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• Mental health: don't overlook environment and its risk factorsSirYour News Feature ?The brains of the family? (Nature454, 154?157; 2008) and accompanying Editorial ?An unnecessary battle? (Nature454, 137?138; 2008) highlight the need to adopt a more integrated perspective when trying to unravel the biological complexity
• Inner-core shear-wave anisotropy and texture from an observation of PKJKP waves
Since the discovery of the Earth?s core a century ago, and the subsequent discovery of a solid inner core (postulated to have formed by the freezing of iron) seismologists have striven to understand this most remote part of the deep Earth. The most direct evidence for a solid inner core would be the observation of shear-mode body waves that traverse it, but these phases are extremely difficult to observe. Two reported observations in short-period data have proved controversial. Arguably more successful have been studies of longer-period data, but such averaging limits the usefulness of the observations to reported sightings. We present two observations of an inner-core shear-wave phase at higher frequencies in stacked data from the Japanese High-Sensitivity Array, Hi-Net. From an analysis of timing, amplitude and waveform of the ?PKJKP? phase we derive constraints on inner-core compressional-wave velocity and shear attenuation at about 0.3?Hz which differ from standard isotropic core models. We can explain waveform features and can partially reconcile the otherwise large differences between core wavespeed and attenuation models that our observations apparently suggest if we invoke shear-wave anisotropy in the inner core. A simple model of an inner core composed of hexagonal close-packed iron with its c axis aligned perpendicular to the rotation axis yields anisotropy that is compatible with both the shear-wave anisotropy that we observe and the well-established 3 per cent compressional-wave anisotropy.
• Inapparent infections and cholera dynamics
In many infectious diseases, an unknown fraction of infections produce symptoms mild enough to go unrecorded, a fact that can seriously compromise the interpretation of epidemiological records. This is true for cholera, a pandemic bacterial disease, where estimates of the ratio of asymptomatic to symptomatic infections have ranged from 3 to 100 (refs 1?5). In the absence of direct evidence, understanding of fundamental aspects of cholera transmission, immunology and control has been based on assumptions about this ratio and about the immunological consequences of inapparent infections. Here we show that a model incorporating high asymptomatic ratio and rapidly waning immunity, with infection both from human and environmental sources, explains 50?yr of mortality data from 26 districts of Bengal, the pathogen?s endemic home. We find that the asymptomatic ratio in cholera is far higher than had been previously supposed and that the immunity derived from mild infections wanes much more rapidly than earlier analyses have indicated. We find, too, that the environmental reservoir (free-living pathogen) is directly responsible for relatively few infections but that it may be critical to the disease?s endemicity. Our results demonstrate that inapparent infections can hold the key to interpreting the patterns of disease outbreaks. New statistical methods, which allow rigorous maximum likelihood inference based on dynamical models incorporating multiple sources and outcomes of infection, seasonality, process noise, hidden variables and measurement error, make it possible to test more precise hypotheses and obtain unexpected results. Our experience suggests that the confrontation of time-series data with mechanistic models is likely to revise our understanding of the ecology of many infectious diseases.
Nature Journals
• The virophage as a unique parasite of the giant mimivirusViruses are obligate parasites of Eukarya, Archaea and Bacteria. Acanthamoeba polyphaga mimivirus (APMV) is the largest known virus; it grows only in amoeba and is visible under the optical microscope. Mimivirus possesses a 1,185-kilobase double-stranded linear chromosome whose coding capacity is greater than that of numerous bacteria and archaea. Here we describe an icosahedral small virus, Sputnik, 50?nm in size, found associated with a new strain of APMV. Sputnik cannot multiply in Acanthamoeba castellanii but grows rapidly, after an eclipse phase, in the giant virus factory found in amoebae co-infected with APMV. Sputnik growth is deleterious to APMV and results in the production of abortive forms and abnormal capsid assembly of the host virus. The Sputnik genome is an 18.343-kilobase circular double-stranded DNA and contains genes that are linked to viruses infecting each of the three domains of life Eukarya, Archaea and Bacteria. Of the 21 predicted protein-coding genes, eight encode proteins with detectable homologues, including three proteins apparently derived from APMV, a homologue of an archaeal virus integrase, a predicted primase?helicase, a packaging ATPase with homologues in bacteriophages and eukaryotic viruses, a distant homologue of bacterial insertion sequence transposase DNA-binding subunit, and a Zn-ribbon protein. The closest homologues of the last four of these proteins were detected in the Global Ocean Survey environmental data set, suggesting that Sputnik represents a currently unknown family of viruses. Considering its functional analogy with bacteriophages, we classify this virus as a virophage. The virophage could be a vehicle mediating lateral gene transfer between giant viruses.
