Determining the role of the ERGIC-53 cargo receptor complex in arenavirus propagation

Arenaviruses and hantaviruses are human pathogens that cause significant morbidity and mortality. The current lack of vaccines and treatment options for these viruses is a global concern. Despite producing only 4 proteins, these viruses are able to maintain a persistent and asymptomatic infection in wild rodents while being continuously shed into the environment. In humans, these viruses cause a spectrum of diseases ranging from aseptic meningitis to severe hemorrhagic fever syndromes. Little is known about how arenavirus and hantavirus proteins engage and interact with the human proteome during the complex process of viral biogenesis, or how the interactions with human proteins contribute to viral propagation as well as the onset and progression of disease. This dissertation provides a road map of the protein interactions formed between a prototypic envelope glycoprotein encoded by either an arenavirus or hantavirus, and the human proteome. The viral envelope glycoprotein (GP) decorates the surface of the virion. The primary function of the GP is to mediate attachment of the virus to specific cellular receptors, and after internalization of the virion, fuse the viral membrane with an internal endosomal membrane. In order to carry out these specific tasks, the viral GPs must first co-opt the extensive machinery found within the cellular secretory pathway to coordinate the proper glycosylation, folding, proteolytic maturation, and targeting of the GP during its biosynthesis. We identified a human protein with a conserved interaction amongst these two groups of viral GPs termed the Endoplasmic Reticulum (ER)-Golgi Intermediate Compartment Protein of 53 kiloDaltons (ERGIC-53). ERGIC-53 is an intracellular cargo receptor that normally cycles within the early secretory pathway of cells, where it is responsible for ferrying a small subset of cellular glycoproteins, most notably the coagulation factors FV and FVIII, from the ER to the Golgi apparatus. Herein we describe a novel role for ERGIC-53 in the propagation of not only arenaviruses, but also coronaviruses and filoviruses. Following infection with an arenavirus, ERGIC-53 leaves the early secretory pathway and becomes incorporated into the virus as it pinches off from the cell surface. Newly formed viruses lacking ERGIC-53 are no longer infectious due, in part, to a defect in their ability to attach to host cells. We suggest that ERGIC-53 represents a promising broad-spectrum antiviral target because of its association with the GPs from many families of pathogenic viruses, as well as its ability to exert control over their infectivity; and finally, because ERGIC-53 itself is not required for human health. The discovery of ERGIC-53 outside of its normal location inside of cells suggests that it may have additional unknown functions. Lastly, by revealing the importance of the cellular protein in controlling viral infectivity, we provide insight into the ongoing co-evolution of virus and host

Piecewise Potential Vorticity Inversion without Far-Field Response?

Given a flow domain D with subdomains D1 and D2, piecewise potential vorticity inversion (PPVI) inverts a potential vorticity (PV) anomaly in D2 and assumes vanishing PV in D1 where boundary conditions must be taken into account. It is a widely held view that the PV anomaly exerts a far-field influence on D1, which is revealed by PPVI. Tests of this assertion are conducted using a simple quasi geostrophic model where an upper layer D2 contains a PV anomaly and D1 is the layer underneath. This anomaly is inverted. Any downward physical impact of PV in D2 must also be represented in the results of a downward piecewise density inversion (PDI) based on the hydrostatic relation and the density in D2 as following from PPVI. There is no doubt about the impact of the mass in D2 on the flow in the lower layer D1. Thus results of PPVI and PDI have to agree closely

Visual Evoked Responses During Standing and Walking

Human cognition has been shaped both by our body structure and by its complex interactions with its environment. Our cognition is thus inextricably linked to our own and others’ motor behavior. To model brain activity associated with natural cognition, we propose recording the concurrent brain dynamics and body movements of human subjects performing normal actions. Here we tested the feasibility of such a mobile brain/body (MoBI) imaging approach by recording high-density electroencephalographic (EEG) activity and body movements of subjects standing or walking on a treadmill while performing a visual oddball response task. Independent component analysis of the EEG data revealed visual event-related potentials that during standing, slow walking, and fast walking did not differ across movement conditions, demonstrating the viability of recording brain activity accompanying cognitive processes during whole body movement. Non-invasive and relatively low-cost MoBI studies of normal, motivated actions might improve understanding of interactions between brain and body dynamics leading to more complete biological models of cognition

Presearch Data Conditioning in the Kepler Science Operations Center Pipeline

We describe the Presearch Data Conditioning (PDC) software component and its context in the Kepler Science Operations Center (SOC) pipeline. The primary tasks of this component are to correct systematic and other errors, remove excess flux due to aperture crowding, and condition the raw flux light curves for over 160,000 long cadence (~thirty minute) and 512 short cadence (~one minute) targets across the focal plane array. Long cadence corrected flux light curves are subjected to a transiting planet search in a subsequent pipeline module. We discuss the science algorithms for long and short cadence PDC: identification and correction of unexplained (i.e., unrelated to known anomalies) discontinuities; systematic error correction; and excess flux removal. We discuss the propagation of uncertainties from raw to corrected flux. Finally, we present examples of raw and corrected flux time series for flight data to illustrate PDC performance. Corrected flux light curves produced by PDC are exported to the Multi-mission Archive at Space Telescope [Science Institute] (MAST) and will be made available to the general public in accordance with the NASA/Kepler data release policy

A hierarchy of happiness? Mokken scaling analysis of the Oxford Happiness Inventory

