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Qu’est-ce qu’un medicament ? Comment le fabrique-t-on ? Comment passe-t-on d’un produit de la chimie a l’identification d’une molecule biologiquement active, puis a un nouvel outil therapeutique ? Comment interagissent, pour atteindre ce but, des equipes de chimistes, de biologistes et de medecins ? Comment la recherche academique et la recherche industrielle collaborent-elles et se completent-elles ? Autant de questions bien (trop) souvent absentes des cursus universitaires, qu’ils soient scientifiques ou medicaux. C’est pour tenter d’y repondre que Servier, l’Inserm et le CNRS ont accepte de partager leur vision a travers une serie de textes que medecine/sciences publiera dans les mois a venir et dont voici les premiers. Les enjeux de cette connaissance sont tout a la fois medicaux, economiques et ethiques. De la chimie a la biologie, de la galenique a la pharmacodynamique, de la physiopathologie a la methodologie des essais cliniques, l’elaboration d’un medicament puise dans toutes ces disciplines qui participent a l’innovation therapeutique.

Alternative splicing (AS) generates vast transcriptomic complexity in the vertebrate nervous system. However, the extent to which trans-acting splicing regulators and their target AS regulatory networks contribute to nervous system development is not well understood. To address these questions, we generated mice lacking the vertebrate- and neural-specific Ser/Arg repeat-related protein of 100 kDa (nSR100/SRRM4). Loss of nSR100 impairs development of the central and peripheral nervous systems in part by disrupting neurite outgrowth, cortical layering in the forebrain, and axon guidance in the corpus callosum. Accompanying these developmental defects are widespread changes in AS that primarily result in shifts to nonneural patterns for different classes of splicing events. The main component of the altered AS program comprises 3- to 27-nucleotide (nt) neural microexons, an emerging class of highly conserved AS events associated with the regulation of protein interaction networks in developing neurons and neurological disorders. Remarkably, inclusion of a 6-nt, nSR100-activated microexon in Unc13b transcripts is sufficient to rescue a neuritogenesis defect in nSR100 mutant primary neurons. These results thus reveal critical in vivo neurodevelopmental functions of nSR100 and further link these functions to a conserved program of neuronal microexon splicing.

The first eigenvalue of the Laplacian on a surface can be viewed as a functional on the space of Riemannian metrics of a given area. Critical points of this functional are called extremal metrics. The only known extremal metrics are a round sphere, a standard projective plane, a Clifford torus and an equilateral torus. We construct an extremal metric on a Klein bottle. It is a metric of revolution, admitting a minimal isometric embedding into a 4-sphere by the first eigenfunctions. Also, this Klein bottle is a bipolar surface for the Lawson's {3,1}-torus. We conjecture that an extremal metric for the first eigenvalue on a Klein bottle is unique, and hence it provides a sharp upper bound for the first eigenvalue on a Klein bottle of a given area. We present numerical evidence and prove the first results towards this conjecture. 20 pages; minor corrections

What does it mean to be human in the 21st century? The pull of engineering on every aspect of our lives, the impact of machines on how we represent ourselves, the influence of computers on our understanding of free-will, individuality and species, and the effect of microorganisms on our behaviour are so great that one cannot discourse on humanity and humanities without considering their entanglement with technology and with the multiple new dimensions of reality that it opens up. The future of humanities should take into account AI, bacteria, software, viruses (both organic and inorganic), hardware, machine language, parasites, big data, monitors, pixels, swarms systems and the Internet. One cannot think of humanity and humanities as distinct from technology anymore.

In the title complex, [Ni(C30H23O2P2)I], the divalent Ni atom is coordinated by two P atoms and one C atom from the 1,3-bis­[(diphenyl­phosphan­yl)­oxy]benzene ligand; the distorted square-planar geometry is completed by an iodide ligand. The largest distortions from ideal square-planar geometry are reflected in the P—Ni—P angle of 164.20 (2)° and the P—Ni—C angles of 82.09 (6) and 82.11 (6)°. The rather short Ni—C bond length [1.890 (2) Å] is anti­cipated in light of the much stronger trans influence of the aryl moiety compared to the iodide ligand. The P-bound phenyl rings adopt different orientations to minimize steric repulsion among themselves.

