Prenatal Lead Levels, Plasma Amyloid β Levels, and Gene Expression in Young Adulthood

Background: Animal studies suggest that early-life lead exposure influences gene expression and production of proteins associated with Alzheimer’s disease (AD)

Coexistence of the topological state and a two-dimensional electron gas on the surface of Bi2Se3

Topological insulators are a recently discovered class of materials with fascinating properties: While the inside of the solid is insulating, fundamental symmetry considerations require the surfaces to be metallic. The metallic surface states show an unconventional spin texture, electron dynamics and stability. Recently, surfaces with only a single Dirac cone dispersion have received particular attention. These are predicted to play host to a number of novel physical phenomena such as Majorana fermions, magnetic monopoles and unconventional superconductivity. Such effects will mostly occur when the topological surface state lies in close proximity to a magnetic or electric field, a (superconducting) metal, or if the material is in a confined geometry. Here we show that a band bending near to the surface of the topological insulator Bi$_2$Se$_3$ gives rise to the formation of a two-dimensional electron gas (2DEG). The 2DEG, renowned from semiconductor surfaces and interfaces where it forms the basis of the integer and fractional quantum Hall effects, two-dimensional superconductivity, and a plethora of practical applications, coexists with the topological surface state in Bi$_2$Se$_3$. This leads to the unique situation where a topological and a non-topological, easily tunable and potentially superconducting, metallic state are confined to the same region of space.Comment: 12 pages, 3 figure

A topological Dirac insulator in a quantum spin Hall phase : Experimental observation of first strong topological insulator

When electrons are subject to a large external magnetic field, the conventional charge quantum Hall effect \cite{Klitzing,Tsui} dictates that an electronic excitation gap is generated in the sample bulk, but metallic conduction is permitted at the boundary. Recent theoretical models suggest that certain bulk insulators with large spin-orbit interactions may also naturally support conducting topological boundary states in the extreme quantum limit, which opens up the possibility for studying unusual quantum Hall-like phenomena in zero external magnetic field. Bulk Bi$_{1-x}$Sb$_x$ single crystals are expected to be prime candidates for one such unusual Hall phase of matter known as the topological insulator. The hallmark of a topological insulator is the existence of metallic surface states that are higher dimensional analogues of the edge states that characterize a spin Hall insulator. In addition to its interesting boundary states, the bulk of Bi$_{1-x}$Sb$_x$ is predicted to exhibit three-dimensional Dirac particles, another topic of heightened current interest. Here, using incident-photon-energy-modulated (IPEM-ARPES), we report the first direct observation of massive Dirac particles in the bulk of Bi$_{0.9}$Sb$_{0.1}$, locate the Kramers' points at the sample's boundary and provide a comprehensive mapping of the topological Dirac insulator's gapless surface modes. These findings taken together suggest that the observed surface state on the boundary of the bulk insulator is a realization of the much sought exotic "topological metal". They also suggest that this material has potential application in developing next-generation quantum computing devices.Comment: 16 pages, 3 Figures. Submitted to NATURE on 25th November(2007

Structural basis for the RING catalyzed synthesis of K63 linked ubiquitin chains

This work was supported by grants from Cancer Research UK (C434/A13067), the Wellcome Trust (098391/Z/12/Z) and Biotechnology and Biological Sciences Research Council (BB/J016004/1).The RING E3 ligase catalysed formation of lysine 63 linked ubiquitin chains by the Ube2V2–Ubc13 E2 complex is required for many important biological processes. Here we report the structure of the RING domain dimer of rat RNF4 in complex with a human Ubc13~Ub conjugate and Ube2V2. The structure has captured Ube2V2 bound to the acceptor (priming) ubiquitin with Lys63 in a position that could lead to attack on the linkage between the donor (second) ubiquitin and Ubc13 that is held in the active “folded back” conformation by the RING domain of RNF4. The interfaces identified in the structure were verified by in vitro ubiquitination assays of site directed mutants. This represents the first view of the synthesis of Lys63 linked ubiquitin chains in which both substrate ubiquitin and ubiquitin-loaded E2 are juxtaposed to allow E3 ligase mediated catalysis.PostprintPeer reviewe

Envelope Determinants of Equine Lentiviral Vaccine Protection

Lentiviral envelope (Env) antigenic variation and associated immune evasion present major obstacles to vaccine development. The concept that Env is a critical determinant for vaccine efficacy is well accepted, however defined correlates of protection associated with Env variation have yet to be determined. We reported an attenuated equine infectious anemia virus (EIAV) vaccine study that directly examined the effect of lentiviral Env sequence variation on vaccine efficacy. The study identified a significant, inverse, linear correlation between vaccine efficacy and increasing divergence of the challenge virus Env gp90 protein compared to the vaccine virus gp90. The report demonstrated approximately 100% protection of immunized ponies from disease after challenge by virus with a homologous gp90 (EV0), and roughly 40% protection against challenge by virus (EV13) with a gp90 13% divergent from the vaccine strain. In the current study we examine whether the protection observed when challenging with the EV0 strain could be conferred to animals via chimeric challenge viruses between the EV0 and EV13 strains, allowing for mapping of protection to specific Env sequences. Viruses containing the EV13 proviral backbone and selected domains of the EV0 gp90 were constructed and in vitro and in vivo infectivity examined. Vaccine efficacy studies indicated that homology between the vaccine strain gp90 and the N-terminus of the challenge strain gp90 was capable of inducing immunity that resulted in significantly lower levels of post-challenge virus and significantly delayed the onset of disease. However, a homologous N-terminal region alone inserted in the EV13 backbone could not impart the 100% protection observed with the EV0 strain. Data presented here denote the complicated and potentially contradictory relationship between in vitro virulence and in vivo pathogenicity. The study highlights the importance of structural conformation for immunogens and emphasizes the need for antibody binding, not neutralizing, assays that correlate with vaccine protection. © 2013 Craigo et al

