The 'tumble' departure mode in weightshift-controlled

The cost of private or recreational flying is high for most conventional aircraft types. During the last 25 years, however, an alternative has become available in the form of the microlight aircraft. It has a relatively low cost of ownership and has opened up flying to a greater audience. However, there have been a number of accidents, usually fatal, to this class of aircraft, which could not be explained through any conventional understanding. The reason for these accidents, which involve a departure from controlled flight followed by aircraft structural failure (generally including mechanical failure of the basebar, wingtips and leading edge), has become known as the `tumble’, owing to the basic motion of the aircraft. This paper analyses the tumble mode, from its initiation through to the steady rotation condition. History has shown that the tumble mode has always resulted in the destruction of an aircraft. In consequence, it is the authors’ opinion that consideration of the tumble during the approval of new designs should concentrate upon avoidance, since there is no identi®able recovery mechanism from the established mode without the use of an external safety device. A programme of research into this phenomenon was initiated in 1997. The peculiar nature of the tumble motion has required the aerodynamic modelling to address the effects of a high pitch rate, which has led to the introduction of unsteady aerodynamic effects. This paper sets out to describe and explain the mode, leading to a model that might reasonably be developed to produce relatively tumble resistant aircraft. Finally, the methods of possible entry are explained; it is intended that this information may be used in pilot training to ensure the avoidance ofthe tumble instability

A phase 1 trial dose-escalation study of tipifarnib on a week-on, week-off schedule in relapsed, refractory or high-risk myeloid leukemia.

Inhibition of farnesyltransferase (FT) activity has been associated with in vitro and in vivo anti-leukemia activity. We report the results of a phase 1 dose-escalation study of tipifarnib, an oral FT inhibitor, in patients with relapsed, refractory or newly diagnosed (if over age 70) acute myelogenous leukemia (AML), on a week-on, week-off schedule. Forty-four patients were enrolled, two patients were newly diagnosed, and the rest were relapsed or refractory to previous treatment, with a median age of 61 (range 33-79). The maximum tolerated dose was determined to be 1200 mg given orally twice daily (b.i.d.) on this schedule. Cycle 1 dose-limiting toxicities were hepatic and renal. There were three complete remissions seen, two at the 1200 mg b.i.d. dose and one at the 1000 mg b.i.d. dose, with minor responses seen at the 1400 mg b.i.d. dose level. Pharmacokinetic studies performed at doses of 1400 mg b.i.d. showed linear behavior with minimal accumulation between days 1-5. Tipifarnib administered on a week-on, week-off schedule shows activity at higher doses, and represents an option for future clinical trials in AML

Complete analysis of the B-cell response to a protein antigen, from in vivo germinal centre formation to 3-D modelling of affinity maturation

Somatic hypermutation of immunoglobulin variable region genes occurs within germinal centres (GCs) and is the process responsible for affinity maturation of antibodies during an immune response. Previous studies have focused almost exclusively on the immune response to haptens, which may be unrepresentative of epitopes on protein antigens. In this study, we have exploited a model system that uses transgenic B and CD4<sup>+</sup> T cells specific for hen egg lysozyme (HEL) and a chicken ovalbumin peptide, respectively, to investigate a tightly synchronized immune response to protein antigens of widely differing affinities, thus allowing us to track many facets of the development of an antibody response at the antigen-specific B cell level in an integrated system <i>in</i> <i>vivo</i>. Somatic hypermutation of immunoglobulin variable genes was analysed in clones of transgenic B cells proliferating in individual GCs in response to HEL or the cross-reactive low-affinity antigen, duck egg lysozyme (DEL). Molecular modelling of the antibody–antigen interface demonstrates that recurring mutations in the antigen-binding site, selected in GCs, enhance interactions of the antibody with DEL. The effects of these mutations on affinity maturation are demonstrated by a shift of transgenic serum antibodies towards higher affinity for DEL in DEL-cOVA immunized mice. The results show that B cells with high affinity antigen receptors can revise their specificity by somatic hypermutation and antigen selection in response to a low-affinity, cross-reactive antigen. These observations shed further light on the nature of the immune response to pathogens and autoimmunity and demonstrate the utility of this novel model for studies of the mechanisms of somatic hypermutation

Participating locally and nationally: explaining the offline and online activism of British party members

