Construction of the descriptive system for the assessment of quality of life AQoL-6D utility instrument

BackgroundMulti attribute utility (MAU) instruments are used to include the health related quality of life (HRQoL) in economic evaluations of health programs. Comparative studies suggest different MAU instruments measure related but different constructs. The objective of this paper is to describe the methods employed to achieve content validity in the descriptive system of the Assessment of Quality of Life (AQoL)-6D, MAU instrument.MethodsThe AQoL program introduced the use of psychometric methods in the construction of health related MAU instruments. To develop the AQoL-6D we selected 112 items from previous research, focus groups and expert judgment and administered them to 316 members of the public and 302 hospital patients. The search for content validity across a broad spectrum of health states required both formative and reflective modelling. We employed Exploratory Factor Analysis and Structural Equation Modelling (SEM) to meet these dual requirements.Results and DiscussionThe resulting instrument employs 20 items in a multi-tier descriptive system. Latent dimension variables achieve sensitive descriptions of 6 dimensions which, in turn, combine to form a single latent QoL variable. Diagnostic statistics from the SEM analysis are exceptionally good and confirm the hypothesised structure of the model.ConclusionsThe AQoL-6D descriptive system has good psychometric properties. They imply that the instrument has achieved construct validity and provides a sensitive description of HRQoL. This means that it may be used with confidence for measuring health related quality of life and that it is a suitable basis for modelling utilities for inclusion in the economic evaluation of health programs.<br /

The very large G-protein coupled receptor VLGR1: a component of the ankle link complex required for the normal development of auditory hair bundles

Sensory hair bundles in the inner ear are composed of stereocilia that can be interconnected by a variety of different link types, including tip links, horizontal top connectors, shaft connectors, and ankle links. The ankle link antigen is an epitope specifically associated with ankle links and the calycal processes of photoreceptors in chicks. Mass spectrometry and immunoblotting were used to identify this antigen as the avian ortholog of the very large G-protein-coupled receptor VLGR1, the product of the Usher syndrome USH2C (Mass1) locus. Like ankle links, Vlgr1 is expressed transiently around the base of developing hair bundles in mice. Ankle links fail to form in the cochleae of mice carrying a targeted mutation in Vlgr1 (Vlgr1/del7TM), and the bundles become disorganized just after birth. FM1-43 [N-(3-triethylammonium)propyl)-4-(4-(dibutylamino)styryl) pyridinium dibromide] dye loading and whole-cell recordings indicate mechanotransduction is impaired in cochlear, but not vestibular, hair cells of early postnatal Vlgr1/del7TM mutant mice. Auditory brainstem recordings and distortion product measurements indicate that these mice are severely deaf by the third week of life. Hair cells from the basal half of the cochlea are lost in 2-month-old Vlgr1/del7TM mice, and retinal function is mildly abnormal in aged mutants. Our results indicate that Vlgr1 is required for formation of the ankle link complex and the normal development of cochlear hair bundles

Functional Modularity of the Arginine Catabolic Mobile Element Contributes to the Success of USA300 Methicillin-Resistant Staphylococcus aureus

The successful USA300 Community-Associated Methicillin-Resistant Staphylococcus aureus (CA-MRSA) lineage predominantly causes skin and soft tissue infections (SSTIs) and is highly associated with carriage of the Arginine Catabolic Mobile Element (ACME). However, the contribution of ACME to USA300 fitness during SSTIs remains incompletely understood. We show that the constitutive ACME-encoded arginine-deiminase system (Arc) allows USA300 to thrive in acidic environments that mimic human skin. Consequently, ACME-Arc drives excessive production of host polyamines, compounds uniquely toxic to S. aureus. To mitigate this, ACME also encodes SpeG, a polyamine-resistance enzyme that is essential for combating excess host polyamines in a murine SSTI model. Inhibiting host polyamine production not only restored ΔspeG persistence within infected wounds but also severely altered the host healing process, implying that polyamines play integral roles in coordinating the wound-healing response. Together, these data underscore the functional modularity of ACME and its contribution to the success of USA300 CA-MRSA

