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In order to guarantee the fulfillment of their complex lifecycle, adult filarial nematodes release millions of microfilariae (MF), which are taken up by mosquito vectors. The current strategy to eliminate lymphatic filariasis as a public health problem focuses upon interrupting this transmission through annual mass drug administration (MDA). It remains unclear however, how many rounds of MDA are required to achieve low enough levels of MF to cease transmission. Interestingly, with the development of further diagnostic tools a relatively neglected cohort of asymptomatic (non-lymphedema) amicrofilaremic (latent) individuals has become apparent. Indeed, epidemiological studies have suggested that there are equal numbers of patent (MF(+)) and latent individuals. Since the latter represent a roadblock for transmission, we studied differences in immune responses of infected asymptomatic male individuals (n = 159) presenting either patent (n = 92 MF(+)) or latent (n = 67 MF(-)) manifestations of Wuchereria bancrofti. These individuals were selected on the basis of MF, circulating filarial antigen in plasma and detectable worm nests. Immunological profiles of either Th1/Th17, Th2, regulatory or innate responses were determined after stimulation of freshly isolated PBMCs with either filarial-specific extract or bystander stimuli. In addition, levels of total and filarial-specific antibodies, both IgG subclasses and IgE, were ascertained from plasma. Results from these individuals were compared with those from 22 healthy volunteers from the same endemic area. Interestingly, we observed that in contrast to MF(+) patients, latent infected individuals had lower numbers of worm nests and increased adaptive immune responses including antigen-specific IL-5. These data highlight the immunosuppressive status of MF(+) individuals, regardless of age or clinical hydrocele and reveal immunological profiles associated with latency and immune-mediated suppression of parasite transmission.

Background Plasmodium falciparum merozoites expose at their surface a large protein complex, which is composed of fragments of merozoite surface protein 1 (MSP-1; called MSP-1 83 , MSP-1 30 , MSP-1 38 , and MSP-1 42 ) plus associated processing products of MSP-6 and MSP-7. During erythrocyte invasion this complex, as well as an integral membrane protein called apical membrane antigen-1 (AMA-1), is shed from the parasite surface following specific proteolysis. Components of the MSP-1/6/7 complex and AMA-1 are presently under development as malaria vaccines. Methods The specificities and effects of antibodies directed against MSP-1, MSP-6, MSP-7 on the growth of blood stage parasites were studied using ELISA and the pLDH-assay. To understand the mode of action of these antibodies, their effects on processing of MSP-1 and AMA-1 on the surface of merozoites were investigated. Results Antibodies targeting epitopes located throughout the MSP-1/6/7 complex interfere with shedding of MSP-1, and as a consequence prevent erythrocyte invasion. Antibodies targeting the MSP-1/6/7 complex have no effect on the processing and shedding of AMA-1 and, similarly, antibodies blocking the shedding of AMA-1 do not affect cleavage of MSP-1, suggesting completely independent functions of these proteins during invasion. Furthermore, some epitopes, although eliciting highly inhibitory antibodies, are only poorly recognized by the immune system when presented in the structural context of the intact antigen. Conclusions The findings reported provide further support for the development of vaccines based on MSP-1/6/7 and AMA-1, which would possibly include a combination of these antigens.