Drawing on survey data on the members of six British parties gathered in the immediate aftermath of the general election of 2015, this article addresses the question of what members do for their parties during campaigns. It identifies a key distinction between traditional forms of activity and more recent forms of online campaign participation. While the well-established general incentives theory of participation continues to offer a useful basis for explaining both types of campaign activism, we find that our understanding is significantly enhanced by considering the impact of national and local political contexts. Whereas the former chiefly adds explanatory value to the model of online participation by party members, the latter considerably improves the model of offline participation

Assisted evolution enables HIV-1 to overcome a high trim5α-imposed genetic barrier to rhesus macaque tropism

Diversification of antiretroviral factors during host evolution has erected formidable barriers to cross-species retrovirus transmission. This phenomenon likely protects humans from infection by many modern retroviruses, but it has also impaired the development of primate models of HIV-1 infection. Indeed, rhesus macaques are resistant to HIV-1, in part due to restriction imposed by the TRIM5α protein (rhTRIM5α). Initially, we attempted to derive rhTRIM5α-resistant HIV-1 strains using two strategies. First, HIV-1 was passaged in engineered human cells expressing rhTRIM5α. Second, a library of randomly mutagenized capsid protein (CA) sequences was screened for mutations that reduced rhTRIM5α sensitivity. Both approaches identified several individual mutations in CA that reduced rhTRIM5α sensitivity. However, neither approach yielded mutants that were fully resistant, perhaps because the locations of the mutations suggested that TRIM5α recognizes multiple determinants on the capsid surface. Moreover, even though additive effects of various CA mutations on HIV-1 resistance to rhTRIM5α were observed, combinations that gave full resistance were highly detrimental to fitness. Therefore, we employed an 'assisted evolution' approach in which individual CA mutations that reduced rhTRIM5α sensitivity without fitness penalties were randomly assorted in a library of viral clones containing synthetic CA sequences. Subsequent passage of the viral library in rhTRIM5α-expressing cells resulted in the selection of individual viral species that were fully fit and resistant to rhTRIM5α. These viruses encoded combinations of five mutations in CA that conferred complete or near complete resistance to the disruptive effects of rhTRIM5α on incoming viral cores, by abolishing recognition of the viral capsid. Importantly, HIV-1 variants encoding these CA substitutions and SIVmac239 Vif replicated efficiently in primary rhesus macaque lymphocytes. These findings demonstrate that rhTRIM5α is difficult to but not impossible to evade, and doing so should facilitate the development of primate models of HIV-1 infection

Comparison of governance approaches for the control of antimicrobial resistance: Analysis of three European countries

Policy makers and governments are calling for coordination to address the crisis emerging from the ineffectiveness of current antibiotics and stagnated pipe-line of new ones – antimicrobial resistance (AMR). Wider contextual drivers and mechanisms are contributing to shifts in governance strategies in health care, but are national health system approaches aligned with strategies required to tackle antimicrobial resistance? This article provides an analysis of governance approaches within healthcare systems including: priority setting, performance monitoring and accountability for AMR prevention in three European countries: England, France and Germany. Advantages and unresolved issues from these different experiences are reported, concluding that mechanisms are needed to support partnerships between healthcare professionals and patients with democratized decision-making and accountability via collaboration. But along with this multi-stakeholder approach to governance, a balance between regulation and persuasion is needed

Which activities threaten independent living of elderly when becoming problematic : inspiration for meaningful service robot functionality

Purpose: In light of the increasing elderly population and the growing demand for home care, the potential of robot support is given increasing attention. In this paper, an inventory of activities was made that threaten independent living of elderly when becoming problematic. Results will guide the further development of an existing service robot, the Care-O-bot®. Method: A systematic literature search of PubMed was performed, focused on the risk factors for institutionalization. Additionally, focus group sessions were conducted in the Netherlands, United Kingdom and France. In these focus group sessions, problematic activities threatening the independence of elderly people were discussed. Three separate target groups were included in the focus group sessions: (1) elderly persons (n = 41), (2) formal caregivers (n = 40) and (3) informal caregivers (n = 32). Results: Activities within the International Classification of Functioning domains mobility, self-care, and interpersonal interaction and relationships were found to be the most problematic. Conclusions: A distinct set of daily activities was identified that may threaten independent living, but no single activity could be selected as the main activity causing a loss of independence as it is often a combination of problematic activities that is person-specific. Supporting the problematic activities need not involve a robotic solution Read More: http://informahealthcare.com/doi/abs/10.3109/17483107.2013.840861Peer reviewe

