Studies on processing, particle formation, and immunogenicity of the HIV-1 gag gene product: a possible component of a HIV vaccine

Antigens in a particulate conformation were shown to be highly immunogenic in mammals. For this reason, the particle forming capacity of derivatives of the HIV-1 group specific core antigen p55 gag was assayed and compared dependent on various expression systems: recombinant bacteria, vaccinia- and baculoviruses were established encoding the entire core protein p55 either in its authentic sequence or lacking the myristylation consensus signal. Moreover, p55 gag was expressed in combination with the protease (p55-PR) or with the entire polymerase (p55-pol), respectively. Budding of 100-160 nm p55 core particles, resembling immature HIV-virions, was observed in the eucaryotic expression systems only. In comparison to the vaccinia virus driven expression of p55 in mammalian cells, considerably higher yields of particulate core antigen were obtained by infection of Spodoptera frugiperda (Sf9) insect cells with the recombinant Autographa californica nuclear polyhedrosis (AcMNPV) baculovirus. Mutation of the NH2-terminal myristylation signal sequence prevented budding of the immature core particles. Expression of the HIV p55-PR gene construct by recombinant baculovirus resulted in complete processing of the p55 gag precursor molecule in this system. The introduction of an artificial frameshift near the natural frameshift site resulted in constitutive expression of the viral protease and complete processing of p55, both in Escherichia coli and in vaccinia virus infected cells. Interestingly, significant processing of p55 resembling that of HIV infected H9 cells could also be achieved in the vaccinia system by fusing the entire pol gene to the gag gene. Moreover, processing was not found to be dependent on amino-terminal myristylation of the gag procursor molecule, which is in contrast to observations with type C and type D retrovirus. However, complete processing of p55 into p24, p17, p9 and p6 abolished particle formation. Purified immature HIV-virus like particles were highly immunogenic in rabbits, leading to a strong humoral immune response after immunization. Empty immature p55 gag particles represent a noninfectious and attractive candidate for a basic vaccine component

Lyapunov design of a simple step-size adaptation strategy based on success

A simple success-based step-size adaptation rule for singleparent Evolution Strategies is formulated, and the setting of the corresponding parameters is considered. Theoretical convergence on the class of strictly unimodal functions of one variable that are symmetric around the optimum is investigated using a stochastic Lyapunov function method developed by Semenov and Terkel [5] in the context of martingale theory. General expressions for the conditional expectations of the next values of step size and distance to the optimum under (1 +, λ)-selection are analytically derived, and an appropriate Lyapunov function is constructed. Convergence rate upper bounds, as well as adaptation parameter values, are obtained through numerical optimization for increasing values of λ. By selecting the number of offspring that minimizes the bound on the convergence rate with respect to the number of function evaluations, all strategy parameter values result from the analysis

The role of working memory and contextual constraints in children's processing of relative clauses

An auditory sentence comprehension task investigated the extent to which the integration of contextual and structural cues was mediated by verbal memory span with 32 English-speaking 6- to 8-year old children. Spoken relative clause sentences were accompanied by visual context pictures which fully (depicting the actions described within the relative clause) or partially (depicting several referents) met the pragmatic assumptions of relativisation. Comprehension of the main and relative clauses of centre-embedded and right-branching structures was compared for each context. Pragmatically-appropriate contexts exerted a positive effect on relative clause comprehension, but children with higher memory spans demonstrated a further benefit for main clauses. Comprehension for centre-embedded main clauses was found to be very poor, independently of either context or memory span. The results suggest that children have access to adult-like linguistic processing mechanisms, and that sensitivity to extra-linguistic cues is evident in young children and develops as cognitive capacity increases

From programme theory to logic models for multispecialty community providers: a realist evidence synthesis

