Fragment-based discovery of a regulatory site in thioredoxin glutathione reductase acting as "doorstop" for NADPH entry

Members of the FAD/NAD-linked reductase family are recognized as crucial targets in drug development for cancers, inflammatory disorders, and infectious diseases. However, individual FAD/NAD reductases are difficult to inhibit in a selective manner with off target inhibition reducing usefulness of identified compounds. Thioredoxin glutathione reductase (TGR), a high molecular weight thioredoxin reductase-like enzyme, has emerged as a promising drug target for the treatment of schistosomiasis, a parasitosis afflicting more than 200 million people. Taking advantage of small molecules selected from a high-throughput screen and using X-ray crystallography, functional assays, and docking studies, we identify a critical secondary site of the enzyme. Compounds binding at this site interfere with well-known and conserved conformational changes associated with NADPH reduction, acting as a doorstop for cofactor entry. They selectivity inhibit TGR from Schistosoma mansoni and are active against parasites in culture. Since many members of the FAD/NAD-linked reductase family have similar catalytic mechanisms the unique mechanism of inhibition identified in this study for TGR broadly opens new routes to selectively inhibit homologous enzymes of central importance in numerous diseases

Lack of clinical AIDS in SIV-infected sooty mangabeys with significant CD4+ T cell loss is associated with double-negative T cells

SIV infection of natural host species such as sooty mangabeys results in high viral replication without clinical signs of simian AIDS. Studying such infections is useful for identifying immunologic parameters that lead to AIDS in HIV-infected patients. Here we have demonstrated that acute, SIV-induced CD4+ T cell depletion in sooty mangabeys does not result in immune dysfunction and progression to simian AIDS and that a population of CD3 +CD4-CD8- T cells (double-negative T cells) partially compensates for CD4+ T cell function in these animals. Passaging plasma from an SIV-infected sooty mangabey with very few CD4 + T cells to SIV-negative animals resulted in rapid loss of CD4 + T cells. Nonetheless, all sooty mangabeys generated SIV-specific antibody and T cell responses and maintained normal levels of plasma lipopolysaccharide. Moreover, all CD4- low sooty mangabeys elicited a de novo immune response following influenza vaccination. Such preserved immune responses as well as the low levels of immune activation observed in these animals were associated with the presence of double-negative T cells capable of producing Th1, Th2, and Th17 cytokines. These studies indicate that SIV-infected sooty mangabeys do not appear to rely entirely on CD4+ T cells to maintain immunity and identify double-negative T cells as a potential subset of cells capable of performing CD4+ T cell-like helper functions upon SIV-induced CD4+ T cell depletion in this species

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.3448Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H

The ALICE experiment at the CERN LHC

ALICE (A Large Ion Collider Experiment) is a general-purpose, heavy-ion detector at the CERN LHC which focuses on QCD, the strong-interaction sector of the Standard Model. It is designed to address the physics of strongly interacting matter and the quark-gluon plasma at extreme values of energy density and temperature in nucleus-nucleus collisions. Besides running with Pb ions, the physics programme includes collisions with lighter ions, lower energy running and dedicated proton-nucleus runs. ALICE will also take data with proton beams at the top LHC energy to collect reference data for the heavy-ion programme and to address several QCD topics for which ALICE is complementary to the other LHC detectors. The ALICE detector has been built by a collaboration including currently over 1000 physicists and engineers from 105 Institutes in 30 countries. Its overall dimensions are 161626 m3 with a total weight of approximately 10 000 t. The experiment consists of 18 different detector systems each with its own specific technology choice and design constraints, driven both by the physics requirements and the experimental conditions expected at LHC. The most stringent design constraint is to cope with the extreme particle multiplicity anticipated in central Pb-Pb collisions. The different subsystems were optimized to provide high-momentum resolution as well as excellent Particle Identification (PID) over a broad range in momentum, up to the highest multiplicities predicted for LHC. This will allow for comprehensive studies of hadrons, electrons, muons, and photons produced in the collision of heavy nuclei. Most detector systems are scheduled to be installed and ready for data taking by mid-2008 when the LHC is scheduled to start operation, with the exception of parts of the Photon Spectrometer (PHOS), Transition Radiation Detector (TRD) and Electro Magnetic Calorimeter (EMCal). These detectors will be completed for the high-luminosity ion run expected in 2010. This paper describes in detail the detector components as installed for the first data taking in the summer of 2008

The attenuation of sweep events within the turbulent boundary layer over a flat plate using a micro-cavity array