Background 37 million individuals are currently infected with Onchocerca volvulus ( O. volvulus ), a parasitic nematode that elicits various dermal manifestations and eye damage in man. Disease control is primarily based on distributing ivermectin in mass drug administration (MDA) programmes which aim at breaking transmission by eliminating microfilariae (MF), the worm's offspring. The majority of infected individuals present generalized onchocerciasis, which is characterized by hyporesponsive immune responses and high parasite burden including MF. Recently, in areas that have been part of MDA programmes, individuals have been identified that present nodules but are amicrofilaridermic (a-MF) and our previous study showed that this group has a distinct immune profile. Expanding on those findings we determined the immune responses of O. volvulus -infected individuals to a Plasmodium- derived antigen MSP-1 (merozoite surface protein-1), which is required by the parasite to enter erythrocytes. Methods Isolated PBMCs from O. volvulus -infected individuals (164 MF + and 46 a-MF) and non-infected volunteers from the same region (NEN), were stimulated with MSP-1 and the resulting supernatant screened for the presence of IL-5, IL-13, IFN-γ, TNF-α, IL-6, IL-17A and IL-10. These findings were then further analyzed following regression analysis using the covariates MF, ivermectin (IVM) and region. The latter referred to the Central or Ashanti regions of Ghana, which, at the time sampling, had received 8 or 1 round of MDA respectively. Results IL-5, IL-13 and IFN-γ responses to MSP-1 were not altered between NEN and O. volvulus -infected individuals nor were any associations revealed in the regression analysis. IL-10, IL-6 and TNF-α MSP-1 responses were, however, significantly elevated in cultures from infected individuals. Interestingly, when compared to a-MF individuals, MSP-induced IL-17A responses were significantly higher in MF + patients. Following multivariable regression analysis these IL-10, IL-6, TNF-α and IL-17A responses were all dominantly associated with the regional covariate. Conclusions Consequently, areas with a lowered infection pressure due to IVM MDA appear to influence bystander responses to Plasmodium -derived antigens in community members even if they have not regularly participated in the therapy.

Efficacy trials of antibody-inducing protein-in-adjuvant vaccines targeting the blood-stage Plasmodium falciparum malaria parasite have so far shown disappointing results. The induction of cell-mediated responses in conjunction with antibody responses is thought to be one alternative strategy that could achieve protective efficacy in humans. Here, we prepared chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) replication-deficient vectors encoding the well-studied P. falciparum blood-stage malaria antigen merozoite surface protein 1 (MSP1). A phase Ia clinical trial was conducted in healthy adults of a ChAd63-MVA MSP1 heterologous prime-boost immunization regime. The vaccine was safe and generally well tolerated. Fewer systemic adverse events (AEs) were observed following ChAd63 MSP1 than MVA MSP1 administration. Exceptionally strong T-cell responses were induced, and these displayed a mixed of CD4+ and CD8+ phenotype. Substantial MSP1-specific serum immunoglobulin G (IgG) antibody responses were also induced, which were capable of recognizing native parasite antigen, but these did not reach titers sufficient to neutralize P. falciparum parasites in vitro. This viral vectored vaccine regime is thus a leading approach for the induction of strong cellular and humoral immunogenicity against difficult disease targets in humans. Further studies are required to assess whether this strategy can achieve protective efficacy against blood-stage malaria infection.

The general purpose of this study was to examine the comparability of the MMPI and the MMPI-2 in relation to their ability to differentiate presenting concerns of a ministerial population. The problem investigated in this study was three-fold: (a) to determine whether or not in a clinical, outpatient population the clinical scales of the MMPI and the MMPI-2 produce highly similar T scores and highest-point scale codes and differentiate presenting problems with a similar hit rate; (b) to determine whether the Family Problems and Work Interference Content scales of the MMPI-2 account for a significant amount of unique variance in differentiating between presenting concerns of marital conflict and work conflicts independent of the clinical scales; and (c) to determine whether the clinical scales of the MMPI-2 account for a significant amount of unique variance in differentiating between presenting concerns of marital conflict and work conflicts independent of the Family Problems and Work Interference Content scales of the MMPI-2. This investigation employed an ex post facto design. The subjects under investigation were drawn from male ministers who received testing and counseling at EMERGE Counseling Center in Akron, Ohio during the years 1989 to 1993. The presenting concerns that had been generated by the case histories of these 300 ministers were classified into seven categories: depression, marital conflict, sexual concerns, extramarital affair, work conflicts, anxiety and stress, and anger problems. The descriptive statistics included means, standard deviations, ranges, and frequencies. The General Linear Model and chi-square procedures were utilized to test the research hypotheses and data analyses. No significant differences were found between the clinical scales of the MMPI and the MMPI-2, or between the eight clinical scales and the two Content scales of the MMPI-2 when differentiating between presenting concerns. In both tests, the clinical scales significantly differentiated between the presenting concerns. However, the single highest pathological score did not significantly differentiate between the presenting concerns in either test. This study supported the equivalency of the two instruments. Implications were drawn from this study regarding the equivalency and the efficacy of the scales and scale codes of the two tests.

