Mutations in MEGF10, a regulator of satellite cell myogenesis, cause early onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD)

Infantile myopathies with diaphragmatic paralysis are genetically heterogeneous, and clinical symptoms do not assist in differentiating between them. We used phased haplotype analysis with subsequent targeted exome sequencing to identify MEGF10 mutations in a previously unidentified type of infantile myopathy with diaphragmatic weakness, areflexia, respiratory distress and dysphagia. MEGF10 is highly expressed in activated satellite cells and regulates their proliferation as well as their differentiation and fusion into multinucleated myofibers, which are greatly reduced in muscle from individuals with early onset myopathy, areflexia, respiratory distress and dysphagia.     

Multiple Hypothesis Testing of Market Risk Forecasting Models

Extending previous risk model backtesting literature, we construct multiple hypothesis testing (MHT) with the stationary bootstrap. We conduct multiple tests which control for the generalized confidence level and employ the bootstrap MHT to design multiple comparison testing. We consider absolute and relative predictive ability to test a range of competing risk models, focusing on value‐at‐risk and expected shortfall (ExS). In devising the test for the absolute predictive ability, we take the route of recent literature and construct balanced simultaneous confidence sets that control for the generalized family‐wise error rate, which is the joint probability of rejecting true hypotheses. We implement a step‐down method which increases the power of the MHT in isolating false discoveries. In testing for the ExS model predictive ability, we design a new simple test to draw inference about recursive model forecasting capability. In the second suite of statistical testing, we develop a novel device for measuring the relative predictive ability in the bootstrap MHT framework. The device, which we coin multiple comparison mapping, provides a statistically robust instrument designed to answer the question: ‘Which model is the best model?’ Copyright © 2016 John Wiley & Sons, Ltd.     

ISPD loss-of-function mutations disrupt dystroglycan O-mannosylation and cause Walker-Warburg syndrome

Walker-Warburg syndrome (WWS) is clinically defined as congenital muscular dystrophy that is accompanied by a variety of brain and eye malformations. It represents the most severe clinical phenotype in a spectrum of diseases associated with abnormal post-translational processing of a-dystroglycan that share a defect in laminin-binding glycan synthesis1. Although mutations in six genes have been identified as causes of WWS, only half of all individuals with the disease can currently be diagnosed on this basis2. A cell fusion complementation assay in fibroblasts from undiagnosed individuals with WWS was used to identify five new complementation groups. Further evaluation of one group by linkage analysis and targeted sequencing identified recessive mutations in the ISPD gene (encoding isoprenoid synthase domain containing). The pathogenicity of the identified ISPD mutations was shown by complementation of fibroblasts with wild-type ISPD. Finally, we show that recessive mutations in ISPD abolish the initial step in laminin-binding glycan synthesis by disrupting dystroglycan O-mannosylation. This establishes a new mechanism for WWS pathophysiology.     

CEP41 is mutated in Joubert syndrome and is required for tubulin glutamylation at the cilium

Tubulin glutamylation is a post-translational modification that occurs predominantly in the ciliary axoneme and has been suggested to be important for ciliary function. However, its relationship to disorders of the primary cilium, termed ciliopathies, has not been explored. Here we mapped a new locus for Joubert syndrome (JBTS), which we have designated as JBTS15, and identified causative mutations in CEP41, which encodes a 41-kDa centrosomal protein. We show that CEP41 is localized to the basal body and primary cilia, and regulates ciliary entry of TTLL6, an evolutionarily conserved polyglutamylase enzyme. Depletion of CEP41 causes ciliopathy-related phenotypes in zebrafish and mice and results in glutamylation defects in the ciliary axoneme. Our data identify CEP41 mutations as a cause of JBTS and implicate tubulin post-translational modification in the pathogenesis of human ciliary dysfunction.     

Peirce on the justification of abduction

What sort of justification can be claimed for abduction? In this paper we reconstruct Peirce’s answer to this question. We show that in his early works on the logic of science Peirce provided an abductive justification of abduction, and that in his mature writings the early solution is enriched by a reference to the place abduction has in a typical scientific inquiry. Since abduction is the first stage of inquiry by which a hypothesis is suggested and which then has to be subjected to inductive testing, the fundamental abduction (ur-abduction) that justifies abduction has also to be subjected to a verification by means of a fundamental induction (ur-induction), namely that the abduction that abduction is valid is verified by an appeal to the history of science.     

Mesenchymal stem cells from preterm to term newborns undergo a significant switch from anaerobic glycolysis to the oxidative phosphorylation

We evaluated the energy metabolism of human mesenchymal stem cells (MSC) isolated from umbilical cord (UC) of preterm (< 37 weeks of gestational age) and term (≥ 37 weeks of gestational age) newborns, using MSC from adult bone marrow as control. A metabolic switch has been observed around the 34th week of gestational age from a prevalently anaerobic glycolysis to the oxidative phosphorylation. This metabolic change is associated with the organization of mitochondria reticulum: preterm MSCs presented a scarcely organized mitochondrial reticulum and low expression of proteins involved in the mitochondrial fission/fusion, compared to term MSCs. These changes seem governed by the expression of CLUH, a cytosolic messenger RNA-binding protein involved in the mitochondria biogenesis and distribution inside the cell; in fact, CLUH silencing in term MSC determined a metabolic fingerprint similar to that of preterm MSC. Our study discloses novel information on the production of energy and mitochondrial organization and function, during the passage from fetal to adult life, providing useful information for the management of preterm birth.     

