A de novo paradigm for mental retardation

The per-generation mutation rate in humans is high. De novo mutations may compensate for allele loss due to severely reduced fecundity in common neurodevelopmental and psychiatric diseases, explaining a major paradox in evolutionary genetic theory. Here we used a family based exome sequencing approach to test this de novo mutation hypothesis in ten individuals with unexplained mental retardation. We identified and validated unique non-synonymous de novo mutations in nine genes. Six of these, identified in six different individuals, are likely to be pathogenic based on gene function, evolutionary conservation and mutation impact. Our findings provide strong experimental support for a de novo paradigm for mental retardation. Together with de novo copy number variation, de novo point mutations of large effect could explain the majority of all mental retardation cases in the population.     

The Combinatorial Approach to Asymmetric Hydrogenation: More Miles out of Monophos

1Introduction In custom manufacturing time-to-market is of overriding importance. Thus, asymmetric hydrogenation will be applied only if an appropriate catalyst can be found in a very short period of time. For this reason we have build up a full-scale capability for High Throughput Experimentation, encompassing several robot systems. As ligand synthesis was the last remaining barrier we have explored, together with the University of Groningen, the use of simple monodentate ligands, such as MonoPhosTM. These ligands can be synthesised in two chemical steps, from BINOL, PCl3 and an amine.Surprisingly, very high enantioselectivities can be obtained in the asymmetric hydrogenation of α-and β-dehydro-amino acids and esters, aromatic enamides, itaconic acid and ester[1]. See Scheme 1 and 2(at page 830).     

Die Reizschwelle der Sinnesorgane als physikalisches Problem

Summary A survey is given of recent work on physical aspects of sensory processes. The reasoning which leads to the generally recognized view that one rod of the retina is excited by only one quantum of light is given in par. II. In par. IIIa summary is given of the papers byHecht andVan der Velden on the number of rods which must be struck in order to obtaina sensation of light. Par. III describes the role of the quantum character of light at higher intensities (de Vries), where it sets a limit to intensity discrimination and visual acuity. The influence of Brownian movement on the process of hearing is discussed in par. VI. It is found that the Brownian movement of the inner ear is close to the threshold actually observed (de Vries), whereas the Brownian motion of the air at the eardrum (seeSivian andWhite) is below the audible threshold. The role of the Brownian movementin the sense cells is described in par. VII; the results are used for an analysis of the mechanism of hearing (see alsode Vries); evidence is obtained that electric voltages are generated in the tectorial membrane (the well-known cochlear microphonics) and that they play an important part in the mechanism of energy transfer to the sense cells (similar voltages were also derived from the cupolæ in the lateral lines of fishes by the present author). Finally some physical arguments are sumarized againstYeagley's theory of bird navigation.     

Der Einfluß der Temperatur des Auges auf die spektrale Empfindlichkeitskurve

Summary The influence of the temperature of the eye on the spectral distribution of its sensitivity was studied. The leading idea was that the small long-wave light quanta could only decompose a molecule of the photochemical substances if this molecule had already a sufficient thermal energy. One must therefore expect the sensitivity for long wavelengths to be higher at high temperatures; moreover this influence of temperature is most pronounced for the longest wavelengths. In the measurements the sensitivity for the wavelengths of 660 mµ and 730 mµ were comparedwith each other. In the accompanying figure the slit width of the apparatus at 660 mµ is shown as a function of temperature. The experimental points are close to the lines which were predicted by the theory.     

Action of plastid phospholipase D on free and lipoprotein-bound phospholipids

Résumé Les phospholipides en état de lipoprotéine sont hydrolysés à un rythme plus accéléré par la phospholipase D des chloroplastes que ne le sont les phospholipides purifiécs. La remarquable affinité de l'enzyme pour les soustrats en forme lipoprotéique se manifeste en l'absence de l'éthère éthylique qui est l'activateur indispensable à l'hydrolyse des phospholipides purifiées.

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This work was supported by a research grant (AI-03171) from the U.S. National Institutes of Health.     

Fanconi anemia is associated with a defect in the BRCA2 partner PALB2

The Fanconi anemia and BRCA networks are considered interconnected, as BRCA2 gene defects have been discovered in individuals with Fanconi anemia subtype D1. Here we show that a defect in the BRCA2-interacting protein PALB2 is associated with Fanconi anemia in an individual with a new subtype. PALB2-deficient cells showed hypersensitivity to cross-linking agents and lacked chromatin-bound BRCA2; these defects were corrected upon ectopic expression of PALB2 or by spontaneous reversion.     

How Lemmings on Wheels Can Make a U-Turn Through Social Inclusion and Democracy

The challenge is (a) to balance both centralised control to preserve the global commons and (b) to involve people in policy making so that they feel culturally engaged and committed to the policy. Dictatorships and forms of World government from above to support the global commons are no more of an answer than forms of liberal democracy that do not engage people in between national elections. Passive voting does not help people in diverse democracies to engage in thinking through ‘if then scenarios’ about their social, economic and environmental future.     

Retinoic acid causes an anteroposterior transformation in the developing central nervous system

All-trans retinoic acid (RA) is well known as a biologically active form of vitamin A and a teratogen. The identification of nuclear receptors for this ligand suggests strongly that it is an endogenous signal molecule, and measurements of RA and teratogenic manipulations suggest further that RA is a morphogen specifying the anteroposterior axis during limb development. Besides the limb, RA and other retinoids affect development of other organs, including the central nervous system (CNS). None of these other effects has been investigated in detail. Our purpose here was to begin analysing the effects of RA on CNS development in Xenopus laevis. We find that RA acts on the developing CNS, transforming anterior neural tissue to a posterior neural specification. These and other findings raise the possibility that RA mediates an inductive interaction regulating anteroposterior differentiation within the CNS. Following recent reports implicating transforming growth factor-beta 2-like and fibroblast growth factor-like factors in mesoderm induction, this indicates that a different type of signal molecule (working through a nuclear receptor, not a plasma membrane receptor) might mediate inductive cell interactions during early embryonic development.     

Interleukin-4 mediates CD8 induction on human CD4+ T-cell clones

CD4 and CD8 antigens are simultaneously expressed on most of the cortical thymocytes, that weakly express the T-cell antigen receptor(TCR)/CD3 complex. Mature peripheral T cells, however, strongly express the TCR complex and are positive for either CD4 or CD8. Nevertheless, a small percentage of peripheral CD3+ T cells express CD4 and CD8 simultaneously. These mature, double positive cells could be intermediates between CD4+CD8+ thymocytes and mature, single positive T cells, or they may originate from single positive T cells that acquire either CD4 or CD8. Here we report that activation and culturing of cloned CD4+ T cells in interleukin-4 (IL-4), results in the acquisition of CD8 due to its de novo synthesis. The IL-4-induced co-expression of CD8 on CD4+ T cells is reversible, in that CD8 disappeared from double positive T-cell clones isolated in IL-4, when they were cultured in IL-2. CD8 induced by IL-4 can be functional as a monoclonal antibody to CD8 inhibited anti-CD3-mediated cytotoxicity by a double positive T-cell clone.