The items of the Oxford Happiness Inventory (OHI, a self-report assessment of happiness, are subjected to an analysis for hierarchy among its items. By using Mokken scaling analyses we can assess whether items can reliably be ordered between persons as severity indicators on a latent trait; in this case, a latent trait of Happiness. OHI item-level data from 1024 participants were entered into the Mokken Scaling Procedure (MSP) seeking reliable scales with H > 0.30. 12 OHI items formed a reliable and statistically significant hierarchy. However, the MSP values indicate a 'weak' scale. The 'most difficult' (happiest) item on the scale is 'feeling energetic' and the 'least difficult' (least happy) is 'I have fun'. Items in the scale are consistent with what is already known about both happiness and low mood. The reduction in the OHI's items from 29 to 12 in the Mokken scale may have utility making it more accessible to participants as well as identifying items with reliably different levels of 'difficulty'. (C) 2010 Elsevier Ltd. All rights reserved

Pervasive effects of a dominant foliar endophytic fungus on host genetic and phenotypic expression in a tropical tree

It is increasingly recognized that macro-organisms (corals, insects, plants, vertebrates) consist of both host tissues and multiple microbial symbionts that play essential roles in their host’s ecological and evolutionary success. Consequently, identifying benefits and costs of symbioses, as well as mechanisms underlying them are research priorities. All plants surveyed under natural conditions harbor foliar endophytic fungi (FEF) in their leaf tissues, often at high densities. Despite producing no visible effects on their hosts, experiments have nonetheless shown that FEF reduce pathogen and herbivore damage. Here, combining results from three genomic, and two physiological experiments, we demonstrate pervasive genetic and phenotypic effects of the apparently asymptomatic endophytes on their hosts. Specifically, inoculation of endophyte-free (E−) Theobroma cacao leaves with Colletotrichum tropicale (E+), the dominant FEF species in healthy T. cacao, induces consistent changes in the expression of hundreds of host genes, including many with known defensive functions. Further, E+ plants exhibited increased lignin and cellulose content, reduced maximum rates of photosynthesis (Amax), and enrichment of nitrogen-15 and carbon-13 isotopes. These phenotypic changes observed in E+ plants correspond to changes in expression of specific functional genes in related pathways. Moreover, a cacao gene (Tc00g04254) highly up-regulated by C. tropicale also confers resistance to pathogen damage in the absence of endophytes or their products in host tissues. Thus, the benefits of increased pathogen resistance in E+ plants are derived in part from up-regulation of intrinsic host defense responses, and appear to be offset by potential costs including reduced photosynthesis, altered host nitrogen metabolism, and endophyte heterotrophy of host tissues. Similar effects are likely in most plant-endophyte interactions, and should be recognized in the design and interpretation of genetic and phenotypic studies of plantsIt is increasingly recognized that macro-organisms (corals, insects, plants, vertebrates) consist of both host tissues and multiple microbial symbionts that play essential roles in their host’s ecological and evolutionary success. Consequently, identifying benefits and costs of symbioses, as well as mechanisms underlying them are research priorities. All plants surveyed under natural conditions harbor foliar endophytic fungi (FEF) in their leaf tissues, often at high densities. Despite producing no visible effects on their hosts, experiments have nonetheless shown that FEF reduce pathogen and herbivore damage. Here, combining results from three genomic, and two physiological experiments, we demonstrate pervasive genetic and phenotypic effects of the apparently asymptomatic endophytes on their hosts. Specifically, inoculation of endophyte-free (E−) Theobroma cacao leaves with Colletotrichum tropicale (E+), the dominant FEF species in healthy T. cacao, induces consistent changes in the expression of hundreds of host genes, including many with known defensive functions. Further, E+ plants exhibited increased lignin and cellulose content, reduced maximum rates of photosynthesis (Amax), and enrichment of nitrogen-15 and carbon-13 isotopes. These phenotypic changes observed in E+ plants correspond to changes in expression of specific functional genes in related pathways. Moreover, a cacao gene (Tc00g04254) highly up-regulated by C. tropicale also confers resistance to pathogen damage in the absence of endophytes or their products in host tissues. Thus, the benefits of increased pathogen resistance in E+ plants are derived in part from up-regulation of intrinsic host defense responses, and appear to be offset by potential costs including reduced photosynthesis, altered host nitrogen metabolism, and endophyte heterotrophy of host tissues. Similar effects are likely in most plant-endophyte interactions, and should be recognized in the design and interpretation of genetic and phenotypic studies of plant

Overview of the Kepler Science Processing Pipeline

The Kepler Mission Science Operations Center (SOC) performs several critical functions including managing the ~156,000 target stars, associated target tables, science data compression tables and parameters, as well as processing the raw photometric data downlinked from the spacecraft each month. The raw data are first calibrated at the pixel level to correct for bias, smear induced by a shutterless readout, and other detector and electronic effects. A background sky flux is estimated from ~4500 pixels on each of the 84 CCD readout channels, and simple aperture photometry is performed on an optimal aperture for each star. Ancillary engineering data and diagnostic information extracted from the science data are used to remove systematic errors in the flux time series that are correlated with these data prior to searching for signatures of transiting planets with a wavelet-based, adaptive matched filter. Stars with signatures exceeding 7.1 sigma are subjected to a suite of statistical tests including an examination of each star's centroid motion to reject false positives caused by background eclipsing binaries. Physical parameters for each planetary candidate are fitted to the transit signature, and signatures of additional transiting planets are sought in the residual light curve. The pipeline is operational, finding planetary signatures and providing robust eliminations of false positives.Comment: 8 pages, 3 figure

Photometer Performance Assessment in Kepler Science Data Processing

This paper describes the algorithms of the Photometer Performance Assessment (PPA) software component in the science data processing pipeline of the Kepler mission. The PPA performs two tasks: One is to analyze the health and performance of the Kepler photometer based on the long cadence science data down-linked via Ka band approximately every 30 days. The second is to determine the attitude of the Kepler spacecraft with high precision at each long cadence. The PPA component is demonstrated to work effectively with the Kepler flight data