Increasing numbers and intercontinental spread of invasive insects on eucalypts

Native to Australasia, Eucalyptus (sensu lato) is one of the most planted genera of trees in the world. However, the sustainability of Eucalyptus species as plantation trees in non-native areas is increasingly threatened by the introduction and spread of Eucalyptus-feeding insects from Australia. We examine patterns and potential trends with respect to the global spread of Eucalyptus-feeding insects. Likely pathways of introduction and drivers of the rapid distribution of these insects, as well as management options are considered. The rate of introductions is shown to have increased nearly fivefold since the 1980s. As a result, the number of non-native pests of eucalypts outside of Australia has doubled in less than three decades. Furthermore, the rate of secondary spread among continents has also increased. Surprisingly, we found no association between area planted and the number of pests or new introductions. Only a small number of countries have been the points of first detection outside the native range; these countries have acted as bridgeheads to other regions. Quarantine regulations aimed at reducing the spread of invasive organisms appear to be ineffective at a global scale, and pathways allowing these invasions to occur are poorly understood or unknown. An expanded suite of management options are needed to provide resilience against the rapid accrual and homogenization of eucalypt pests, thereby ensuring the sustainability of eucalypt forestry worldwide.Tree Protection Cooperative Programme (TPCP), the National Research Foundation (NRF) and the Department of Trade and Industry (DTI) of South Africa.http://link.springer.com/journal/105302017-04-30hb2016Forestry and Agricultural Biotechnology Institute (FABI)GeneticsZoology and Entomolog

Numerical Prediction of Submesoscale Flow in the Nocturnal Stable Boundary Layer over Complex Terrain

Numerical weather prediction models often perform poorly for weakly forced, highly variable winds in nocturnal stable boundary layers (SBLs). When used as input to air-quality and dispersion models, these wind errors can lead to large errors in subsequent plume forecasts. Finer grid resolution and improved model numerics and physics can help reduce these errors. The Advanced Research Weather Research and Forecasting model (ARW-WRF) has higher-order numerics that may improve predictions of finescale winds (scales <~20 km) in nocturnal SBLs. However, better understanding of the physics controlling SBL flow is needed to take optimal advantage of advanced modeling capabilities. To facilitate ARW-WRF evaluations, a small network of instrumented towers was deployed in the ridge-and-valley topography of central Pennsylvania (PA). Time series of local observations and model forecasts on 1.333- and 0.444-km grids were filtered to isolate deterministic lower-frequency wind components. The time-filtered SBL winds have substantially reduced root-mean-square errors and biases, compared to raw data. Subkilometer horizontal and very fine vertical resolutions are found to be important for reducing model speed and direction errors. Nonturbulent fluctuations in unfiltered, very finescale winds, parts of which may be resolvable by ARW-WRF, are shown to generate horizontal meandering in stable weakly forced conditions. These submesoscale motions include gravity waves, primarily horizontal 2D motions, and other complex signatures. Vertical structure and low-level biases of SBL variables are shown to be sensitive to parameter settings defining minimum “background” mixing in very stable conditions in two representative turbulence schemes.Keywords: Numerical weather prediction/forecasting, Boundary laye

Discovery and Validation of a New Class of Small Molecule Toll-Like Receptor 4 (TLR4) Inhibitors

Many inflammatory diseases may be linked to pathologically elevated signaling via the receptor for lipopolysaccharide (LPS), toll-like receptor 4 (TLR4). There has thus been great interest in the discovery of TLR4 inhibitors as potential anti-inflammatory agents. Recently, the structure of TLR4 bound to the inhibitor E5564 was solved, raising the possibility that novel TLR4 inhibitors that target the E5564-binding domain could be designed. We utilized a similarity search algorithm in conjunction with a limited screening approach of small molecule libraries to identify compounds that bind to the E5564 site and inhibit TLR4. Our lead compound, C34, is a 2-acetamidopyranoside (MW 389) with the formula C17H27NO9, which inhibited TLR4 in enterocytes and macrophages in vitro, and reduced systemic inflammation in mouse models of endotoxemia and necrotizing enterocolitis. Molecular docking of C34 to the hydrophobic internal pocket of the TLR4 co-receptor MD-2 demonstrated a tight fit, embedding the pyran ring deep inside the pocket. Strikingly, C34 inhibited LPS signaling ex-vivo in human ileum that was resected from infants with necrotizing enterocolitis. These findings identify C34 and the β-anomeric cyclohexyl analog C35 as novel leads for small molecule TLR4 inhibitors that have potential therapeutic benefit for TLR4-mediated inflammatory diseases. © 2013 Neal et al

The mouse Gene Expression Database (GXD): 2019 update.

