Antibody and B cell responses to Plasmodium sporozoites

Antibodies are capable of blocking infection of the liver by Plasmodium sporozoites. Accordingly the induction of anti-sporozoite antibodies is a major aim of various vaccine approaches to malaria. In recent years our knowledge of the specificity and quantities of antibodies required for protection has been greatly expanded by clinical trials of various whole sporozoite and subunit vaccines. Moreover, the development of humanized mouse models and transgenic parasites have also aided our ability to assess the specificity of antibodies and their ability to block infection. Nonetheless, considerable gaps remain in our knowledge - in particular in understanding what antigens are recognized by infection blocking antibodies and in knowing how we can induce robust, long-lived antibody responses. Maintaining high levels of circulating antibodies is likely to be of primary importance, as antibodies must block infection in the short time it takes for sporozoites to reach the liver from the skin. It is clear that a better understanding of the development of protective B cell-mediated immunity will aid the development and refinement of malaria vaccines.The authors acknowledge the support of the Australian National University and Perpetual Foundation for research in the Cockburn laboratory

Complex responses to movement-based disease control: when livestock trading helps

Livestock disease controls are often linked to movements between farms, for example, via quarantine and pre- or post-movement testing. Designing effective controls, therefore, benefits from accurate assessment of herd-to-herd transmission. Household models of human infections make use of R*, the number of groups infected by an initial infected group, which is a metapopulation level analogue of the basic reproduction number R0 that provides a better characterization of disease spread in a metapopulation. However, existing approaches to calculate R* do not account for individual movements between locations which means we lack suitable tools for livestock systems. We address this gap using next-generation matrix approaches to capture movements explicitly and introduce novel tools to calculate R* in any populations coupled by individual movements. We show that depletion of infectives in the source group, which hastens its recovery, is a phenomenon with important implications for design and efficacy of movement-based controls. Underpinning our results is the observation that R* peaks at intermediate livestock movement rates. Consequently, under movement-based controls, infection could be controlled at high movement rates but persist at intermediate rates. Thus, once control schemes are present in a livestock system, a reduction in movements can counterintuitively lead to increased disease prevalence. We illustrate our results using four important livestock diseases (bovine viral diarrhoea, bovine herpes virus, Johne's disease and Escherichia coli O157) that each persist across different movement rate ranges with the consequence that a change in livestock movements could help control one disease, but exacerbate another

Near-IR studies of recurrent nova V745 Scorpii during its 2014 outburst

The recurrent nova (RN) V745 Scorpii underwent its third known outburst on 2014 February 6. Infrared monitoring of the eruption on an almost daily basis, starting from 1.3d after discovery, shows the emergence of a powerful blast wave generated by the high velocity nova ejecta exceeding 4000 kms$^{-1}$ plowing into its surrounding environment. The temperature of the shocked gas is raised to a high value exceeding 10$^{8}$K immediately after outburst commencement. The energetics of the outburst clearly surpass those of similar symbiotic systems like RS Oph and V407 Cyg which have giant secondaries. The shock does not show a free-expansion stage but rather shows a decelerative Sedov-Taylor phase from the beginning. Such strong shockfronts are known to be sites for $\gamma$ ray generation. V745 Sco is the latest nova, apart from five other known novae, to show $\gamma$ ray emission. It may be an important testbed to resolve the crucial question whether all novae are generically $\gamma$ ray emitters by virtue of having a circumbinary reservoir of material that is shocked by the ejecta rather than $\gamma$ ray generation being restricted to only symbiotic systems with a shocked red giant (RG) wind. The lack of a free-expansion stage favors V745 Sco to have a density enhancement around the white dwarf (WD), above that contributed by a RG wind. Our analysis also suggests that the WD in V745 Sco is very massive and a potential progenitor for a future SN Ia explosion.Comment: To appear in ApJ (Letters

Anti-DNA autoantibodies initiate experimental lupus nephritis by binding directly to the glomerular basement membrane in mice

The strongest serological correlate for lupus nephritis is antibody to double-stranded DNA, although the mechanism by which anti-DNA antibodies initiate lupus nephritis is unresolved. Most recent reports indicate that anti-DNA must bind chromatin in the glomerular basement membrane or mesangial matrix to form glomerular deposits. Here we determined whether direct binding of anti-DNA antibody to glomerular basement membrane is critical to initiate glomerular binding of anti-DNA in experimental lupus nephritis. Mice were co-injected with IgG monoclonal antibodies or hybridomas with similar specificity for DNA and chromatin but different IgG subclass and different relative affinity for basement membrane. Only anti-DNA antibodies that bound basement membrane bound to glomeruli, activated complement, and induced proteinuria whether injected alone or co-injected with a non-basement-membrane–binding anti-DNA antibody. Basement membrane–binding anti-DNA antibodies co-localized with heparan sulfate proteoglycan in glomerular basement membrane and mesangial matrix but not with chromatin. Thus, direct binding of anti-DNA antibody to antigens in the glomerular basement membrane or mesangial matrix may be critical to initiate glomerular inflammation. This may accelerate and exacerbate glomerular immune complex formation in human and murine lupus nephritis

Detecting a salt dome overhang with magnetotellurics: 3D inversion methodology and synthetic model studies

