CCDC39 is required for assembly of inner dynein arms and the dynein regulatory complex and for normal ciliary motility in humans and dogs

Primary ciliary dyskinesia (PCD) is an inherited disorder characterized by recurrent infections of the upper and lower respiratory tract, reduced fertility in males and situs inversus in about 50% of affected individuals (Kartagener syndrome). It is caused by motility defects in the respiratory cilia that are responsible for airway clearance, the flagella that propel sperm cells and the nodal monocilia that determine left-right asymmetry. Recessive mutations that cause PCD have been identified in genes encoding components of the outer dynein arms, radial spokes and cytoplasmic pre-assembly factors of axonemal dyneins, but these mutations account for only about 50% of cases of PCD. We exploited the unique properties of dog populations to positionally clone a new PCD gene, CCDC39. We found that loss-of-function mutations in the human ortholog underlie a substantial fraction of PCD cases with axonemal disorganization and abnormal ciliary beating. Functional analyses indicated that CCDC39 localizes to ciliary axonemes and is essential for assembly of inner dynein arms and the dynein regulatory complex.     

Variation in genome-wide mutation rates within and between human families

J.B.S. Haldane proposed in 1947 that the male germline may be more mutagenic than the female germline. Diverse studies have supported Haldane's contention of a higher average mutation rate in the male germline in a variety of mammals, including humans. Here we present, to our knowledge, the first direct comparative analysis of male and female germline mutation rates from the complete genome sequences of two parent-offspring trios. Through extensive validation, we identified 49 and 35 germline de novo mutations (DNMs) in two trio offspring, as well as 1,586 non-germline DNMs arising either somatically or in the cell lines from which the DNA was derived. Most strikingly, in one family, we observed that 92% of germline DNMs were from the paternal germline, whereas, in contrast, in the other family, 64% of DNMs were from the maternal germline. These observations suggest considerable variation in mutation rates within and between families.     

Multiple newly identified loci associated with prostate cancer susceptibility

Prostate cancer is the most common cancer affecting males in developed countries. It shows consistent evidence of familial aggregation, but the causes of this aggregation are mostly unknown. To identify common alleles associated with prostate cancer risk, we conducted a genome-wide association study (GWAS) using blood DNA samples from 1,854 individuals with clinically detected prostate cancer diagnosed at 相似文献   

The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm

Recently, two common sequence variants on 9p21, tagged by rs10757278-G and rs10811661-T, were reported to be associated with coronary artery disease (CAD) and type 2 diabetes (T2D), respectively. We proceeded to further investigate the contributions of these variants to arterial diseases and T2D. Here we report that rs10757278-G is associated with, in addition to CAD, abdominal aortic aneurysm (AAA; odds ratio (OR) = 1.31, P = 1.2 x 10(-12)) and intracranial aneurysm (OR = 1.29, P = 2.5 x 10(-6)), but not with T2D. This variant is the first to be described that affects the risk of AAA and intracranial aneurysm in many populations. The association of rs10811661-T to T2D replicates in our samples, but the variant does not associate with any of the five arterial diseases examined. These findings extend our insight into the role of the sequence variant tagged by rs10757278-G and show that it is not confined to atherosclerotic diseases.     

La dualité des « Prolans » urinaires

Conclusions La préhypophyse sécrète deux hormones, l'auxogène et la crinogène. On peut, en détruisant ou éliminant le crinogène, obtenir des extraits à effet auxogène pur. L'urine de femme castrée ne contient que le principe auxogène: la lutéinisation, observée dans certains cas, est un effet secondaire dû à l'intervention de l'hypophyse de l'animal traité.L'urine de femme enceinte contient deux prolans: un principe crinogène identique à celui de l'hypophyse et agissant, comme ce dernier, directement sur l'ovaire; un principe hypophysotrope, stimulant l'hypophyse de l'animal — dans la mesure où elle est présente ou capable de réponse — et se traduisant dans l'ovaire par un effet auxogène de type physiologique.Les deux principes de l'UFE peuvent être séparés ou l'un peut être détruit avec conservation partielle de l'autre. Les taux des deux prolans varient d'une urine à l'autre, pour une même urine au cours de la gestation ou au cours du chauffage.L'existence de ces deux principes est importante à considérer lorsqu'on utilise, dans la pratique médicale, des extraits d'UFE qui sont, en réalité, des mélanges variables de deux hormones, dont les effets physiologiques et, par suite, les indications thérapentiques ne sont certainement pas les mémes.     