The mouse Gene Expression Database (GXD) is an extensive, well-curated community resource freely available at www.informatics.jax.org/expression.shtml. Covering all developmental stages, GXD includes data from RNA in situ hybridization, immunohistochemistry, RT-PCR, northern blot and western blot experiments in wild-type and mutant mice. GXD\u27s gene expression information is integrated with the other data in Mouse Genome Informatics and interconnected with other databases, placing these data in the larger biological and biomedical context. Since the last report, the ability of GXD to provide insights into the molecular mechanisms of development and disease has been greatly enhanced by the addition of new data and by the implementation of new web features. These include: improvements to the Differential Gene Expression Data Search, facilitating searches for genes that have been shown to be exclusively expressed in a specified structure and/or developmental stage; an enhanced anatomy browser that now provides access to expression data and phenotype data for a given anatomical structure; direct access to the wild-type gene expression data for the tissues affected in a specific mutant; and a comparison matrix that juxtaposes tissues where a gene is normally expressed against tissues, where mutations in that gene cause abnormalities

Autofix for backward-fit sidechains: using MolProbity and real-space refinement to put misfits in their place

Misfit sidechains in protein crystal structures are a stumbling block in using those structures to direct further scientific inference. Problems due to surface disorder and poor electron density are very difficult to address, but a large class of systematic errors are quite common even in well-ordered regions, resulting in sidechains fit backwards into local density in predictable ways. The MolProbity web site is effective at diagnosing such errors, and can perform reliable automated correction of a few special cases such as 180° flips of Asn or Gln sidechain amides, using all-atom contacts and H-bond networks. However, most at-risk residues involve tetrahedral geometry, and their valid correction requires rigorous evaluation of sidechain movement and sometimes backbone shift. The current work extends the benefits of robust automated correction to more sidechain types. The Autofix method identifies candidate systematic, flipped-over errors in Leu, Thr, Val, and Arg using MolProbity quality statistics, proposes a corrected position using real-space refinement with rotamer selection in Coot, and accepts or rejects the correction based on improvement in MolProbity criteria and on χ angle change. Criteria are chosen conservatively, after examining many individual results, to ensure valid correction. To test this method, Autofix was run and analyzed for 945 representative PDB files and on the 50S ribosomal subunit of file 1YHQ. Over 40% of Leu, Val, and Thr outliers and 15% of Arg outliers were successfully corrected, resulting in a total of 3,679 corrected sidechains, or 4 per structure on average. Summary Sentences: A common class of misfit sidechains in protein crystal structures is due to systematic errors that place the sidechain backwards into the local electron density. A fully automated method called “Autofix” identifies such errors for Leu, Val, Thr, and Arg and corrects over one third of them, using MolProbity validation criteria and Coot real-space refinement of rotamers

Putting lives in danger? Tinker, tailor, journalist, spy: the use of journalistic cover

The Anglo-American intelligence agencies’ use of journalists as spies or propagandists and the practice of providing intelligence agents in the field with journalistic cover have been a source of controversy for many decades. This paper examines the extent to which these covert practices have taken place and whether they have put journalists’ lives in danger. This paper, drawing on various methodologies, examines a number of cases where the arrest, murder or kidnap of journalists was justified on the grounds that the journalist was a ‘spy’. This has been followed through with research using a range of sources that shows there have been many occasions when the distinction between spies and journalists has been opaque. The paper concludes that widespread use of journalistic cover by spies has put lives in danger but the extent is unquantifiable

Real-Time PyMOL Visualization for Rosetta and PyRosetta

Computational structure prediction and design of proteins and protein-protein complexes have long been inaccessible to those not directly involved in the field. A key missing component has been the ability to visualize the progress of calculations to better understand them. Rosetta is one simulation suite that would benefit from a robust real-time visualization solution. Several tools exist for the sole purpose of visualizing biomolecules; one of the most popular tools, PyMOL (Schrödinger), is a powerful, highly extensible, user friendly, and attractive package. Integrating Rosetta and PyMOL directly has many technical and logistical obstacles inhibiting usage. To circumvent these issues, we developed a novel solution based on transmitting biomolecular structure and energy information via UDP sockets. Rosetta and PyMOL run as separate processes, thereby avoiding many technical obstacles while visualizing information on-demand in real-time. When Rosetta detects changes in the structure of a protein, new coordinates are sent over a UDP network socket to a PyMOL instance running a UDP socket listener. PyMOL then interprets and displays the molecule. This implementation also allows remote execution of Rosetta. When combined with PyRosetta, this visualization solution provides an interactive environment for protein structure prediction and design