AFTI/F-16 flight test results and lessons

The advanced fighter technology integration (AFTI) F-16 aircraft is a highly complex digital flight control system integrated with advanced avionics and cockpit. The use of dissimilar backup modes if the primary system fails requires the designer to trade off system simplicity and capability. The tradeoff is evident in the AFTI/F-16 aircraft with its limited stability and fly by wire digital flight control systems when a generic software failure occurs the backup or normal mode must provide equivalent envelop protection during the transition to degraded flight control. The complexity of systems like the AFTI/F-16 system defines a second design issue, which is divided into two segments: (1) the effect on testing, (2) and the pilot's ability to act correctly in the limited time available for cockpit decisions. The large matrix of states possible with the AFTI/F-16 flight control system illustrates the difficulty of both testing the system and choosing real time pilot actions. The third generic issue is the possible reductions in the user's reliability expectations where false single channel information can be displayed at the pilot vehicle interface while the redundant set remains functional

Identification of novel subgroup a variants with enhanced receptor binding and replicative capacity in primary isolates of anaemogenic strains of feline leukaemia virus

<b>BACKGROUND:</b> The development of anaemia in feline leukaemia virus (FeLV)-infected cats is associated with the emergence of a novel viral subgroup, FeLV-C. FeLV-C arises from the subgroup that is transmitted, FeLV-A, through alterations in the amino acid sequence of the receptor binding domain (RBD) of the envelope glycoprotein that result in a shift in the receptor usage and the cell tropism of the virus. The factors that influence the transition from subgroup A to subgroup C remain unclear, one possibility is that a selective pressure in the host drives the acquisition of mutations in the RBD, creating A/C intermediates with enhanced abilities to interact with the FeLV-C receptor, FLVCR. In order to understand further the emergence of FeLV-C in the infected cat, we examined primary isolates of FeLV-C for evidence of FeLV-A variants that bore mutations consistent with a gradual evolution from FeLV-A to FeLV-C.<p></p> <b>RESULTS:</b> Within each isolate of FeLV-C, we identified variants that were ostensibly subgroup A by nucleic acid sequence comparisons, but which bore mutations in the RBD. One such mutation, N91D, was present in multiple isolates and when engineered into a molecular clone of the prototypic FeLV-A (Glasgow-1), enhanced replication was noted in feline cells. Expression of the N91D Env on murine leukaemia virus (MLV) pseudotypes enhanced viral entry mediated by the FeLV-A receptor THTR1 while soluble FeLV-A Env bearing the N91D mutation bound more efficiently to mouse or guinea pig cells bearing the FeLV-A and -C receptors. Long-term in vitro culture of variants bearing the N91D substitution in the presence of anti-FeLV gp70 antibodies did not result in the emergence of FeLV-C variants, suggesting that additional selective pressures in the infected cat may drive the subsequent evolution from subgroup A to subgroup C.<p></p> <b>CONCLUSIONS:</b> Our data support a model in which variants of FeLV-A, bearing subtle differences in the RBD of Env, may be predisposed towards enhanced replication in vivo and subsequent conversion to FeLV-C. The selection pressures in vivo that drive the emergence of FeLV-C in a proportion of infected cats remain to be established

Clinical and genetic characterization of leukoencephalopathies in adults

Leukodystrophies and genetic leukoencephalopathies are a rare group of disorders leading to progressive degeneration of cerebral white matter. They are associated with a spectrum of clinical phenotypes dominated by dementia, psychiatric changes, movement disorders and upper motor neuron signs. Mutations in at least 60 genes can lead to leukoencephalopathy with often overlapping clinical and radiological presentations. For these reasons, patients with genetic leukoencephalopathies often endure a long diagnostic odyssey before receiving a definitive diagnosis or may receive no diagnosis at all. In this study, we used focused and whole exome sequencing to evaluate a cohort of undiagnosed adult patients referred to a specialist leukoencephalopathy service. In total, 100 patients were evaluated using focused exome sequencing of 6100 genes. We detected pathogenic or likely pathogenic variants in 26 cases. The most frequently mutated genes were NOTCH3, EIF2B5, AARS2 and CSF1R. We then carried out whole exome sequencing on the remaining negative cases including four family trios, but could not identify any further potentially disease-causing mutations, confirming the equivalence of focused and whole exome sequencing in the diagnosis of genetic leukoencephalopathies. Here we provide an overview of the clinical and genetic features of these disorders in adults

Modulation of the virus-receptor interaction by mutations in the V5 loop of feline immunodeficiency virus (FIV) following in vivo escape from neutralising antibody