The Spt-Ada-Gcn5 acetyltransferase (SAGA) complex is a highly conserved, 19-subunit histone acetyltransferase complex that activates transcription through acetylation and deubiquitination of nucleosomal histones in Saccharomyces cerevisiae. Because SAGA has been shown to display conformational variability, we applied gradient fixation to stabilize purified SAGA and systematically analyzed this flexibility using single-particle EM. Our two- and three-dimensional studies show that SAGA adopts three major conformations, and mutations of specific subunits affect the distribution among these. We also located the four functional modules of SAGA using electron microscopy-based labeling and transcriptional activator binding analyses and show that the acetyltransferase module is localized in the most mobile region of the complex. We further comprehensively mapped the subunit interconnectivity of SAGA using cross-linking mass spectrometry, revealing that the Spt and Taf subunits form the structural core of the complex. These results provide the necessary restraints for us to generate a model of the spatial arrangement of all SAGA subunits. According to this model, the chromatin-binding domains of SAGA are all clustered in one face of the complex that is highly flexible. Our results relate information of overall SAGA structure with detailed subunit level interactions, improving our understanding of its architecture and flexibility.

Mashups enable end-users to "mix and match" data and services available on the web to create applications. Their creation is supported by a complex ecosystem of i) data providers who offer open APIs to users, ii) users who combine APIs into mashups, and iii) platforms, such as the ProgrammableWeb or Mashape, that facilitate the construction and publication of mashups. In this article, we argue that the evolution of the mashup ecosystem can be explained in terms of ecosystem niches anchored around hub or keystone APIs. The members of a niche are focused on an area of specialization (e.g., mapping applications) and contribute their knowledge to the value proposition of the ecosystem as a whole. To demonstrate the formation of niches in the mashup ecosystem, we model groups of related mashups as species, and we reconstruct the evolution of mashup species through phylogenetic analysis.

Worldwide, stocking of fish represents a valuable tool for conservation and maintenance of species exploited by recreational fishing. Releases of hatchery-reared fish are more and more recognized to have numerous demographic, ecological, and genetic impacts on wild populations. However, consequences on intraspecific trophic relationships have rarely been investigated. In this study, we assessed the impacts of supplementation stocking and resulting introgressive hybridization on the trophic niches occupied by stocked, local, and hybrid lake trout (Salvelinus namaycush) within populations of piscivorous and planktivorous ecotypes stocked from a wild piscivorous source population. We compared trophic niches using stable isotope analysis (δ13 C and δ15 N) and trophic position among the three genetic origins. Putative genetic effects were tested with phenotype-genotype association of "life history" ecological traits (body size, growth rate, condition index, and trophic niche) and genotypes (RADseq SNP markers) using redundant discriminant analysis (RDA). Results showed that sympatry resulting from the stocking of contrasting ecotypes is a risk factor for niche partitioning. Planktivorous populations are more susceptible to niche partitioning, by competitive exclusion of the local fish from a littoral niche to an alternative pelagic/profundal niche. Observed niche partitioning is probably a manifestation of competitive interactions between ecotypes. Our results emphasize that ecotypic variation should be considered for more efficient management and conservation practices and in order to mitigate negative impact of supplementation stocking.

Abstract Background While mental health challenges in the classroom have increased over the past several years, existing research suggests that many educators feel unprepared to broach the topics of mental health and mental illness with their students. This paper outlines the development and gathering of preliminary evidence of validity for two new scales designed to assess teachers’ confidence and worries related to delivering mental health content in the classroom. Methods Content evidence was collected through the use of two methods: a focus group held with members of the Elementary Teachers’ Federation of Ontario, and a consensus survey conducted among a sample of educational experts recruited from an Ontario university. Internal structure evidence was derived from the initial intake survey of an evaluation of a new online guide designed to give elementary school teachers the tools and knowledge to develop lesson plans related to mental health. Internal consistency reliability of test scores was estimated with Cronbach’s alpha. Results Both scales loaded on a single dimension with all items loading strongly (factor loadings greater than .60). Cronbach’s alpha coefficients of .96 for scores on the Teacher Confidence Scale and .93 for scores on the What Worries Me Scale estimated strong internal consistency reliability. Conclusions We identified two unidimensional scales measuring concerns educators may have about discussing the topic of mental health in a classroom setting. The Teacher Confidence Scale for Delivering Mental Health Content contains 12 items measuring educators’ confidence in delivering mental health related materials in the classroom. The What Worries Me Scale contains 11 items. These scales may be useful for evaluating programs, educational workshops, and other initiatives aimed at improving teachers’ abilities to provide mental health content in the classroom.