size genes in other yeast species. A potent size regulator specific toC. albicanswas the conserved p38/HOG MAPK module that mediates the osmotic stress response. Basal HOG activity inhibited the SBF G1/S transcription factor complex in a stress-independent fashion to delay the G1/S transition. The HOG network also governed ribosome biogenesis through the master transcriptional regulator Sfp1. Hog1 bound to the promoters and cognate transcription factors for both the G1/S and ribosome biogenesis regulons and thereby directly linked cell growth and division. These results illuminate the evolutionary plasticity of size control and identify the HOG module as a nexus of cell cycle and growth regulation.

Since the earlier works in 2000 by Aurbach et al 1, magnesium-ion batteries emerged as an alternative to lithium-ion batteries thanks to many advantages: magnesium is the 5th most abundant metal in the earth crust, its divalent character and its ionic radius similar to lithium ionic radius gives it a volumetric capacity higher than lithium (3833 Ah/L and 2046 Ah/L respectively). Eventually the absence of dendritic growth on metallic magnesium is a plus in term of security. Several cathode materials were proposed for Mg-ions battery, nevertheless the reference positive electrode material in Mg-Ion technology remained the Chevrel Phase with the formula Mo6S8. The Chevrel phase, synthesized by R. Chevrel et al 2 in 1974, was described as an octahedral cluster of molybdenum located in a cube of sulfur that forms a Mo6S8 pattern. Structural analysis3 (X-Ray Diffraction) showed the existence of 12 insertions sites localized inside a cube of sulfur surrounded by Mo6S8 clusters. The electrochemistry highlighted 2 types of insertion sites able to host Mg2+ at different potentials. Mg trapping into the Chevrel Phase was also noticed but curiously this phenomenom doesn’t occur in the analogous phase Mo6Se8 4 thanks to the lower ionicity of Se compared to S. The anionic framework plays a major role in the redox process during Mg insertion, this study is a comparative analysis of Mo6S8 and analogous Mo6Se8 using electrochemistry and X-ray Photoemission Spectroscopy to get a direct observation of the redox mecanism during charge/discharge of the material. We performed ex situ XPS core peak analyses on Mo6S8 and Mo6Se8 analogous electrodes at different states of charge to probe the molybdenum, the sulfur and the selenium oxydation states and the environment (polarized or metallic) of inserted magnesium ions. These results will be discussed based on a step-by-step XPS study before and after cycling, and will be correlated with the electrochemical performances. References: (1) D. Aurbach, Z. Lu, A. Schechter, Y. Gofer, H. Gizbar, R. Turgeman, Y. Cohen, M. Moshkovich & E. Levi, Nature vol 407 (2000) 724 (2) R. Chevrel et al, Mat. Res. BuLl. Vol. 9, pp. 1487-1498, 1974. (3) R. Chevrel, M. Sergent Superconductivity in Ternary Compounds I Volume 32 of the series Topics in Current Physics pp 25-86 (4) M.D. Levi et al, Solid State Ionics Volume 176, Issues 19–22, June 2005, Pages 1695–1699

Mediator is a multi-subunit protein complex that regulates gene expression in eukaryotes by integrating physiological and developmental signals and transmitting them to the general RNA polymerase II machinery. We examined, in the fungal pathogen Candida albicans, a set of conditional alleles of genes encoding Mediator subunits of the head, middle, and tail modules that were found to be essential in the related ascomycete Saccharomyces cerevisiae. Intriguingly, while the Med4, 8, 10, 11, 14, 17, 21 and 22 subunits were essential in both fungi, the structurally highly conserved Med7 subunit was apparently non-essential in C. albicans. While loss of CaMed7 did not lead to loss of viability under normal growth conditions, it dramatically influenced the pathogen's ability to grow in different carbon sources, to form hyphae and biofilms, and to colonize the gastrointestinal tracts of mice. We used epitope tagging and location profiling of the Med7 subunit to examine the distribution of the DNA sites bound by Mediator during growth in either the yeast or the hyphal form, two distinct morphologies characterized by different transcription profiles. We observed a core set of 200 genes bound by Med7 under both conditions; this core set is expanded moderately during yeast growth, but is expanded considerably during hyphal growth, supporting the idea that Mediator binding correlates with changes in transcriptional activity and that this binding is condition specific. Med7 bound not only in the promoter regions of active genes but also within coding regions and at the 3′ ends of genes. By combining genome-wide location profiling, expression analyses and phenotyping, we have identified different Med7p-influenced regulons including genes related to glycolysis and the Filamentous Growth Regulator family. In the absence of Med7, the ribosomal regulon is de-repressed, suggesting Med7 is involved in central aspects of growth control., Author Summary In this study, we have investigated Mediator function in the human fungal pathogen C. albicans. An initial screening of conditionally regulated Mediator subunits showed that the Med7 of C. albicans was not essential, in contrast to the situation noted for S. cerevisiae. While loss of CaMed7 did not lead to loss of viability under normal growth conditions, it dramatically influenced the pathogen's ability to grow in different carbon sources, to form hyphae and biofilms, and to colonize the gastrointestinal tracts of mice. We used location profiling to determine Mediator binding under yeast and hyphal morphologies characterized by different transcription profiles. We observed a core set of specific and common genes bound by Med7 under both conditions; this specific core set is expanded considerably during hyphal growth, supporting the idea that Mediator binding correlates with changes in transcriptional activity and that this binding is condition specific. Med7 bound not only in the promoter regions of active genes but also of inactive genes and within coding regions and at the 3′ ends of genes. By combining genome-wide location profiling, expression analyses and phenotyping, we have identified different Med7 regulons including genes related to glycolysis and the Filamentous Growth Regulator family.

