Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia

The brachyolmias constitute a clinically and genetically heterogeneous group of skeletal dysplasias characterized by a short trunk, scoliosis and mild short stature. Here, we identify a locus for an autosomal dominant form of brachyolmia on chromosome 12q24.1-12q24.2. Among the genes in the genetic interval, we selected TRPV4, which encodes a calcium permeable cation channel of the transient receptor potential (TRP) vanilloid family, as a candidate gene because of its cartilage-selective gene expression pattern. In two families with the phenotype, we identified point mutations in TRPV4 that encoded R616Q and V620I substitutions, respectively. Patch clamp studies of transfected HEK cells showed that both mutations resulted in a dramatic gain of function characterized by increased constitutive activity and elevated channel activation by either mechano-stimulation or agonist stimulation by arachidonic acid or the TRPV4-specific agonist 4alpha-phorbol 12,13-didecanoate (4alphaPDD). This study thus defines a previously unknown mechanism, activation of a calcium-permeable TRP ion channel, in skeletal dysplasia pathogenesis.     

Common nonsynonymous variants in PCSK1 confer risk of obesity

Mutations in PCSK1 cause monogenic obesity. To assess the contribution of PCSK1 to polygenic obesity risk, we genotyped tag SNPs in a total of 13,659 individuals of European ancestry from eight independent case-control or family-based cohorts. The nonsynonymous variants rs6232, encoding N221D, and rs6234-rs6235, encoding the Q665E-S690T pair, were consistently associated with obesity in adults and children (P = 7.27 x 10(-8) and P = 2.31 x 10(-12), respectively). Functional analysis showed a significant impairment of the N221D-mutant PC1/3 protein catalytic activity.     

Bayesian Forecasting for Time Series of Categorical Data

Time series of categorical data is not a widely studied research topic. Particularly, there is no available work on the Bayesian analysis of categorical time series processes. With the objective of filling that gap, in the present paper we consider the problem of Bayesian analysis including Bayesian forecasting for time series of categorical data, which is modelled by Pegram's mixing operator, applicable for both ordinal and nominal data structures. In particular, we consider Pegram's operator‐based autoregressive process for the analysis. Real datasets on infant sleep status are analysed for illustrations. We also illustrate that the Bayesian forecasting is more accurate than the corresponding frequentist's approach when we intend to forecast a large time gap ahead. Copyright © 2016 John Wiley & Sons, Ltd.     

Autotaxin

Autotaxin is a protein of approximately 900 amino acids discovered in the early 1990s. Over the past 15 years, a strong association between cancer cells and autotaxin production has been observed. Recent publications indicate that autotaxin and the capacity of cancer to metastasise are intimately linked. The discovery of new molecular targets in pharmacology is a mixture of pure luck, hard work and industrial strategy. Despite a crucial and desperate need for new therapeutic tools, many targets are approached in oncology, but only a few are validated and end up at the patient bed. Outside the busy domain of kinases, few targets have been discovered that can be useful in treating cancer, particularly metastatic processes. The fortuitous relationship between autotaxin and lysophosphatidic acid renders the results of observations made in the diabetes/obesity context considerably important. The literature provides observations that may aid in redesigning experiments to validate autotaxin as a potential oncology target.     

Changes to cellular water and element content induced by nucleolar stress: investigation by a cryo-correlative nano-imaging approach

The cell is a crowded volume, with estimated mean mass percentage of macromolecules and of water ranging from 7.5 to 45 and 55 to 92.5 %, respectively. However, the concentrations of macromolecules and water at the nanoscale within the various cell compartments are unknown. We recently developed a new approach, correlative cryo-analytical scanning transmission electron microscopy, for mapping the quantity of water within compartments previously shown to display GFP-tagged protein fluorescence on the same ultrathin cryosection. Using energy-dispersive X-ray spectrometry (EDXS), we then identified various elements (C, N, O, P, S, K, Cl, Mg) in these compartments and quantified them in mmol/l. Here, we used this new approach to quantify water and elements in the cytosol, mitochondria, condensed chromatin, nucleoplasm, and nucleolar components of control and stressed cancerous cells. The water content of the control cells was between 60 and 83 % (in the mitochondria and nucleolar fibrillar centers, respectively). Potassium was present at concentrations of 128–462 mmol/l in nucleolar fibrillar centers and condensed chromatin, respectively. The induction of nucleolar stress by treatment with a low dose of actinomycin-D to inhibit rRNA synthesis resulted in both an increase in water content and a decrease in the elements content in all cell compartments. We generated a nanoscale map of water and elements within the cell compartments, providing insight into their changes induced by nucleolar stress.     

La phosphatase des os et le mécanisme général de l'ossification

Summary A general survey of the actual knowledges on the bone phosphatase is given. The enzyme plays an important rôle in the calcification of bone and teeth, this process being unable to proceed at a physiological speed without the participation of a phosphatase. The biological function of the enzyme is thus to accelerate and not to promote the calcification.The knowledge of the mechanism of phosphatase activity in the skeletal organs and of the chemical composition of the bone salt cannot lead to a full understanding of the physiology of ossification. A prominent function in this field is devoted to the proteins of the ground substance of bone and to their evolution. The study of the protein matrix of bone is now the most important subject of work for the biochemistry of ossification.

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Conférence faite le 28 mai 1946 au Hallerianum de l'Université de Berne.