Flexible metal-organic frameworks (MOFs) are structurally flexible, porous, crystalline solids that show a structural transition in response to a stimulus. If MOF-based solid-state and microelectronic devices are to be capable of leveraging such structural flexibility, then the integration of MOF thin films into a device configuration is crucial. Here we report the targeted and precise anchoring of Cu-based alkylether-functionalised layered-pillared MOF crystallites onto substrates via stepwise liquid-phase epitaxy. The structural transformation during methanol sorption is monitored by in-situ grazing incidence X-ray diffraction. Interestingly, spatially-controlled anchoring of the flexible MOFs on the surface induces a distinct structural responsiveness which is different from the bulk powder and can be systematically controlled by varying the crystallite characteristics, for instance dimensions and orientation. This fundamental understanding of thin-film flexibility is of paramount importance for the rational design of MOF-based devices utilising the structural flexibility in specific applications such as selective sensors. Understanding the structural dynamics of flexible metal-organic frameworks at a thin-film level is key if they are to be implemented in devices. Here, Fischer and colleagues anchor flexible MOF crystallites onto substrates and identify a structural responsiveness that is distinct to that of the bulk.

Human population expansion and associated degradation of the habitat of many wildlife species cause loss of biodiversity and species extinctions. The small Simen Mountains National Park in Ethiopia is one of the last strongholds for the preservation of a number of afro-alpine mammals, plants and birds, and it is home to the rare endemic Walia ibex, Capra walie. The narrow distribution range of this species as well as potential competition for resources with livestock, especially with domestic goat, Capra hircus, may compromise its future survival. Based on a curated afro-alpine taxonomic reference library constructed for plant taxon identification, we investigated the diet of the Walia ibex and addressed the dietary overlap with domestic goat using DNA metabarcoding of faecal samples. Faeces of both species were collected from different localities in the National Park. We show that both species are browsers, with forbs, shrubs and trees comprising the largest proportion of their diet, supplemented by grasses. There was a considerable overlap in dietary preferences. Several of the preferred diet items of the Walia ibex (Alchemilla sp., Hypericum revolutum, Erica arborea and Rumex sp.) were also among the most preferred diet items of the domestic goat. These results indicate that there is potential for competition between the two species, especially during the dry season, when resources are limited. Our findings, in combination with the expected increase in domestic herbivores, suggest that management plans should consider the potential threat posed by domestic goats to ensure future survival of the endangered Walia ibex.

Single Xe clusters are superheated using an intense optical laser pulse and the structural evolution is imaged with a single X-ray pulse. Ultrafast surface softening on the nanometre scale is resolved within 100 fs at the vacuum/sample interface. The ability to observe ultrafast structural changes in nanoscopic samples is essential for understanding non-equilibrium phenomena such as chemical reactions 1 , matter under extreme conditions 2 , ultrafast phase transitions 3 and intense light–matter interactions 4 . Established imaging techniques are limited either in time or spatial resolution and typically require samples to be deposited on a substrate, which interferes with the dynamics. Here, we show that coherent X-ray diffraction images from isolated single samples can be used to visualize femtosecond electron density dynamics. We recorded X-ray snapshot images from a nanoplasma expansion, a prototypical non-equilibrium phenomenon 4 , 5 . Single Xe clusters are superheated using an intense optical laser pulse and the structural evolution of the sample is imaged with a single X-ray pulse. We resolved ultrafast surface softening on the nanometre scale at the plasma/vacuum interface within 100 fs of the heating pulse. Our study is the first time-resolved visualization of irreversible femtosecond processes in free, individual nanometre-sized samples.