<b>BACKGROUND:</b> In the acute phase of infection with feline immunodeficiency virus (FIV), the virus targets activated CD4+ T cells by utilising CD134 (OX40) as a primary attachment receptor and CXCR4 as a co-receptor. The nature of the virus-receptor interaction varies between isolates; strains such as GL8 and CPGammer recognise a "complex" determinant on CD134 formed by cysteine-rich domains (CRDs) 1 and 2 of the molecule while strains such as PPR and B2542 require a more "simple" determinant comprising CRD1 only for infection. These differences in receptor recognition manifest as variations in sensitivity to receptor antagonists. In this study, we ask whether the nature of the virus-receptor interaction evolves in vivo.<p></p> <b>RESULTS:</b> Following infection with a homogeneous viral population derived from a pathogenic molecular clone, a quasispecies emerged comprising variants with distinct sensitivities to neutralising antibody and displaying evidence of conversion from a "complex" to a "simple" interaction with CD134. Escape from neutralising antibody was mediated primarily by length and sequence polymorphisms in the V5 region of Env, and these alterations in V5 modulated the virus-receptor interaction as indicated by altered sensitivities to antagonism by both anti-CD134 antibody and soluble CD134.<p></p> <b>CONCLUSIONS:</b> The FIV-receptor interaction evolves under the selective pressure of the host humoral immune response, and the V5 loop contributes to the virus-receptor interaction. Our data are consistent with a model whereby viruses with distinct biological properties are present in early versus late infection and with a shift from a "complex" to a "simple" interaction with CD134 with time post-infection.<p></p&gt

Posterior cortical atrophy and Alzheimer’s disease : a meta-analytic review of neuropsychological and brain morphometry studies

This paper presents the first systematic review and meta-analysis of neuropsychological and brain morphometry studies comparing posterior cortical atrophy (PCA) to typical Alzheimer's disease (tAD). Literature searches were conducted for brain morphometry and neuropsychological studies including a PCA and a tAD group. Compared to healthy controls (HC), PCA patients exhibited significant decreases in temporal, occipital and parietal gray matter (GM) volumes, whereas tAD patients showed extensive left temporal atrophy. Compared to tAD patients, participants with PCA showed greater GM volume reduction in the right occipital gyrus extending to the posterior lobule. In addition, PCA patients showed less GM volume loss in the left parahippocampal gyrus and left hippocampus than tAD patients. PCA patients exhibit significantly greater impairment in Immediate Visuospatial Memory as well as Visuoperceptual and Visuospatial Abilities than patients with tAD. However, tAD patients showed greater impairment in Delayed Auditory/Verbal Memory than patients with PCA. PCA is characterized by significant atrophy of the occipital and parietal regions and severe impairments in visuospatial functioning.JA is funded by a doctoral grant from the Foundation for Science and Technology, FCT (SFRH/BD/64457/2009, co-funded by FSE/POPH). JA and AS are funded by project PIC/IC/83290/2007, which is supported by FEDER (POFC-COMPETE) and FCT. JMS is supported by a fellowship of the project SwitchBox-FP7-HEALTH-2010-grant 259772-2. These organizations had no role in the study design, data collection, analysis, interpretation, or in the decision to submit the paper for publication

A primary electron beam facility at CERN -- eSPS Conceptual design report

The design of a primary electron beam facility at CERN is described. The study has been carried out within the framework of the wider Physics Beyond Colliders study. It re-enables the Super Proton Synchrotron (SPS) as an electron accelerator, and leverages the development invested in Compact Linear Collider (CLIC) technology for its injector and as an accelerator research and development infrastructure. The facility would be relevant for several of the key priorities in the 2020 update of the European Strategy for Particle Physics, such as an electron-positron Higgs factory, accelerator R\&D, dark sector physics, and neutrino physics. In addition, it could serve experiments in nuclear physics. The electron beam delivered by this facility would provide access to light dark matter production significantly beyond the targets predicted by a thermal dark matter origin, and for natures of dark matter particles that are not accessible by direct detection experiments. It would also enable electro-nuclear measurements crucial for precise modelling the energy dependence of neutrino-nucleus interactions, which is needed to precisely measure neutrino oscillations as a function of energy. The implementation of the facility is the natural next step in the development of X-band high-gradient acceleration technology, a key technology for compact and cost-effective electron/positron linacs. It would also become the only facility with multi-GeV drive bunches and truly independent electron witness bunches for plasma wakefield acceleration. A second phase capable to deliver positron witness bunches would make it a complete facility for plasma wakefield collider studies. [...

CTF3 Design Report: Preliminary Phase

The design of CLIC is based on a two-beam scheme, where the short pulses of high power 30 GHz RF are extracted from a drive beam running parallel to the main beam. The 3rd generation CLIC Test Facility (CTF3) will demonstrate the generation of the drive beam with the appropriate time structure, the extraction of 30 GHz RF power from this beam, as well as acceleration of a probe beam with 30 GHz RF cavities. The project makes maximum use of existing equipment and infrastructure of the LPI complex, which became available after the closure of LEP. In the first stage of the project, the "Preliminary Phase", the existing LIL linac and the EPA ring, both modified to suit the new requirements, are used to investigate the technique of frequency multiplication by means of interleaving bunches from subsequent trains. This report describes the design of this phase