International audience; The popularity of statically typed programming languages compiling to JavaScript shows that there exists a fringe of the programmer population interested in leveraging the benefits of static typing to write Web applications. To be of any use, these languages need to statically expose the Web browser dynamically typed native API, which seems to be a contradiction in terms. Indeed, we observe that existing statically typed languages compiling to JavaScript expose the browser API in ways that either are not type safe, or when they are, typically over constrain the programmers. This article presents new ways to encode the challenging parts of the Web browser API in static type systems such that both type safety and expressive power are preserved. Our first encoding relies on type parameters and can be implemented in most mainstream languages but drags phantom types up to the usage sites. The second encoding does not suffer from this inconvenience but requires the support of dependent types in the language.

International audience; Writing large Web applications is known to be difficult. One challenge comes from the fact that the application's logic is scattered into heterogeneous clients and servers, making it difficult to share code between both sides or to move code from one side to the other. Another challenge is performance: while Web applications rely on ever more code on the client-side, they may run on smart phones with limited hardware capabilities. These two challenges raise the following problem: how to benefit from high-level languages and libraries making code complexity easier to manage and abstracting over the clients and servers differences without trading this ease of engineering for performance? This article presents high-level abstractions defined as deep embedded DSLs in Scala that can generate efficient code leveraging the characteristics of both client and server environments. We compare performance on client-side against other candidate technologies and against hand written low-level JavaScript code. Though code written with our DSL has a high level of abstraction, our benchmark on a real world application reports that it runs as fast as hand tuned low-level JavaScript code.

The suitability of the current Canadian procedures for seismic design of irregular industrial buildings is studied through the example of a titanium refinery located near Montreal, Canada. The building is braced by low-ductility concentrically braced steel frames and characterized by an irregular geometry, as well as an irregular mass and stiffness distributions. Three-dimensional elastic dynamic time history analyses were carried out for selected acceleration records compatible with the design spectra at the site. The results are compared to those obtained from the equivalent static force procedure and the response spectrum analysis method to evaluate how well these methods can predict deformations and forces in such highly irregular building. The study shows that the equivalent static method can adequately predict the displacements but may underestimate column and brace axial forces. In general, response spectrum analysis method provides appropriate estimates of the seismic response parameters given that a sufficient number of modes is considered in the analysis.

Dans Fatobougou (Le village des fous), un téléfilm de Boubacar Sidibé diffusé à la télévision malienne en 2007, un jeune homme blanc échappe à un acte de cannibalisme farcesque dans un village bambara, au Mali, grâce à un vieil homme qui l’invite à monter sur son cheval de bois. Tous deux partent au galop, la scène provoquant alors de grands éclats de rire chez les téléspectateurs maliens. Le cheval de bois du téléfilm pourrait ainsi fonctionner comme emblème, comme représentant de ces « chev...

Large solid propellant rocket motors may be subjected to aero-acoustic instabilities arising from a coupling between the burnt gas flow and the acoustic eigenmodes of the combustion chamber. Given the size and cost of any single firing test or launch, it is of first importance to predict and avoid these instabilities at the design level. The main purpose of this paper is to build a numerical tool in order to evaluate how the coupling of the fluid flow and the whole structure of the motor influences the amplitude of the aeroacoustic oscillations living inside of the rocket. A particular attention was paid to the coupling algorithm between the fluid and the solid solvers in order to ensure the best energy conservation through the interface. A computation of a subscaled version of the Ariane 5 solid propellant engine is presented as illustration.

Steel-framed industrial buildings generally per formed well in recent earthquakes with most of the structural damage that has been reported being limited to individual components or connections, not to structural collapse. For instance, the damage observed after the 1999 Kocaeli, Turkey, earthquake included bolt shearing at column to roof truss connections in automotive plants, buckled and fractured braces, stretching and fracture of anchor bolts in moment-resist ing frames, and shearing of anchor bolts (Bendimerad et al. 1999; Rahnama & Morrow 2000; Sezen et al. 2000; Johnson et al. 2000). The 1994 Northridge earthquake caused yielding and failure of anchor bolts in an asphalt rock plant and brace buckling in a brewing facility (Tremblay et al. 1995). Failure of welds at brace connections was ob served after the 1988 Spitak, Armenia, earthquake (Yanev 1989).