Biologically diverse molecular variants within a single HIV-1 isolate

AIDS is a disorder characterized by a slow progressive impairment of immune function and by infection of human immunodeficiency viruses (HIV-1, HIV-2). Our knowledge of how these viruses cause disease in man, or how the related lentiviruses (visna and equine infectious anaemia virus) cause disease in animals, is still fragmentary. In particular, the significance of genetic variation in HIV-1, occurring within populations, within individuals and over periods of time, and the mechanisms of viral persistence remain unclear. To address these issues we prepared a series of proviral clones of HIV-1 originating from a single patient and compared their biological properties. Here we show that hybrid genomes (in which the envelope region of six viral clones were separately substituted into a prototype HIV-1 genome) generated viruses with widely differing capacity to grow in human T cells, cell lines and monocytoid cultures. These data suggest that extensive biological variation exists in vivo within an infected individual and is in part determined at the level of the viral envelope.     

Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations

Evidence for the etiology of autism spectrum disorders (ASDs) has consistently pointed to a strong genetic component complicated by substantial locus heterogeneity. We sequenced the exomes of 20 individuals with sporadic ASD (cases) and their parents, reasoning that these families would be enriched for de novo mutations of major effect. We identified 21 de novo mutations, 11 of which were protein altering. Protein-altering mutations were significantly enriched for changes at highly conserved residues. We identified potentially causative de novo events in 4 out of 20 probands, particularly among more severely affected individuals, in FOXP1, GRIN2B, SCN1A and LAMC3. In the FOXP1 mutation carrier, we also observed a rare inherited CNTNAP2 missense variant, and we provide functional support for a multi-hit model for disease risk. Our results show that trio-based exome sequencing is a powerful approach for identifying new candidate genes for ASDs and suggest that de novo mutations may contribute substantially to the genetic etiology of ASDs.     

对臭氧科学的攻击

获诺贝尔奖的科学家们若干年前就断言含氯氟烃聚合物破坏臭氧层，那么为什么现在关于这个问题的辩论仍很激烈呢？1995年12月，当诺贝尔化学奖获得者出现在布满鲜花的斯德哥尔摩演奏大厅接受古斯塔夫历世国王卡尔颁发的奖品时，他们遇到了一些纠察的阻挠。为什么呢？因为这3名诺贝尔奖获得者中的两个人，F·舍伍德·罗兰（F．SMIwmxZR0wioh）和马匹奥·莫里拉（Mall。Molina）由于他们在臭氧减少的化学理论方面的开拓性工作而正在受到嘉奖。他们的研究表明，被叫做含氯氟烃的化合物--曾广泛用作致冷剂和喷壶中的推进剂--是保护我们免受太…     

安哥拉山羊及其杂种羊DNA指纹图谱分析

应用寡苷酸探针(CA/GATA/TCC)     

Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn's disease

We report results of a nonsynonymous SNP scan for ulcerative colitis and identify a previously unknown susceptibility locus at ECM1. We also show that several risk loci are common to ulcerative colitis and Crohn's disease (IL23R, IL12B, HLA, NKX2-3 and MST1), whereas autophagy genes ATG16L1 and IRGM, along with NOD2 (also known as CARD15), are specific for Crohn's disease. These data provide the first detailed illustration of the genetic relationship between these common inflammatory bowel diseases.     

Patterning the zebrafish axial skeleton requires early chordin function

Members of the bone morphogenetic protein (BMP) family actively promote ventral cell fates, such as epidermis and blood, in the vertebrate gastrula. More dorsally, the organizer region counteracts BMP signalling through secretion of BMP-binding antagonists chordin and noggin, allowing dorsally derived tissues such as neurectoderm and somitic muscle to develop. BMPs also function in skeletal development and regeneration of bone following injury. Noggin antagonism is thought to prevent osteogenesis at sites of joint formation, whereas chordin has not yet been implicated in skeletogenesis. Analyses of zebrafish mutants have confirmed the action of chordin (chd) in opposing ventralizing signals at gastrulation. Some ventralized mutants recover and develop into fertile adults, thereby revealing a requirement for chd function for the later processes of fin and caudal skeletal patterning. We observe in mutants the misexpression of genes encoding BMPs and putative downstream genes, and ectopic sclerotomal cells. Through injections of chd mRNA into the early embryo, we restored wild-type gene expression patterns, and the resultant fish, although genotypically mutant, developed normal axial skeletons and fins. Our results demonstrate that chordin function during gastrulation is important for the correct morphogenesis of the adult zebrafish skeleton.     

