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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.