This is the final version. Available from the publisher via the DOI in this record.Background: The NHS policy of constructing multispecialty community providers (MCPs) rests on a complex set of assumptions about how health systems can replace hospital use with enhanced primary care for people with complex, chronic or multiple health problems, while contributing savings to health-care budgets. Objectives: To use policy-makers’ assumptions to elicit an initial programme theory (IPT) of how MCPs can achieve their outcomes and to compare this with published secondary evidence and revise the programme theory accordingly. Design: Realist synthesis with a three-stage method: (1) for policy documents, elicit the IPT underlying the MCP policy, (2) review and synthesise secondary evidence relevant to those assumptions and (3) compare the programme theory with the secondary evidence and, when necessary, reformulate the programme theory in a more evidence-based way. Data sources: Systematic searches and data extraction using (1) the Health Management Information Consortium (HMIC) database for policy statements and (2) topically appropriate databases, including MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, PsycINFO, the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Applied Social Sciences Index and Abstracts (ASSIA). A total of 1319 titles and abstracts were reviewed in two rounds and 116 were selected for full-text data extraction. We extracted data using a formal data extraction tool and synthesised them using a framework reflecting the main policy assumptions. Results: The IPT of MCPs contained 28 interconnected context–mechanism–outcome relationships. Few policy statements specified what contexts the policy mechanisms required. We found strong evidence supporting the IPT assumptions concerning organisational culture, interorganisational network management, multidisciplinary teams (MDTs), the uses and effects of health information technology (HIT) in MCP-like settings, planned referral networks, care planning for individual patients and the diversion of patients from inpatient to primary care. The evidence was weaker, or mixed (supporting some of the constituent assumptions but not others), concerning voluntary sector involvement, the effects of preventative care on hospital admissions and patient experience, planned referral networks and demand management systems. The evidence about the effects of referral reductions on costs was equivocal. We found no studies confirming that the development of preventative care would reduce demands on inpatient services. The IPT had overlooked certain mechanisms relevant to MCPs, mostly concerning MDTs and the uses of HITs. Limitations: The studies reviewed were limited to Organisation for Economic Co-operation and Development countries and, because of the large amount of published material, the period 2014–16, assuming that later studies, especially systematic reviews, already include important earlier findings. No empirical studies of MCPs yet existed. Conclusions: Multidisciplinary teams are a central mechanism by which MCPs (and equivalent networks and organisations) work, provided that the teams include the relevant professions (hence, organisations) and, for care planning, individual patients. Further primary research would be required to test elements of the revised logic model, in particular about (1) how MDTs and enhanced general practice compare and interact, or can be combined, in managing referral networks and (2) under what circumstances diverting patients from in-patient to primary care reduces NHS costs and improves the quality of patient experience.National Institute for Health Research (NIHR

Passive-performance, analysis, and upgrades of a 1-ton seismic attenuation system

The 10m Prototype facility at the Albert-Einstein-Institute (AEI) in Hanover, Germany, employs three large seismic attenuation systems to reduce mechanical motion. The AEI Seismic-Attenuation-System (AEI-SAS) uses mechanical anti-springs in order to achieve resonance frequencies below 0.5Hz. This system provides passive isolation from ground motion by a factor of about 400 in the horizontal direction at 4Hz and in the vertical direction at 9Hz. The presented isolation performance is measured under vacuum conditions using a combination of commercial and custom-made inertial sensors. Detailed analysis of this performance led to the design and implementation of tuned dampers to mitigate the effect of the unavoidable higher order modes of the system. These dampers reduce RMS motion substantially in the frequency range between 10 and 100Hz in 6 degrees of freedom. The results presented here demonstrate that the AEI-SAS provides substantial passive isolation at all the fundamental mirror-suspension resonances

The importance of ship log data: reconstructing North Atlantic, European and Mediterranean sea level pressure fields back to 1750

Local to regional climate anomalies are to a large extent determined by the state of the atmospheric circulation. The knowledge of large-scale sea level pressure (SLP) variations in former times is therefore crucial when addressing past climate changes across Europe and the Mediterranean. However, currently available SLP reconstructions lack data from the ocean, particularly in the pre-1850 period. Here we present a new statistically-derived 5°×5° resolved gridded seasonal SLP dataset covering the eastern North Atlantic, Europe and the Mediterranean area (40°W-50°E; 20°N-70°N) back to 1750 using terrestrial instrumental pressure series and marine wind information from ship logbooks. For the period 1750-1850, the new SLP reconstruction provides a more accurate representation of the strength of the winter westerlies as well as the location and variability of the Azores High than currently available multiproxy pressure field reconstructions. These findings strongly support the potential of ship logbooks as an important source to determine past circulation variations especially for the pre-1850 period. This new dataset can be further used for dynamical studies relating large-scale atmospheric circulation to temperature and precipitation variability over the Mediterranean and Eurasia, for the comparison with outputs from GCMs as well as for detection and attribution studie