The Sec61p Complex Mediates the Integration of a Membrane Protein by Allowing Lipid Partitioning of the Transmembrane Domain

AbstractWe have investigated how the transmembrane (TM) domain of a membrane protein is cotranslationally integrated into the endoplasmic reticulum. We demonstrate that the Sec61p channel allows the TM domain to bypass the barrier posed by the polar head groups of the lipid bilayer and come into contact with the hydrophobic interior of the membrane. Together with the TRAM protein, Sec61p provides a site in the membrane, at the interface of channel and lipid, through which a TM domain can dynamically equilibrate between the lipid and aqueous phases, depending on the hydrophobicity of the TM domain and the length of the polypeptide segment tethering it to the ribosome. Our results suggest a unifying, lipid-partitioning model which can explain the general behavior of hydrophobic topogenic sequences

Lepton number violating interactions and their effects on neutrino oscillation experiments

Mixing between bosons that transform differently under the standard model gauge group, but identically under its unbroken subgroup, can induce interactions that violate the total lepton number. We discuss four-fermion operators that mediate lepton number violating neutrino interactions both in a model-independent framework and within supersymmetry (SUSY) without R-parity. The effective couplings of such operators are constrained by: i) the upper bounds on the relevant elementary couplings between the bosons and the fermions, ii) by the limit on universality violation in pion decays, iii) by the data on neutrinoless double beta decay and, iv) by loop-induced neutrino masses. We find that the present bounds imply that lepton number violating neutrino interactions are not relevant for the solar and atmospheric neutrino problems. Within SUSY without R-parity also the LSND anomaly cannot be explained by such interactions, but one cannot rule out an effect model-independently. Possible consequences for future terrestrial neutrino oscillation experiments and for neutrinos from a supernova are discussed.Comment: 28 pages, 2 figures, Late

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Cooperation of transmembrane segments during the integration of a double-spanning protein into the ER membrane

While membrane insertion of single-spanning membrane proteins into the endoplasmic reticulum (ER) is relatively well understood, it is unclear how multi-spanning proteins integrate. We have investigated the cotranslational ER integration of a double-spanning protein that is derived from leader peptidase. Both transmembrane (TM) segments are inserted into the membrane by the Sec61 channel. While the first, long and hydrophobic TM segment (TM1) inserts into the lipid bilayer on its own, the second, shorter TM anchor (TM2) collaborates with TM1 during its integration. TM1 diffuses away from the Sec61 complex in the absence of TM2, but is close to Sec61 when TM2 arrives inside the channel. These data suggest that the exit of a weak TM segment from the Sec61 channel into the lipid phase can be facilitated by its interaction with a previously integrated strong and stabilizing TM anchor

Overview on AWI's airborne gravity surveys and its new research aircraft POLAR 5

The Alfred-Wegener-Institute (AWI) operates ski-equipped aircraft since 1983 in both polar regions for logistics and airborne research with varying scientific equipment for the German and international scientific community. Hitherto AWI utilized aircraft of type Dornier Do228, respectively Do 128. Since October 2007 POLAR 5 is in operation. Being a former DC-3, the aircraft was completely refurbished and became a Basler BT-67. Compared to the so far used research aircraft POLAR 5 has a higher payload and a larger range. The instrumentation available onboard of AWIs polar aircraft for airborne geophysical suveys comprises magnetometers, ice thickness radar, several altimeter systems, and a LaCoste-Rhomberg ships gravity meter, modified by ZLS Corp. for airborne use. Geodetic GPS receivers, basic meteorology, and a data acquisition system for gathering all data during flights complete the equipment.Prior to the first aero-gravity survey in the polar regions, the first aero-gravity survey was conducted above the Baltic Sea in 1996. Since then 4 offshore surveys in the Arctic, flown in the northeast if Greenland, and 12 surveys in Antarctica, covering Dronning Maud Land and the adjacent sea, have been accomplished. Main subject of the surveys is the tectonic structure of the ocean, respectively the bedrock underneath the Antarctic ice sheet. Most surveys have been flown with POLAR 2, a Dornier DO228-101, whereas the latest 2 surveys were accomplished with POLAR 5. Further surveys in the Arctic and Antarctic are planned

Management of insect pests of farmed-stored maize in Kenya, with particular reference to Prostephanus truncatus (Horn)

SIGLEAvailable from British Library Document Supply Centre-DSC:DXN024471 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

High‐resolution wavelength‐dispersive spectroscopy of K‐shell transitions in hydrogen‐like gold

International audienc