• Molecular architecture of native HIV-1 gp120 trimers
The envelope glycoproteins (Env) of human and simian immunodeficiency viruses (HIV and SIV, respectively) mediate virus binding to the cell surface receptor CD4 on target cells to initiate infection. Env is a heterodimer of a transmembrane glycoprotein (gp41) and a surface glycoprotein (gp120), and forms trimers on the surface of the viral membrane. Using cryo-electron tomography combined with three-dimensional image classification and averaging, we report the three-dimensional structures of trimeric Env displayed on native HIV-1 in the unliganded state, in complex with the broadly neutralizing antibody b12 and in a ternary complex with CD4 and the 17b antibody. By fitting the known crystal structures of the monomeric gp120 core in the b12- and CD4/17b-bound conformations into the density maps derived by electron tomography, we derive molecular models for the native HIV-1 gp120 trimer in unliganded and CD4-bound states. We demonstrate that CD4 binding results in a major reorganization of the Env trimer, causing an outward rotation and displacement of each gp120 monomer. This appears to be coupled with a rearrangement of the gp41 region along the central axis of the trimer, leading to closer contact between the viral and target cell membranes. Our findings elucidate the structure and conformational changes of trimeric HIV-1 gp120 relevant to antibody neutralization and attachment to target cells.
• Large recurrent microdeletions associated with schizophrenia
Reduced fecundity, associated with severe mental disorders, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk of disorders such as autism, schizophrenia and mental retardation. Thus, rare variants may account for a larger fraction of the overall genetic risk than previously assumed. In contrast to rare single nucleotide mutations, rare copy number variations (CNVs) can be detected using genome-wide single nucleotide polymorphism arrays. This has led to the identification of CNVs associated with mental retardation and autism. In a genome-wide search for CNVs associating with schizophrenia, we used a population-based sample to identify de novo CNVs by analysing 9,878 transmissions from parents to offspring. The 66 de novo CNVs identified were tested for association in a sample of 1,433 schizophrenia cases and 33,250 controls. Three deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II). All three deletions significantly associate with schizophrenia and related psychoses in the combined sample. The identification of these rare, recurrent risk variants, having occurred independently in multiple founders and being subject to negative selection, is important in itself. CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia.
• Rare chromosomal deletions and duplications increase risk of schizophrenia
Schizophrenia is a severe mental disorder marked by hallucinations, delusions, cognitive deficits and apathy, with a heritability estimated at 73?90% (ref. 1). Inheritance patterns are complex, and the number and type of genetic variants involved are not understood. Copy number variants (CNVs) have been identified in individual patients with schizophrenia and also in neurodevelopmental disorders, but large-scale genome-wide surveys have not been performed. Here we report a genome-wide survey of rare CNVs in 3,391 patients with schizophrenia and 3,181 ancestrally matched controls, using high-density microarrays. For CNVs that were observed in less than 1% of the sample and were more than 100 kilobases in length, the total burden is increased 1.15-fold in patients with schizophrenia in comparison with controls. This effect was more pronounced for rarer, single-occurrence CNVs and for those that involved genes as opposed to those that did not. As expected, deletions were found within the region critical for velo-cardio-facial syndrome, which includes psychotic symptoms in 30% of patients. Associations with schizophrenia were also found for large deletions on chromosome 15q13.3 and 1q21.1. These associations have not previously been reported, and they remained significant after genome-wide correction. Our results provide strong support for a model of schizophrenia pathogenesis that includes the effects of multiple rare structural variants, both genome-wide and at specific loci.
