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Summary The bone disorder osteogenesis imperfecta (OI) is genetically heterogeneous. Most affected individuals have an autosomal dominant disorder caused by heterozygous variants in either of the type I collagen genes (COL1A1 or COL1A2). To date, two reports have linked Mesoderm Development LRP Chaperone (MESD) to autosomal recessive OI type XX. Four different biallelic pathogenic variants in MESD were shown to cause a progressively deforming phenotype, associated with recurrent fractures and oligodontia in five individuals in five families. Recently, compound heterozygosity for a frameshift predicted to lead to a premature termination codon in exon 2 of the 3-exon gene and a second frameshift in the terminal exon in MESD were detected in three stillbirths in one family with severe OI consistent with the neonatal lethal phenotype. We have identified four additional individuals from four independent families with biallelic variants in MESD: the earlier reported c.632dupA (p.Lys212Glufs∗19) and c.676C>T (p.Arg226∗)—which are associated with a severe form of OI—and one new pathogenic variant, c.603-606delTAAA (p.Asn201Lysfs∗15), which causes a neonatal lethal form of OI. MESD acts in the WNT signaling pathway, where it is thought to play a role in the folding of the WNT co-receptors low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/LRP6) and in chaperoning their transit to the cell surface. Our report broadens the phenotypic and genetic spectrum of MESD-related OI, provides additional insight into the pathogenic pathways, and underscores the necessity of MESD for normal WNT signaling in bone formation., Mesoderm Development LRP Chaperone (MESD) has been linked to autosomal recessive osteogenesis imperfecta type XX. Our report describes four new individuals and broadens the phenotypic and genetic spectrum of MESD-related OI, provides additional insight into the pathogenic pathways, and underscores the necessity of MESD for normal WNT signaling in bone formation. more...

WOS: 000333998400002, Since its discovery within a travertine quarry, the fragmentary cranium of the only known Turkish Homo erectus, the Kocabas hominid, has led to conflicting biochronological estimations. First estimated to be similar to 500 lea old, the partial skull presents a combination of archaic and evolved features that puts it as an intermediate specimen between the Drnanisi fossils (Homo georgicus) and the Chinese Zhoukoudian skulls (Homo erectus) respectively dated to 1.8 to similar to 0.8 Ma. Here we present a multidisciplinary study combining sedimentological, paleontological and paleoanthropological observations together with cosmogenic nuclide concentration and paleomagnetic measurements to provide an absolute chronological framework for the Upper fossiliferous Travertine unit where the Kocabas hominid and fauna were discovered. The Al-26/(10) Be burial ages determined on pebbles from conglomeratic levels framing the Upper fossiliferous Travertine unit, which exhibits an inverse polarity, constrains its deposition to before the Cobb Mountain sub-chron, that is between 1.22 and similar to 1.5 Ma. The alternative match of the normal polarity recorded above the travertine with the Jaramillo subchron (lower limit 1.07 Ma) may also be marginally compatible with cosmogenic nuclides interpretation, thus the proposed minimum age of 1.1 Ma for the end of massive travertine deposition. The actual age of the fossils is likely to be in the 1.1-1.3 Ma range. This absolute date is in close agreement with the paleoanthropological conclusions based on morphometric comparisons implying that Kocabas hominid belongs to the Homo erectus s.l. group that includes Chinese and African fossils, and is different from Middle and Upper Pleistocene specimens. Furthermore, this date is confirmed by the large mammal assemblage, typical of the late Villafranchian. Because it attests to the antiquity of human occupation of the Anatolian Peninsula and one of the waves of settlements out of Africa, this work challenges the current knowledge of the Homo erectus dispersal over Eurasia. (C) 2014 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/)., Scientific and Technical Research Council of TurkeyTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [110Y335, 12-05-91372-ST_a]; French Scientific Research National Center (CNRS) [110Y335, 12-05-91372-ST_a]; Pernod-Ricard company; Turkish Academy of Sciences (TUBA-GEBIP)Turkish Academy of Sciences; Ege UniversityEge University [TTM/001/2010, TTM/002/2011], The study was supported by international bilateral cooperation project between the Scientific and Technical Research Council of Turkey and the French Scientific Research National Center (CNRS) with research grant number of TUBITAK-CNRS 110Y335, and grant of RFBI 12-05-91372-ST_a. We are grateful to the Pernod-Ricard company which supports also this research program. M.C.A. thanks the grant of Outstanding Young Scientist Award from the Turkish Academy of Sciences (TUBA-GEBIP). We particularly thank Koray Ates and the logistic support of Faber Marble Group. S.M. thanks the Ege University projects TTM/001/2010, TTM/002/2011. We are deeply grateful to T. Tanju Kaya (Ege Univ. Natural Hist. Museum), for providing us all the comparative material from the Museum catalogue. The AMS measurements were performed thanks to the ASTER Team (M. Arnold, G. Aumaitre, and K. Keddadouche) at the ASTER AMS national facility (CEREGE, Aix-en-Provence) that is supported by the INSU/CNRS, the French Ministry of Research and Higher Education, IRD and CEA. We also thank L. Leanni for her help during the chemical processing, Ph. Dussoulliez for artwork support, and N. Marriner for proof-reading the manuscript. The new reconstruction of the Kocabas skull was done with the help of Patricia Wils from the French National Museum of Natural History. We acknowledge the patience and effort of the editor B. Marty in the reviewing process, as well as reviewers for their challenging questions and suggestions. more...

