Recent discovery of an argyrolagid (Mammalia, Metatheria) for the Marplatan stage (middle Pliocene-early Pleistocene) of northwestern Argentina

We present the first remains of an argyrolagid from the Uquía Formation (middle Pliocene-early Pleistocene; Marplatan) recovered at San Roque, Humahuaca, Jujuy Province, Argentina. The material is part of a microvertebrate fossil assemblage generated by trophic activity of predator birds that also includes amphibians, lizards, birds, rodents and didelphids. The remains represent three individuals and include fragments of maxilla and dentaries, and postcranial fragmentary bones (humeri, astragali, calcanei, and ungueal phalanges). The upper teeth show a simplified occlusal morphology, typical of this family. The most conspicuous features of lower teeth are: the presence of procumbent incisors, a mesiolabial expansion defining a shallow groove on m1, deep lingual groove absent on m1 and m2 but present on m3 and m4, m4 reduced with a deep labial groove and a shallow distal concavity. The morphology of lower molars (particularly, on m4 the deep labial groove and the distal shallow concavity) allows us to refer the material to Microtragulus bolivianus Hoffstetter and Villarroel. This species differs from other species of Microtragulus by: the absence of lingual groove on m1, labial groove of mesial lobe on m2, and lingual groove on m2, and the presence of larger m4 with a labial groove (M. reigi Simpson); its larger size, the deepest labial groove, and the presence of lingual groove on m3 and labial groove on m4 (M. catamarcensis [Kraglievich]); and by the absence of lingual groove on m1 and the presence of deeper labial grooves (M. rusconii Goin, Montalvo and Visconti). Rodents recorded in this assemblage (Microcavia, octodontids) are nowadays typical dwellers of dry and open areas, suggesting similar paleoenvironmental conditions for these levels of the Uquía Formation. The presence of Microtragulus bolivianus in western Bolivia and northwestern Argentina suggests that a continuous area of xeric conditions was already established in this region by the end of the Pliocene.Sesiones libresFacultad de Ciencias Naturales y Muse

Structure of mammalian respiratory complex I.

Complex I (NADH:ubiquinone oxidoreductase), one of the largest membrane-bound enzymes in the cell, powers ATP synthesis in mammalian mitochondria by using the reducing potential of NADH to drive protons across the inner mitochondrial membrane. Mammalian complex I (ref. 1) contains 45 subunits, comprising 14 core subunits that house the catalytic machinery (and are conserved from bacteria to humans) and a mammalian-specific cohort of 31 supernumerary subunits. Knowledge of the structures and functions of the supernumerary subunits is fragmentary. Here we describe a 4.2-Å resolution single-particle electron cryomicroscopy structure of complex I from Bos taurus. We have located and modelled all 45 subunits, including the 31 supernumerary subunits, to provide the entire structure of the mammalian complex. Computational sorting of the particles identified different structural classes, related by subtle domain movements, which reveal conformationally dynamic regions and match biochemical descriptions of the 'active-to-de-active' enzyme transition that occurs during hypoxia. Our structures therefore provide a foundation for understanding complex I assembly and the effects of mutations that cause clinically relevant complex I dysfunctions, give insights into the structural and functional roles of the supernumerary subunits and reveal new information on the mechanism and regulation of catalysis

Cryo-EM structures of complex I from mouse heart mitochondria in two biochemically defined states.

Complex I (NADH:ubiquinone oxidoreductase) uses the reducing potential of NADH to drive protons across the energy-transducing inner membrane and power oxidative phosphorylation in mammalian mitochondria. Recent cryo-EM analyses have produced near-complete models of all 45 subunits in the bovine, ovine and porcine complexes and have identified two states relevant to complex I in ischemia-reperfusion injury. Here, we describe the 3.3-Å structure of complex I from mouse heart mitochondria, a biomedically relevant model system, in the 'active' state. We reveal a nucleotide bound in subunit NDUFA10, a nucleoside kinase homolog, and define mechanistically critical elements in the mammalian enzyme. By comparisons with a 3.9-Å structure of the 'deactive' state and with known bacterial structures, we identify differences in helical geometry in the membrane domain that occur upon activation or that alter the positions of catalytically important charged residues. Our results demonstrate the capability of cryo-EM analyses to challenge and develop mechanistic models for mammalian complex I

Predicted Benign and Synonymous Variants in CYP11A1 Cause Primary Adrenal Insufficiency Through Missplicing.

Primary adrenal insufficiency (PAI) is a potentially life-threatening condition that can present with nonspecific features and can be difficult to diagnose. We undertook next generation sequencing in a cohort of children and young adults with PAI of unknown etiology from around the world and identified a heterozygous missense variant (rs6161, c.940G>A, p.Glu314Lys) in CYP11A1 in 19 individuals from 13 different families (allele frequency within undiagnosed PAI in our cohort, 0.102 vs 0.0026 in the Genome Aggregation Database; P A, Thr330 = ; c.1173C>T, Ser391 =). Although p.Glu314Lys is predicted to be benign and showed no loss-of-function in an Escherichia coli assay system, in silico and in vitro studies revealed that the rs6161/c.940G>A variant, plus the c.990G>A and c.1173C>T changes, affected splicing and that p.Glu314Lys produces a nonfunctional protein in mammalian cells. Taken together, these findings show that compound heterozygosity involving a relatively common and predicted "benign" variant in CYP11A1 is a major contributor to PAI of unknown etiology, especially in European populations. These observations have implications for personalized management and demonstrate how variants that might be overlooked in standard analyses can be pathogenic when combined with other very rare disruptive changes.Medical Research Council UK Project (grant MR/K020455/1 to L.A.M.).J.C.A. is a Wellcome Trust Senior Research Fellow in Clinical Science (grants 098513/Z/12/Z and 209328/Z/17/Z) with research support from Great Ormond Street Hospital Children’s Charity (grant V2518) and the National Institute for Health Research, Great Ormond Street Hospital Biomedical Research Centre (grant IS-BRC-1215-20012).Funding also included support from The Mater Medical Research Institute (to M.H.) and National Institutes of Health (grant R01GM086596 to R.J.A.)

Conception of a high resolution x‐ray computed tomography device; application to damage initiation imaging inside materials

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