颈椎前路单节段融合中加压钉和限制型固定板的力学特性

研究了一款颈椎前路加压钉在颈椎前路融合手术中临近椎体的应力。分别采用传统结构的固定板和新结构加压钉,对12具人体颈椎标本实施C4-C5节段椎间盘切除术后的前路融合固定,利用生物力学试验机和高精度三维运动测试系统进行试验,比较了两种不同结构固定板(钉)植入颈椎后在前屈15°或后伸20°运动条件下的融合性能,以及在50N及100N的轴向载荷条件下二者的静态载荷分布。结果表明:在固定效果上,前路加压钉和限制型前路固定板两者功能相仿,不存在显著差异;针对C4-C5椎间植入体上所承受的压力,选用前路加压钉较选用限制型前路固定板为佳。     

New material of the earliest hominid from the Upper Miocene of Chad

Discoveries in Chad by the Mission Paleoanthropologique Franco-Tchadienne have substantially changed our understanding of early human evolution in Africa. In particular, the TM 266 locality in the Toros-Menalla fossiliferous area yielded a nearly complete cranium (TM 266-01-60-1), a mandible, and several isolated teeth assigned to Sahelanthropus tchadensis and biochronologically dated to the late Miocene epoch (about 7 million years ago). Despite the relative completeness of the TM 266 cranium, there has been some controversy about its morphology and its status in the hominid clade. Here we describe new dental and mandibular specimens from three Toros-Menalla (Chad) fossiliferous localities (TM 247, TM 266 and TM 292) of the same age. This new material, including a lower canine consistent with a non-honing C/P3 complex, post-canine teeth with primitive root morphology and intermediate radial enamel thickness, is attributed to S. tchadensis. It expands the hypodigm of the species and provides additional anatomical characters that confirm the morphological differences between S. tchadensis and African apes. S. tchadensis presents several key derived features consistent with its position in the hominid clade close to the last common ancestor of chimpanzees and humans.     

Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy

Although many genes that predispose for epilepsy in humans have been determined, those that underlie the classical syndromes of idiopathic generalized epilepsy (IGE) have yet to be identified. We report that an Ala322Asp mutation in GABRA1, encoding the alpha1 subunit of the gamma-aminobutyric acid receptor subtype A (GABA(A)), is found in affected individuals of a large French Canadian family with juvenile myoclonic epilepsy. Compared with wildtype receptors, GABA(A) receptors that contain the mutant subunit show a lesser amplitude of GABA-activated currents in vitro, indicating that seizures may result from loss of function of this inhibitory ligand-gated channel. Our results confirm that mutation of GABRA1 predisposes towards a common idiopathic generalized epilepsy syndrome in humans.     

Geology and palaeontology of the Upper Miocene Toros-Menalla hominid locality,Chad

All six known specimens of the early hominid Sahelanthropus tchadensis come from Toros-Menalla site 266 (TM 266), a single locality in the Djurab Desert, northern Chad, central Africa. Here we present a preliminary analysis of the palaeontological and palaeoecological context of these finds. The rich fauna from TM 266 includes a significant aquatic component such as fish, crocodiles and amphibious mammals, alongside animals associated with gallery forest and savannah, such as primates, rodents, elephants, equids and bovids. The fauna suggests a biochronological age between 6 and 7 million years. Taken together with the sedimentological evidence, the fauna suggests that S. tchadensis lived close to a lake, but not far from a sandy desert, perhaps the oldest record of desert conditions in the Neogene of northern central Africa.     

Widespread local house-sparrow extinctions

House-sparrow populations have declined sharply in Western Europe in recent decades, but the reasons for this decline have yet to be identified, despite intense public interest in the matter. Here we use a combination of field experimentation, genetic analysis and demographic data to show that a reduction in winter food supply caused by agricultural intensification is probably the principal explanation for the widespread local extinctions of rural house-sparrow populations in southern England. We show that farmland populations exhibit fine-level genetic structuring and that some populations are unable to sustain themselves (sinks), whereas others act as sources.