FRET studies of various conformational states adopted by transthyretin

Transthyretin (TTR) is an extracellular protein able to deposit into well-defined protein aggregates called amyloid, in pathological conditions known as senile systemic amyloidosis, familial amyloid polyneuropathy, familial amyloid cardiomyopathy and leptomeningeal amyloidosis. At least three distinct partially folded states have been described for TTR, including the widely studied amyloidogenic state at mildly acidic pH. Here, we have used fluorescence resonance energy transfer (FRET) experiments in a monomeric variant of TTR (M-TTR) and in its W41F and W79F mutants, taking advantage of the presence of a unique, solvent-exposed, cysteine residue at position 10, that we have labelled with a coumarin derivative (DACM, acceptor), and of the two natural tryptophan residues at positions 41 and 79 (donors). Trp41 is located in an ideal position as it is one of the residues of β-strand C, whose degree of unfolding is debated. We found that the amyloidogenic state at low pH has the same FRET efficiency as the folded state at neutral pH in both M-TTR and W79F-M-TTR, indicating an unmodified Cys10–Trp41 distance. The partially folded state populated at low denaturant concentrations also has a similar FRET efficiency, but other spectroscopic probes indicate that it is distinct from the amyloidogenic state at acidic pH. By contrast, the off-pathway state accumulating transiently during refolding has a higher FRET efficiency, indicating non-native interactions that reduce the Cys10–Trp41 spatial distance, revealing a third distinct conformational state. Overall, our results clarify a negligible degree of unfolding of β-strand C in the formation of the amyloidogenic state and establish the concept that TTR is a highly plastic protein able to populate at least three distinct conformational states.     

Early dispersal of modern humans in Europe and implications for Neanderthal behaviour

The appearance of anatomically modern humans in Europe and the nature of the transition from the Middle to Upper Palaeolithic are matters of intense debate. Most researchers accept that before the arrival of anatomically modern humans, Neanderthals had adopted several 'transitional' technocomplexes. Two of these, the Uluzzian of southern Europe and the Chatelperronian of western Europe, are key to current interpretations regarding the timing of arrival of anatomically modern humans in the region and their potential interaction with Neanderthal populations. They are also central to current debates regarding the cognitive abilities of Neanderthals and the reasons behind their extinction. However, the actual fossil evidence associated with these assemblages is scant and fragmentary, and recent work has questioned the attribution of the Chatelperronian to Neanderthals on the basis of taphonomic mixing and lithic analysis. Here we reanalyse the deciduous molars from the Grotta del Cavallo (southern Italy), associated with the Uluzzian and originally classified as Neanderthal. Using two independent morphometric methods based on microtomographic data, we show that the Cavallo specimens can be attributed to anatomically modern humans. The secure context of the teeth provides crucial evidence that the makers of the Uluzzian technocomplex were therefore not Neanderthals. In addition, new chronometric data for the Uluzzian layers of Grotta del Cavallo obtained from associated shell beads and included within a Bayesian age model show that the teeth must date to ~45,000-43,000 calendar years before present. The Cavallo human remains are therefore the oldest known European anatomically modern humans, confirming a rapid dispersal of modern humans across the continent before the Aurignacian and the disappearance of Neanderthals.     

Ambra1 regulates autophagy and development of the nervous system

Autophagy is a self-degradative process involved both in basal turnover of cellular components and in response to nutrient starvation or organelle damage in a wide range of eukaryotes. During autophagy, portions of the cytoplasm are sequestered by double-membraned vesicles called autophagosomes, and are degraded after fusion with lysosomes for subsequent recycling. In vertebrates, this process acts as a pro-survival or pro-death mechanism in different physiological and pathological conditions, such as neurodegeneration and cancer; however, the roles of autophagy during embryonic development are still largely uncharacterized. Beclin1 (Becn1; coiled-coil, myosin-like BCL2-interacting protein) is a principal regulator in autophagosome formation, and its deficiency results in early embryonic lethality. Here we show that Ambra1 (activating molecule in Beclin1-regulated autophagy), a large, previously unknown protein bearing a WD40 domain at its amino terminus, regulates autophagy and has a crucial role in embryogenesis. We found that Ambra1 is a positive regulator of the Becn1-dependent programme of autophagy, as revealed by its overexpression and by RNA interference experiments in vitro. Notably, Ambra1 functional deficiency in mouse embryos leads to severe neural tube defects associated with autophagy impairment, accumulation of ubiquitinated proteins, unbalanced cell proliferation and excessive apoptotic cell death. In addition to identifying a new and essential element regulating the autophagy programme, our results provide in vivo evidence supporting the existence of a complex interplay between autophagy, cell growth and cell death required for neural development in mammals.