International audience; The Cueva del Angel archaeological site is an open-air sedimentary sequence, remnant of a collapsed cave and part of a karst complex. The faunal assemblage dominated by Equus ferus, large bovids and cervids has been subjected to intense anthropic actions reflecting selective predation. The fauna may be correlated with European faunistic associations of the end of the Middle Pleistocene to the beginning of the Upper Pleistocene. The Cueva del Angel lithic assemblage (dominated by non-modified flakes and abundant retouched tools with the presence of 46 handaxes) appears to fit well within the regional diversity of a well developed non-Levallois final Acheulean industry. A preliminary 230Th/234U age estimate, the review of the lithic assemblage and faunal evidence would favour a chronological positioning of the site in a period stretching from the end of the Middle Pleistocene to the beginning of the Upper Pleistocene (MIS 11-MIS 5). The Acheulean lithic assemblage found at the Cueva del Angel fits very well with the hypothesis of a continuation of Acheulean cultural traditions in the site, distinct from the contemporaneous uniquely Mousterian complexes witnessed in other parts of the Iberian Peninsula, and Western Europe. more...

International audience; Refined radio-isotopic dating techniques have been applied to Orgnac 3, a Late Acheulean and Early Middle Palaeolithic site in France. Evidence of Levallois core technology appeared in level 4b in the middle of the sequence, became predominant in the upper horizons, and was best represented in uppermost level 1, making the site one of the oldest examples of Levallois technology. In our dating study, fourteen speleothem samples from levels 7, 6 and 5b, were U/Th-dated. Four pure calcite samples from the speleothem PL1 (levels 5b, 6) yield ages between 265 ± 4 (PL1-3) and 312 ± 15 (PL1-6) thousand years ago (ka). Three samples from the top of a second stalagmite, PL2, yield dates ranging from 288 ± 10 ka (PL2-1) to 298 ± 17 ka (PL2-3). Three samples from the base of PL2 (level 7) yield much younger U/Th dates between 267 and 283 ka. These dates show that the speleothems PL1 and PL2 are contemporaneous and formed during marine isotope stage (MIS) 9 and MIS 8. Volcanic minerals in level 2, the upper sequence, were dated by the 40Ar/39Ar method, giving a weighted mean of 302.9 ± 2.5 ka (2σ) and an inverse isochron age of 302.9 ± 5.9 ka (2σ). Both 40Ar/39Ar dating of volcanic sanidines and U/Th dating of relatively pure and dense cave calcites are known to be well established. The first parallel application of the two geochronometers to Orgnac 3 yields generally consistent results, which point to the reliability of the two methods. The difference between their age results is discussed. more...