For most aeronautical applications skin friction drag is a significant issue for efficient operation. It is estimated that 49% of the total drag an aircraft experiences is due to skin friction drag and a small reduction of 5% would currently result in an annual saving of $3.3 billion US dollars. The large Reynolds number at which aerospace applications typically operate results in a turbulent boundary layer, which causes a large increase in shear stresses and a subsequent increase in skin friction drag. The key culprits for the large shear stresses are the turbulent boundary layer structures that form once the boundary layer transitions from the initial laminar state, the most influential of which are the coherent structures. These structures pump fluid into (sweep) and away (ejection) from the near wall region and generate the shear stresses. Hence the aim of this research is to manipulate the turbulent boundary layer to reduce the effect of the aforementioned coherent structures. Specific attention has been applied to the passive application of a micro-cavity array as a potential control technique to attenuate the coherent structures. The micro-cavity array consists of a cavity arranged flush with the surface, underneath of which is a backing cavity similar to the design of a Helmholtz resonator. As a passive control technique, this device aims to have the advantages of an easy implementation and the absence of an external power source, with targeted control of the coherent structures commonly achieved by active systems. The micro-cavity array aims to capture and dampen the sweep events, therefore reducing the strength of both the ejection and sweep events due to their high dependence on one another. As such the present work assesses the ability of an array of micro-cavities to reduce the turbulent properties of a fully developed boundary layer. Previous results from the flow excited Helmholtz resonator and a two-dimensional square cavity on a flat plate have confirmed the potential of the micro-cavity array. Both techniques achieved successful control of the boundary layer and attenuation of the coherent structures. However these applications had limitations at higher Reynolds numbers and as a result a smaller device such as the micro-cavity is proposed and forms the basis of this thesis. Being of smaller size, the shear layer is hypothesised not to break apart while traversing the small orifices of the micro-cavity, which occurs for the larger flow excited Helmholtz resonator and results in an adverse pressure gradient and an undesirable increase in the disturbances and viscous drag in the boundary layer. To investigate the potential of the proposed micro-cavity array, the device has been thoroughly examined experimentally at a range of Reynolds numbers (1195 < Reθ < 3771). Experiments were predominately focused on identifying the potential of the micro-cavity, whilst evaluating the impact of the orifice distribution along the cavity array and the effect of other geometric parameters, including the length of the cavity array and the backing volume. Measurements were made using a single hot-wire and a constant temperature hot-wire anemometry system downstream of the cavity arrays, with all results being compared against canonical boundary layer profiles to record the effect of the micro-cavity array. These experiments demonstrated the success of the micro-cavity array in controlling the turbulent boundary layer and identified the mechanism causing the recorded attenuation of the boundary layer. The results showed that the optimal orifice diameter must be equal to a value of approximately 60 times the viscous length scale. This resulted in a maximum reduction in the turbulence and sweep intensities of 13% and 14%, respectively. The results demonstrated that for a cavity orifice diameter less than 20 times the viscous length scale, the sweep events are restricted and no events are captured by the array. Additionally, if the diameter of the orifice exceeds 145 times the viscous length scale, separation of the shear layer was observed, causing an increase in the turbulence energy production in the near wall region. The volume of the backing cavity was also shown to be a very important characteristic in the design of the micro-cavity array, while the orifice length of the cavity array had negligible effect in modifying the reduction of the turbulent energy by the cavity array. The maximum reduction in turbulence generation occurred when the backing volume was as large as possible, which reduced the reactive impedance of the microcavity device. However, the sweep intensity reduction reached a limiting value as the volume increased. The reduction in turbulent energy was also shown to occur irrespective of whether the individual cavity arrays shared a common backing volume or had individual backing volumes. Consequently a strongly supported finding is that the cavity array weakens the sweep intensity of the captured sweep events by damping the energy of the events through the friction losses in the cavity array and also in the large volume of the backing cavity. This results in a reduction in the strength of the bursting events responsible for the shear stresses in the near wall region. The body of work presented here is only the beginning of the development of the knowledge required for this area of work. The results of this study demonstrate an improved understanding of the micro-cavity array as a potential flow control device for the turbulent boundary layer in the future and as such requires further investigation.Thesis (Ph.D.) -- University of Adelaide, School of Mechanical Engineering, 201

Attenuation of turbulence by the passive control of sweep events in a turbulent boundary layer using micro-cavities

Cavity arrays have been previously identified to disrupt the sweep events and consequently the bursting cycle in the boundary layer by capturing the structures responsible for the Reynolds stresses. In the present study, the sensitivity of a flushed-surface cavity array in reducing the turbulent energy production has been investigated. Two plates of varying thicknesses and four different backing cavity volumes were considered, at three different Reynolds numbers. The volume of the backing cavity was shown to be the most important characteristic in determining the attenuation of streamwise velocity fluctuations within the logarithmic region of the turbulent boundary layer. However, the results also demonstrated that the orifice length of the cavity array had negligible effect in modifying the reduction of the turbulent energy by the cavity array in this investigation. The results show that the maximum reduction in turbulence generation achieved for this study occurs when the backing volume is 3.1 × 106 times greater than the viscous length scale at Reθ = 3771. The reduction in turbulence intensity, sweep intensity, and energy spectrum were shown to be 5.6%, 6.3%, and 13.4%, respectively. By decreasing the cavity volume to zero, no change in the turbulent boundary layer turbulence statistics was found. The results suggest a larger reduction in turbulence intensity, sweep intensity, and energy spectrum that can be achieved with a larger backing volume.Anton Silvestri, Farzin Ghanadi, Maziar Arjomandi, Rey Chin, Benjamin Cazzolato and Anthony Zande