Conservation of biodiversity may in the future increasingly depend upon the availability of scientific information to set suitable restoration targets. In traditional paleoecology, sediment-based pollen provides a means to define preanthropogenic impact conditions, but problems in establishing the exact provenance and ecologically meaningful levels of taxonomic resolution of the evidence are limiting. We explored the extent to which the use of sedimentary ancient DNA (sedaDNA) may complement pollen data in reconstructing past alpine environments in the tropics. We constructed a record of afro-alpine plants retrieved from DNA preserved in sediment cores from 2 volcanic crater sites in the Albertine Rift, eastern Africa. The record extended well beyond the onset of substantial anthropogenic effects on tropical mountains. To ensure high-quality taxonomic inference from the sedaDNA sequences, we built an extensive DNA reference library covering the majority of the afro-alpine flora, by sequencing DNA from taxonomically verified specimens. Comparisons with pollen records from the same sediment cores showed that plant diversity recovered with sedaDNA improved vegetation reconstructions based on pollen records by revealing both additional taxa and providing increased taxonomic resolution. Furthermore, combining the 2 measures assisted in distinguishing vegetation change at different geographic scales; sedaDNA almost exclusively reflects local vegetation, whereas pollen can potentially originate from a wide area that in highlands in particular can span several ecozones. Our results suggest that sedaDNA may provide information on restoration targets and the nature and magnitude of human-induced environmental changes, including in high conservation priority, biodiversity hotspots, where understanding of preanthropogenic impact (or reference) conditions is highly limited. La conservación de la biodiversidad en el futuro puede depender cada vez más de la disponibilidad de la información científica para establecer objetivos de restauración adecuados. En la paleoecología tradicional el polen hallado en sedimentos proporciona un medio para definir las condiciones de impactos preantropogénicas, pero hay problemas en el momento de establecer su proveniencia exacta y los niveles ecológicamente significativos de su resolución taxonómica. Exploramos el grado en el que el uso de ADN sedimentario antiguo (ADN seda) puede complementar la información del polen en la reconstrucción de ambientes alpinos del pasado en los trópicos. Construimos un registro de plantas afro-alpinas tomadas de ADN preservado en núcleos sedimentarios de dos sitios de cráteres volcánicos en la Falla Albertina, al oriente de África. El registro se extendió más allá del comienzo de los efectos antropogénicos sustanciales en las montañas tropicales. Para asegurar la inferencia taxonómica de alta calidad de las secuencias de ADN seda, construimos una biblioteca extensa de referencias de ADN cubriendo la mayoría de la flora afro-alpina, secuenciado el ADN de especímenes taxonómicamente verificados. Las comparaciones con los registros de polen de los mismos núcleos sedimentarios mostraron que la diversidad de plantas recuperada con el ADN seda mejoró las reconstrucciones de vegetación con base en los registros de polen al revelar tanto taxones adicionales como proporcionando una resolución taxonómica incrementada. Además, el combinar las dos medidas ayudó a distinguir cambios en la vegetación en diferentes escalas geográficas; el ADN seda casi siempre refleja exclusivamente la vegetación local, mientras que el polen puede originarse potencialmente a partir de un área amplia que en las tierras altas en particular puede abarcar varias ecozonas. Nuestros resultados sugieren que el ADN seda puede proporcionar información sobre los objetivos de restauración y la naturaleza y magnitud de los cambios ambientales inducidos por el ser humano, incluyendo en prioridad de alta conservación, hotspots de biodiversidad, donde entender las condiciones del impacto preantropogénico (o su referencia) es difícil.

X-ray free-electron lasers have enabled new approaches to the structural determination of protein crystals that are too small or radiation-sensitive for conventional analysis 1 . For sufficiently short pulses, diffraction is collected before significant changes occur to the sample, and it has been predicted that pulses as short as 10 fs may be required to acquire atomic-resolution structural information 1 , 2 , 3 , 4 . Here, we describe a mechanism unique to ultrafast, ultra-intense X-ray experiments that allows structural information to be collected from crystalline samples using high radiation doses without the requirement for the pulse to terminate before the onset of sample damage. Instead, the diffracted X-rays are gated by a rapid loss of crystalline periodicity, producing apparent pulse lengths significantly shorter than the duration of the incident pulse. The shortest apparent pulse lengths occur at the highest resolution, and our measurements indicate that current X-ray free-electron laser technology 5 should enable structural determination from submicrometre protein crystals with atomic resolution. Researchers describe a mechanism capable of compressing fast and intense X-ray pulses through the rapid loss of crystalline periodicity. It is hoped that this concept, combined with X-ray free-electron laser technology, will allow scientists to obtain structural information at atomic resolutions.