• Significant contribution of Archaea to extant biomass in marine subsurface se...
Deep drilling into the marine sea floor has uncovered a vast sedimentary ecosystem of microbial cells. Extrapolation of direct counts of stained microbial cells to the total volume of habitable marine subsurface sediments suggests that between 56?Pg (ref. 1) and 303?Pg (ref. 3) of cellular carbon could be stored in this largely unexplored habitat. From recent studies using various culture-independent techniques, no clear picture has yet emerged as to whether Archaea or Bacteria are more abundant in this extensive ecosystem. Here we show that in subsurface sediments buried deeper than 1?m in a wide range of oceanographic settings at least 87% of intact polar membrane lipids, biomarkers for the presence of live cells, are attributable to archaeal membranes, suggesting that Archaea constitute a major fraction of the biomass. Results obtained from modified quantitative polymerase chain reaction and slot-blot hybridization protocols support the lipid-based evidence and indicate that these techniques have previously underestimated archaeal biomass. The lipid concentrations are proportional to those of total organic carbon. On the basis of this relationship, we derived an independent estimate of amounts of cellular carbon in the global marine subsurface biosphere. Our estimate of 90?Pg of cellular carbon is consistent, within an order of magnitude, with previous estimates, and underscores the importance of marine subsurface habitats for global biomass budgets.
• Cytokine loops driving senescence
Cellular senescence, the permanent state of cell-cycle arrest, is emerging as an intrinsic barrier against tumorigenesis and a mechanism contributing to organismal ageing. Unexpected findings now identify multiple secreted inflammatory cytokines, their cognate receptors and positive-feedback loops with corresponding transcription factors, as key mediators of both oncogene-induced and replicative senescence.
• From risk to function
In association with the Wellcome Trust, we are pleased to announce the second Genomics of Common Diseases conference to be held September 6?9, 2008, in Cambridge, MA, USA.
• Common nonsynonymous variants in PCSK1 confer risk of obesity
Philippe Froguel and colleagues report that common nonsynonymous variants in PCSK1, encoding a prohormone convertase, confer risk of obesity in individuals of European ancestry.
• Identification of renal Cd36 as a determinant of blood pressure and risk for ...
Theodore Kurtz and colleagues report that Cd36 expression in the kidney underlies a quantitative trait locus for essential hypertension in the rat. Cd36 affects levels of cyclic GMP, a downstream effector of nitric oxide signaling, consistent with published data that reduced nitric oxide activity in the kidney is associated with hypertension.
• Genome-wide association defines more than 30 distinct susceptibility loci for...
Mark Daly and colleagues present results of a combined analysis of data from three recent genome-wide association studies for Crohn's disease, followed by replication in a large independent sample collection. Their results confirm 11 previously reported risk loci and provide genome-wide significant evidence for 21 new loci associated with the disease.
• On the move
Leukocytes express an array of chemoattractant and adhesion receptors that govern their migration, behavior and survival.
• Regulation of NKG2D ligands: a purposeful but delicate affair
New findings show that cellular microRNAs 'calibrate' the baseline expression of mRNAs encoding stress-inducible ligands of the activating NKG2D receptor. This regulation serves to protect innocent cells but may be exploited by tumors and viruses to thwart immune attack.
• Human microRNAs regulate stress-induced immune responses mediated by the rece...
The mechanisms controlling expression of the stress-induced NKG2D ligands MICA and MICB are not fully understood. Mandelboim and colleagues suggest that microRNAs maintain low MICA and MICB expression in the absence of cell stress.