An integrated silicon sensor with microfluidic chip for monitoring potassium and pH

We present ion-sensitive field effect transistor-based sensors, integrated with a microfluidic chip, for monitoring pH and potassium cations. The sensor is strategically located at the base of a well so that the response time of the device depends both on the mean flow through the device and the diffusion coefficient of the analyte being monitored. This would enable monitoring of ions in the presence of larger molecules. The dependence of the device response time on diffusive transport of analytes was examined through a numerical study of the flow field and the passive diffusion of a chemical species. The predicted device response time was compared with the experimental measurements and reasonable agreement found. The general dependence of device response time on geometry, flow rate, and analyte diffusion coefficient was derived. These devices can be used with biological fluids where monitoring of pH and cations provide vital information about the well-being of patients. © 2010 Springer-Verlag

What causes increasing and unnecessary use of radiological investigations? a survey of radiologists' perceptions

<p>Abstract</p> <p>Background</p> <p>Growth in use and overuse of diagnostic imaging significantly impacts the quality and costs of health care services. What are the modifiable factors for increasing and unnecessary use of radiological services? Various factors have been indentified, but little is known about their relative impact. Radiologists hold key positions for providing such knowledge. Therefore the purpose of this study was to obtain radiologists' perspective on the causes of increasing and unnecessary use of radiological investigations.</p> <p>Methods</p> <p>In a mailed questionnaire radiologist members of the Norwegian Medical Association were asked to rate potential causes of increased investigation volume (fifteen items) and unnecessary investigations (six items), using five-point-scales. Responses were analysed by using summary statistics and Factor Analysis. Associations between variables were determined using Students' t-test, Spearman rank correlation and Chi-Square tests.</p> <p>Results</p> <p>The response rate was 70% (374/537). The highest rated causes of increasing use of radiological investigations were: a) new radiological technology, b) peoples' demands, c) clinicians' intolerance for uncertainty, d) expanded clinical indications, and e) availability. 'Over-investigation' and 'insufficient referral information' were reported the most frequent causes of unnecessary investigations. Correlations between causes of increasing and unnecessary radiology use were identified.</p> <p>Conclusion</p> <p>In order to manage the growth in radiological imaging and curtail inappropriate investigations, the study findings point to measures that influence the supply and demand of services, specifically to support the decision-making process of physicians.</p

APPL Proteins FRET at the BAR: Direct Observation of APPL1 and APPL2 BAR Domain-Mediated Interactions on Cell Membranes Using FRET Microscopy

Human APPL1 and APPL2 are homologous RAB5 effectors whose binding partners include a diverse set of transmembrane receptors, signaling proteins, and phosphoinositides. APPL proteins associate dynamically with endosomal membranes and are proposed to function in endosome-mediated signaling pathways linking the cell surface to the cell nucleus. APPL proteins contain an N-terminal Bin/Amphiphysin/Rvs (BAR) domain, a central pleckstrin homology (PH) domain, and a C-terminal phosphotyrosine binding (PTB) domain. Previous structural and biochemical studies have shown that the APPL BAR domains mediate homotypic and heterotypic APPL-APPL interactions and that the APPL1 BAR domain forms crescent-shaped dimers. Although previous studies have shown that APPL minimal BAR domains associate with curved cell membranes, direct interaction between APPL BAR domains on cell membranes in vivo has not been reported.Herein, we used a laser-scanning confocal microscope equipped with a spectral detector to carry out fluorescence resonance energy transfer (FRET) experiments with cyan fluorescent protein/yellow fluorescent protein (CFP/YFP) FRET donor/acceptor pairs to examine interactions between APPL minimal BAR domains at the subcellular level. This comprehensive approach enabled us to evaluate FRET levels in a single cell using three methods: sensitized emission, standard acceptor photobleaching, and sequential acceptor photobleaching. We also analyzed emission spectra to address an outstanding controversy regarding the use of CFP donor/YFP acceptor pairs in FRET acceptor photobleaching experiments, based on reports that photobleaching of YFP converts it into a CFP-like species.All three methods consistently showed significant FRET between APPL minimal BAR domain FRET pairs, indicating that they interact directly in a homotypic (i.e., APPL1-APPL1 and APPL2-APPL2) and heterotypic (i.e., APPL1-APPL2) manner on curved cell membranes. Furthermore, the results of our experiments did not show photoconversion of YFP into a CFP-like species following photobleaching, supporting the use of CFP donor/YFP acceptor FRET pairs in acceptor photobleaching studies

Intron Dynamics in Ribosomal Protein Genes

The role of spliceosomal introns in eukaryotic genomes remains obscure. A large scale analysis of intron presence/absence patterns in many gene families and species is a necessary step to clarify the role of these introns. In this analysis, we used a maximum likelihood method to reconstruct the evolution of 2,961 introns in a dataset of 76 ribosomal protein genes from 22 eukaryotes and validated the results by a maximum parsimony method. Our results show that the trends of intron gain and loss differed across species in a given kingdom but appeared to be consistent within subphyla. Most subphyla in the dataset diverged around 1 billion years ago, when the “Big Bang” radiation occurred. We speculate that spliceosomal introns may play a role in the explosion of many eukaryotes at the Big Bang radiation