Single donor ionization energies in a nanoscale CMOS channel

One consequence of the continued downwards scaling of transistors is the reliance on only a few discrete atoms to dope the channel, and random fluctuations of the number of these dopants is already a major issue in the microelectonics industry. While single-dopant signatures have been observed at low temperature, studying the impact of only one dopant up to room temperature requires extremely small lengths. Here, we show that a single arsenic dopant dramatically affects the off-state behavior of an advanced microelectronics field effect transistor (FET) at room temperature. Furthermore, the ionization energy of this dopant should be profoundly modified by the close proximity of materials with a different dielectric constant than the host semiconductor. We measure a strong enhancement, from 54meV to 108meV, of the ionization energy of an arsenic atom located near the buried oxide. This enhancement is responsible for the large current below threshold at room temperature and therefore explains the large variability in these ultra-scaled transistors. The results also suggest a path to incorporating quantum functionalities into silicon CMOS devices through manipulation of single donor orbitals

Assessment of a novel, capsid-modified adenovirus with an improved vascular gene transfer profile

<p>Background: Cardiovascular disorders, including coronary artery bypass graft failure and in-stent restenosis remain significant opportunities for the advancement of novel therapeutics that target neointimal hyperplasia, a characteristic of both pathologies. Gene therapy may provide a successful approach to improve the clinical outcome of these conditions, but would benefit from the development of more efficient vectors for vascular gene delivery. The aim of this study was to assess whether a novel genetically engineered Adenovirus could be utilised to produce enhanced levels of vascular gene expression.</p> <p>Methods: Vascular transduction capacity was assessed in primary human saphenous vein smooth muscle and endothelial cells using vectors expressing the LacZ reporter gene. The therapeutic capacity of the vectors was compared by measuring smooth muscle cell metabolic activity and migration following infection with vectors that over-express the candidate therapeutic gene tissue inhibitor of matrix metalloproteinase-3 (TIMP-3).</p> <p>Results: Compared to Adenovirus serotype 5 (Ad5), the novel vector Ad5T*F35++ demonstrated improved binding and transduction of human vascular cells. Ad5T*F35++ mediated expression of TIMP-3 reduced smooth muscle cell metabolic activity and migration in vitro. We also demonstrated that in human serum samples pre-existing neutralising antibodies to Ad5T*F35++ were less prevalent than Ad5 neutralising antibodies.</p> <p>Conclusions: We have developed a novel vector with improved vascular transduction and improved resistance to human serum neutralisation. This may provide a novel vector platform for human vascular gene transfer.</p&gt

Persistence within dendritic cells marks an antifungal evasion and dissemination strategy of Aspergillus terreus

Aspergillus terreus is an airborne human fungal pathogen causing life-threatening invasive aspergillosis in immunocompromised patients. In contrast to Aspergillus fumigatus, A. terreus infections are associated with high dissemination rates and poor response to antifungal treatment. Here, we compared the interaction of conidia from both fungal species with MUTZ-3-derived dendritic cells (DCs). After phagocytosis, A. fumigatus conidia rapidly escaped from DCs, whereas A. terreus conidia remained persisting with long-term survival. Escape from DCs was independent from DHN-melanin, as A. terreus conidia expressing wA showed no increased intracellular germination. Within DCs A. terreus conidia were protected from antifungals, whereas A. fumigatus conidia were efficiently cleared. Furthermore, while A. fumigatus conidia triggered expression of DC activation markers such as CD80, CD83, CD54, MHCII and CCR7, persistent A. terreus conidia were significantly less immunogenic. Moreover, DCs confronted with A. terreus conidia neither produced pro-inflammatory nor T-cell stimulating cytokines. However, TNF-α addition resulted in activation of DCs and provoked the expression of migration markers without inactivating intracellular A. terreus conidia. Therefore, persistence within DCs and possibly within other immune cells might contribute to the low response of A. terreus infections to antifungal treatment and could be responsible for its high dissemination rates