• Hepatocyte-specific ablation of Foxa2 alters bile acid homeostasis and result...
The transcription factor Foxa2, which is key for the hepatic control of glucose metabolism, is now shown in this report to also be crucial for proper bile acid homestasis in the liver, as well as to be misregulated in human cholestatic diseases.
• Gene expression?based survival prediction in lung adenocarcinoma: a multi-sit...
Studies of gene expression in lung cancer have the potential to affect patient care, but the general applicability of the derived classifiers is unclear. David Beer and his colleagues now analyze more than 400 lung tumors from subjects at six institutions using eight different classifiers and show that the combination of molecular and clinical data best predicts patient survival (pages 812?813).
• Mouse embryonic stem cell?based functional assay to evaluate mutations in BRCA2
Kuznetsov and his colleagues address a pressing problem in risk assessment for predisposition to breast cancer?whether a particular allele is cancer predisposing or not. Using a two-tiered approach, they have developed a functional assay for the classification of BRCA2 sequence variants of unknown importance. The assay may serve as a model to generate functional assays for other human disease genes.
• Chip?NMR biosensor for detection and molecular analysis of cells
A major challenge in biomedicine is the rapid and accurate measurement of biomarkers in biological samples. Here, Lee et al. describe a chip-based NMR diagnostic platform that can perform sensitive and selective measurements on small volumes of unprocessed biological samples. This miniaturized biosensing system is high throughput, low cost and portable, and its utility is shown in a number of biomedical applications.
• Predicting the future for people with lung cancer
A large multicenter study shows that lung adenocarcinomas have messenger RNA expression signatures that greatly add to the use of clinical data in predicting an individual's survival (pages 822?827).
• The stress hormone corticosterone conditions AMPAR surface trafficking and sy...
Corticosterone triggers increased AMPA receptor membrane mobility and surface expression, according to a new study by Groc and colleagues. This mechanism helps to explain the observed modulation of synaptic plasticity and strength induced by this stress hormone.
Nature Reviews
• Therapeutics: Unravelling lethalityDrugs that target topoisomerases, enzymes that relieve the topological stress that occurs during DNA replication, are often effective anticancer agents, but it is not clear how these drugs work.Baxter and Diffley examined the effects of mutants of Top2, the only type II topoisomerase
• Angiogenesis: Survival of the infected
The development of Kaposi sarcoma, a highly vascular tumour of endothelial cell origin, is associated with a herpes virus, KSHV (Kaposi sarcoma-associated herpesvirus). Individual KSHV genes have been shown to upregulate the phosphoinositide 3-kinase (PI3K)?Akt?mammalian target of rapamycin (mTOR, also known as FRAP1)
• Education, education, education
The combined effect of prevention, screening and intervention has been a steady decrease in adult mortality rates from the four major types of cancer in the USA since the early 1990s, but are the benefits spread evenly through society?Writing in the Journal of the
• Genome-wide association studies: a new window into immune-mediated diseases
Given the recent explosion of genetic discoveries, 2007 is becoming known to human geneticists as the year of genome-wide association studies. In fact, more genetic risk factors for common diseases were identified in this one year than had been collectively reported before 2007. In particular,
• Cancer as an overhealing wound: an old hypothesis revisited
What is the relationship between the wound-healing process and the development of cancer? Malignant tumours often develop at sites of chronic injury, and tissue injury has an important role in the pathogenesis of malignant disease, with chronic inflammation being the most important risk factor. The
• In Brief
Neurological disordersLarge recurrent microdeletions associated with schizophreniaStefansson,H.et al. Nature30 Jul 2008 (doi: 10.1038/nature07229)Rare chromosomal deletions and duplications increase risk of schizophrenia The International Schizophrenia Consortium Nature30 Jul 2008 (doi: 10.1038/nature07239)The genetics