The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy

Hereditary inclusion body myopathy (HIBM; OMIM 600737) is a unique group of neuromuscular disorders characterized by adult onset, slowly progressive distal and proximal weakness and a typical muscle pathology including rimmed vacuoles and filamentous inclusions. The autosomal recessive form described in Jews of Persian descent is the HIBM prototype. This myopathy affects mainly leg muscles, but with an unusual distribution that spares the quadriceps. This particular pattern of weakness distribution, termed quadriceps-sparing myopathy (QSM), was later found in Jews originating from other Middle Eastern countries as well as in non-Jews. We previously localized the gene causing HIBM in Middle Eastern Jews on chromosome 9p12-13 (ref. 5) within a genomic interval of about 700 kb (ref. 6). Haplotype analysis around the HIBM gene region of 104 affected people from 47 Middle Eastern families indicates one unique ancestral founder chromosome in this community. By contrast, single non-Jewish families from India, Georgia (USA) and the Bahamas, with QSM and linkage to the same 9p12-13 region, show three distinct haplotypes. After excluding other potential candidate genes, we eventually identified mutations in the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) gene in the HIBM families: all patients from Middle Eastern descent shared a single homozygous missense mutation, whereas distinct compound heterozygotes were identified in affected individuals of families of other ethnic origins. Our findings indicate that GNE is the gene responsible for recessive HIBM.     

Common variants near MC4R are associated with fat mass, weight and risk of obesity

To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits.     

Orbital forcing of Cretaceous river discharge in tropical Africa and ocean response

The tropics have been suggested as the drivers of global ocean and atmosphere circulation and biogeochemical cycling during the extreme warmth of the Cretaceous period; but the links between orbital forcing, freshwater runoff and the biogeochemistry of continental margins in extreme greenhouse conditions are not fully understood. Here we present Cretaceous records of geochemical tracers for freshwater runoff obtained from a sediment core off the Ivory Coast that indicate that alternating periods of arid and humid African climate were driven by orbital precession. Our simulations of the precession-driven patterns of river discharge with a global climate model suggest that ocean anoxia and black shale sedimentation were directly caused by high river discharge, and occurred specifically when the northern equinox coincided with perihelion (the minimum distance between the Sun and the Earth). We conclude that, in a warm climate, the oceans off tropical continental margins respond rapidly and sensitively to even modest changes in river discharge.     

Professional forecasters' expectations,consistency, and international spillovers

This paper focuses on the expectation formation process of professional forecasters by relying on survey data on forecasts regarding gross domestic product growth, consumer price index inflation and 3-month interest rates for a broad set of countries. We examine the interrelation between macroeconomic forecasts and also the impact of uncertainty on forecasts by allowing for cross-country interdependencies and time variation in the coefficients. We find that professional forecasts are often in line with the Taylor rule and identify significant expectation spillovers from monetary policy in the USA.     

Following the signal sequence from ribosomal tunnel exit to signal recognition particle

Membrane and secretory proteins can be co-translationally inserted into or translocated across the membrane. This process is dependent on signal sequence recognition on the ribosome by the signal recognition particle (SRP), which results in targeting of the ribosome-nascent-chain complex to the protein-conducting channel at the membrane. Here we present an ensemble of structures at subnanometre resolution, revealing the signal sequence both at the ribosomal tunnel exit and in the bacterial and eukaryotic ribosome-SRP complexes. Molecular details of signal sequence interaction in both prokaryotic and eukaryotic complexes were obtained by fitting high-resolution molecular models. The signal sequence is presented at the ribosomal tunnel exit in an exposed position ready for accommodation in the hydrophobic groove of the rearranged SRP54 M domain. Upon ribosome binding, the SRP54 NG domain also undergoes a conformational rearrangement, priming it for the subsequent docking reaction with the NG domain of the SRP receptor. These findings provide the structural basis for improving our understanding of the early steps of co-translational protein sorting.     

Neue Gesichtspunkte zum 5. Buch Euklids

Summary The author's purpose is to read the main work of Euclid with modern eyes and to find out what knowledge a mathematician of today, familiar with the works of V. D. Waerden and Bourbaki, can gain by studying Euclid's theory of magnitudes, and what new insight into Greek mathematics occupation with this subject can provide.The task is to analyse and to axiomatize by modern means (i) in a narrower sense Book V. of the Elements, i.e. the theory of proportion of Eudoxus, (ii) in a wider sense the whole sphere of magnitudes which Euclid applies in his Elements. This procedure furnishes a clear picture of the inherent structure of his work, thereby making visible specific characteristics of Greek mathematics.After a clarification of the preconditions and a short survey of the historical development of the theory of proportions (Part I of this work), an exact analysis of the definitions and propositions of Book V. of the Elements is carried out in Part II. This is done word by word. The author applies his own system of axioms, set up in close accordance with Euclid, which permits one to deduce all definitions and propositions of Euclid's theory of magnitudes (especially those of Books V. and VI.).In this way gaps and tacit assumptions in the work become clearly visible; above all, the logical structure of the system of magnitudes given by Euclid becomes evident: not ratio — like something sui generis — is the governing concept of Book V., but magnitudes and their relation of having a ratio form the base of the theory of proportions. These magnitudes represent a well defined structure, a so-called Eudoxic Semigroup with the numbers as operators; it can easily be imbedded in a general theory of magnitudes equally applicable to geometry and physics.The transition to ratios — a step not executed by Euclid — is examined in Part III; it turns out to be particularly unwieldy. An elegant way opens up by interpreting proportion as a mapping of totally ordered semigroups. When closely examined, this mapping proves to be an isomorphism, thus suggesting the application of the modern theory of homomorphism. This theory permits a treatment of the theory of proportions as developed by Eudoxus and Euclid which is hardly surpassable in brevity and elegance in spite of its close affinity to Euclid. The generalization to a classically founded theory of magnitudes is now self-evident.

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Vorgelegt von J. E. Hofmann     

Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways

To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.