Common variants at 6q22 and 17q21 are associated with intracranial volume

During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (P < 5 × 10(-8)) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 × 10(-11)), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 × 10(-12)), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 × 10(-3) for 6q22 and 1.2 × 10(-3) for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size.     

Primary structure of the precursor to the three major surface antigens of Plasmodium falciparum merozoites

Recently, a class of protein antigens of high relative molecular mass (Mt) which can induce protective immunity against blood-stage malaria has been identified. In Plasmodium falciparum the protein has a Mr of approximately 195,000 (P195). It is the precursor of three proteins of Mr 83,000 (83K), 42K and 19K which are the major surface antigens of merozoites; thus it may also be useful for immunization against P. falciparum. Three studies describing the isolation of single short complementary DNA clones for part of the P195 gene sequence have been reported. Here we describe the complete structure of the P195 gene determined from further DNA clones, its organization within genomic DNA and the location of the specific processing fragments within the primary amino-acid sequence.     

Structure of the immature retroviral capsid at 8 Å resolution by cryo-electron microscopy

The assembly of retroviruses such as HIV-1 is driven by oligomerization of their major structural protein, Gag. Gag is a multidomain polyprotein including three conserved folded domains: MA (matrix), CA (capsid) and NC (nucleocapsid). Assembly of an infectious virion proceeds in two stages. In the first stage, Gag oligomerization into a hexameric protein lattice leads to the formation of an incomplete, roughly spherical protein shell that buds through the plasma membrane of the infected cell to release an enveloped immature virus particle. In the second stage, cleavage of Gag by the viral protease leads to rearrangement of the particle interior, converting the non-infectious immature virus particle into a mature infectious virion. The immature Gag shell acts as the pivotal intermediate in assembly and is a potential target for anti-retroviral drugs both in inhibiting virus assembly and in disrupting virus maturation. However, detailed structural information on the immature Gag shell has not previously been available. For this reason it is unclear what protein conformations and interfaces mediate the interactions between domains and therefore the assembly of retrovirus particles, and what structural transitions are associated with retrovirus maturation. Here we solve the structure of the immature retroviral Gag shell from Mason-Pfizer monkey virus by combining cryo-electron microscopy and tomography. The 8-? resolution structure permits the derivation of a pseudo-atomic model of CA in the immature retrovirus, which defines the protein interfaces mediating retrovirus assembly. We show that transition of an immature retrovirus into its mature infectious form involves marked rotations and translations of CA domains, that the roles of the amino-terminal and carboxy-terminal domains of CA in assembling the immature and mature hexameric lattices are exchanged, and that the CA interactions that stabilize the immature and mature viruses are almost completely distinct.     

A road map for efficient and reliable human genome epidemiology

Networks of investigators have begun sharing best practices, tools and methods for analysis of associations between genetic variation and common diseases. A Network of Investigator Networks has been set up to drive the process, sponsored by the Human Genome Epidemiology Network. A workshop is planned to develop consensus guidelines for reporting results of genetic association studies. Published literature databases will be integrated, and unpublished data, including 'negative' studies, will be captured by online journals and through investigator networks. Systematic reviews will be expanded to include more meta-analyses of individual-level data and prospective meta-analyses. Field synopses will offer regularly updated overviews.     

Paracrystallization of actomyosin

Zusammenfassung Beschreibung der In-vitro-Bildung grosser, parakristalliner Aggregate des Hennen-Aktomyosins. Dicke und dünne Filamente der Aggregate zeigen parable Anordnung, die für quergestreifte Muskeln typisch ist. Ebenfalls treten Querbänder zwischen dicken und dünnen Filamenten des entspannten Muskels auf, und das aktiv entspannte Proteinsystem des gereinigten Aktomyosins bleibt voll funktionell.     

A sensorory input inhibiting heart rate in an insect,Rhodnius prolixus

The dorsal vessel of the blood feeding insect,Rhodnius prolixus, was found to increase or decrease its rate of contraction in response to a number of different stimuli. Handling increased contraction rates whereas tactile stimulation of the ventral abdominal cuticle inhibited contraction. Injection of very low concentrations of serotonin or of high concentrations of octopamine enhanced the inhibitory effect, apparently by acting via the nervous system. Higher concentrations of serotonin increased heart rate by acting directly on the myocardium. The inhibitory response is suggested to be one facet of a generalised thigmotactic response.     

Isolation of plasmid DNA fromAgrobacterium by isopycnic density gradient centrifugation in vertical rotors

Summary Fixed angle and vertical rotors are compared in terms of their sample load, run time, and resolution for the preparation of plasmid DNA fromAgrobacterium.Acknowledgments. This work was supported by a CASE Studentship from the SRC and ICI Corporate Laboratories to J.D., and a grant from the SRC to M.R.D. and E.C.C. The authors thank Mr B.V. Case for photographic assistance.     

Interaction network containing conserved and essential protein complexes in Escherichia coli

Proteins often function as components of multi-subunit complexes. Despite its long history as a model organism, no large-scale analysis of protein complexes in Escherichia coli has yet been reported. To this end, we have targeted DNA cassettes into the E. coli chromosome to create carboxy-terminal, affinity-tagged alleles of 1,000 open reading frames (approximately 23% of the genome). A total of 857 proteins, including 198 of the most highly conserved, soluble non-ribosomal proteins essential in at least one bacterial species, were tagged successfully, whereas 648 could be purified to homogeneity and their interacting protein partners identified by mass spectrometry. An interaction network of protein complexes involved in diverse biological processes was uncovered and validated by sequential rounds of tagging and purification. This network includes many new interactions as well as interactions predicted based solely on genomic inference or limited phenotypic data. This study provides insight into the function of previously uncharacterized bacterial proteins and the overall topology of a microbial interaction network, the core components of which are broadly conserved across Prokaryota.     

Orbitally induced oscillations in the East Antarctic ice sheet at the Oligocene/Miocene boundary

Between 34 and 15 million years (Myr) ago, when planetary temperatures were 3-4 degrees C warmer than at present and atmospheric CO2 concentrations were twice as high as today, the Antarctic ice sheets may have been unstable. Oxygen isotope records from deep-sea sediment cores suggest that during this time fluctuations in global temperatures and high-latitude continental ice volumes were influenced by orbital cycles. But it has hitherto not been possible to calibrate the inferred changes in ice volume with direct evidence for oscillations of the Antarctic ice sheets. Here we present sediment data from shallow marine cores in the western Ross Sea that exhibit well dated cyclic variations, and which link the extent of the East Antarctic ice sheet directly to orbital cycles during the Oligocene/Miocene transition (24.1-23.7 Myr ago). Three rapidly deposited glacimarine sequences are constrained to a period of less than 450 kyr by our age model, suggesting that orbital influences at the frequencies of obliquity (40 kyr) and eccentricity (125 kyr) controlled the oscillations of the ice margin at that time. An erosional hiatus covering 250 kyr provides direct evidence for a major episode of global cooling and ice-sheet expansion about 23.7 Myr ago, which had previously been inferred from oxygen isotope data (Mi1 event).