Dynamic assembly of silent chromatin during thymocyte maturation

Considerable knowledge has been gained from temporal analyses of molecular events culminating in gene activation, but technical hurdles have hindered comparable studies of gene silencing. Here we describe the temporal assembly of silent chromatin at the mouse terminal transferase gene (Dntt), which is silenced and repositioned to pericentromeric heterochromatin during thymocyte maturation. Silencing was nucleated at the Dntt promoter by the ordered deacetylation of histone H3 at Lys9 (H3-Lys9), loss of methylation at H3-Lys4 and acquisition of methylation at H3-Lys9, followed by bidirectional spreading of each event. Deacetylation at H3-Lys9 coincided with pericentromeric repositioning, and neither of these early events required de novo protein synthesis. CpG methylation increased primarily in mature T cells that had left the thymus. A transformed thymocyte line supported reversible inactivation of Dntt without repositioning. In these cells, histone modification changes were nucleated at the promoter but did not spread. These results provide a foundation for elucidating the mechanisms of silent chromatin assembly during development.     

Genome duplication in the teleost fish Tetraodon nigroviridis reveals the early vertebrate proto-karyotype

Tetraodon nigroviridis is a freshwater puffer fish with the smallest known vertebrate genome. Here, we report a draft genome sequence with long-range linkage and substantial anchoring to the 21 Tetraodon chromosomes. Genome analysis provides a greatly improved fish gene catalogue, including identifying key genes previously thought to be absent in fish. Comparison with other vertebrates and a urochordate indicates that fish proteins have diverged markedly faster than their mammalian homologues. Comparison with the human genome suggests approximately 900 previously unannotated human genes. Analysis of the Tetraodon and human genomes shows that whole-genome duplication occurred in the teleost fish lineage, subsequent to its divergence from mammals. The analysis also makes it possible to infer the basic structure of the ancestral bony vertebrate genome, which was composed of 12 chromosomes, and to reconstruct much of the evolutionary history of ancient and recent chromosome rearrangements leading to the modern human karyotype.     

The infinite and infinitesimal quantities of du Bois-Reymond and their reception

The mixed fortunes of Paul du Bois-Reymond's infinitary calculus and ideal boundary between convergence and divergence are traced from 1870 to 1914. Cantor, Dedekind, Peano, Russell, Pringsheim and others objected. Stolz, Borel, Hardy and others accepted, at least in part, and built further. Hausdorff to some extent effected a compromise. The differing attitudes of the different participants toward infinitesimals and infinitely large quantities are described. In addition to shedding some light on the status of infinites, the whole story serves as a study of mathematical change, and shows that the proof-refutation process described by Lakatos is only one aspect of mathematical development. The story also sheds some light on the rise of 20^th century functional analysis, algebra and topology.Wer je den grossen Bau der Welt bedacht und fühlte nicht, wie Gottes hoher Geist noch über den Gesetzen wacht und kreist-wie blind erscheint, wer Schöpfertum verlacht! Wir kennen kaum den kleinsten Teil davon: Gesetz ist Wunder, Zahl ist Weltenton. Albrecht Haushofer, Moabit Sonnets, 1944, LXIX, Kosmos     

Mid-infrared images of beta Pictoris and the possible role of planetesimal collisions in the central disk

When viewed in optical starlight scattered by dust, the nearly edge-on debris disk surrounding the A5V star beta Pictoris (distance 19.3 pc; ref. 1) extends farther than 1,450 au from the star. Its large-scale complexity has been well characterized, but the detailed structure of the disk's central approximately 200-au region has remained elusive. This region is of special interest, because planets may have formed there during the star's 10-20-million-year lifetime, perhaps resulting in both the observed tilt of 4.6 degrees relative to the large-scale main disk and the partial clearing of the innermost dust. A peculiarity of the central disk (also possibly related to the presence of planets) is the asymmetry in the brightness of the 'wings', in which the southwestern wing is brighter and more extended at 12 microm than the northeastern wing. Here we present thermal infrared images of the central disk that imply that the brightness asymmetry results from the presence of a bright clump composed of particles that may differ in size from dust elsewhere in the disk. We suggest that this clump results from the collisional grinding of resonantly trapped planetesimals or the cataclysmic break-up of a planetesimal.