Detecting a salt dome overhang is known to be problematic by seismic methods alone. We used magnetotellurics (MT) as a complementary method to seismics to investigate the detectability of a salt dome overhang. A comparison of MT responses for 3D synthetic salt models with and without overhang shows that MT is very sensitive to shallow salt structures and suggests that it should be possible to detect an overhang. To further investigate the resolution capability of MT for a salt dome overhang, we performed a 3D MT inversion study and investigated the impact of model parametrization and regularization. We showed that using the logarithms of the conductivities as model parameters is crucial for inverting data from resistive salt structures because, in this case, commonly used Tikhonov-type stabilizers work more equally for smoothing the resistive and conductive structures. The use of a logarithmic parametrization also accelerated the convergence and produced better inversion results. When the Laplace operator was used as a regularization functional, we still observed that the inversion algorithm allows spatial resistivity gradients. These spatial gradients are reduced if a regularization based on first derivatives in contrast to the Laplace operator is introduced. To demonstrate the favorable performance when logarithmic parametrization and gradient-based regularization are employed, we first inverted a data set simulated for a simple model of two adjacent blocks. Subsequently, we applied the code to a more realistic salt dome overhang detectability study. The results from the detectability study are encouraging and suggest that 3D MT inversion can be applied to decide whether the overhang is present in the shallow salt structure even in the case when only profile data are available. However, to resolve the overhang, a dense MT site coverage above the flanks of the salt dome is required

The motion of two masses coupled to a massive spring

We discuss the classical motion of a spring of arbitrary mass coupled to two arbitrary massive blocks attached at its ends. A general approach to the problem is presented and some general results are obtained. Examples for which a simple elastic function can be inferred are discussed and the normal modes and normal frequencies obtained. An approximation procedure to the evaluation of the normel frequencies in the case of uniform elastic function and mass density is also discussed.Comment: Standard Latex file plus three eps figure

BCL46 and other genomic alterations in non-Hodgkin's lymphoma (NHL)

This study reports on the frequency and disease association pattern of a number of gene rearrangements in a large panel of lymphoid tumours (n = 94). We detected the t(11;14) translocation, involving rearrangement of the BCL - 1 locus, in 60% of mantle cell lymphomas. The BCL - 2 gene, located at band 18q21, was rearranged in 42% of follicle centre lymphomas (FCL) and in 15% of diffuse large B-cell (DLBC) lymphomas. In this study, 80% of the c-MYC rearrangements were detected in aggressive diffuse lymphoma subsets but, interestingly, 9% of FCL showed involvement of t(8q24) translocation. In our study, rearrangements of the BCL-6 gene at band 3q27 were found in 31% of DLBC lymphomas. Interestingly, 50% of the BCL-6 rearrangement positive lymphoma cases had coexisting gene rearrangements involving all of the aforementioned gene loci. The molecular dissection of these genes will improve our understanding of the genesis of the diverse clinicopathological subtypes

Assessing pesticide concentrations and fluxes in the stream of a small vineyard catchment. Effect of sampling frequency

This study reports on the occurrence and behaviour of six pesticides and one metabolite in a small stream draining a vineyard catchment. Base flow and flood events were monitored in order to assess the variability of pesticide concentrations according to the season and to evaluate the role of sampling frequency on the evaluation of fluxes estimates. Results showed that dissolved pesticide concentrations displayed a strong temporal and spatial variability. A large mobilisation of pesticides was observed during floods, with total dissolved pesticide fluxes per event ranging from 5.7*10-3 g/Ha to 0.34 g/Ha. These results highlight the major role of floods in the transport of pesticides in this small stream which contributed to more than 89% of the total load of diuron during August 2007. The evaluation of pesticide loads using different sampling strategies and method calculation, showed that grab sampling largely underestimated pesticide concentrations and fluxes transiting through the stream

Right ventricular dysfunction after resuscitation predicts poor outcomes in cardiac arrest patients independent of left ventricular function.

OBJECTIVE: Determination of clinical outcomes following resuscitation from cardiac arrest remains elusive in the immediate post-arrest period. Echocardiographic assessment shortly after resuscitation has largely focused on left ventricular (LV) function. We aimed to determine whether post-arrest right ventricular (RV) dysfunction predicts worse survival and poor neurologic outcome in cardiac arrest patients, independent of LV dysfunction. METHODS: A single-center, retrospective cohort study at a tertiary care university hospital participating in the Penn Alliance for Therapeutic Hypothermia (PATH) Registry between 2000 and 2012. PATIENTS: 291 in- and out-of-hospital adult cardiac arrest patients at the University of Pennsylvania who had return of spontaneous circulation (ROSC) and post-arrest echocardiograms. MEASUREMENTS AND MAIN RESULTS: Of the 291 patients, 57% were male, with a mean age of 59 ± 16 years. 179 (63%) patients had LV dysfunction, 173 (59%) had RV dysfunction, and 124 (44%) had biventricular dysfunction on the initial post-arrest echocardiogram. Independent of LV function, RV dysfunction was predictive of worse survival (mild or moderate: OR 0.51, CI 0.26-0.99, p CONCLUSIONS: Echocardiographic findings of post-arrest RV dysfunction were equally prevalent as LV dysfunction. RV dysfunction was significantly predictive of worse outcomes in post-arrest patients after accounting for LV dysfunction. Post-arrest RV dysfunction may be useful for risk stratification and management in this high-mortality population

Evidence for a role for the group I metabotropic glutamate receptor in the inhibitory effect of tumor necrosis factor-α on long-term potentiation

Pro-inflammatory cytokines are known to be elevated in several neuropathological states that are associated with learning and memory. We have previously demonstrated in our laboratory that the inhibition of long-term potentiation (LTP) in the dentate gyrus region of the rat hippocampus, by tumor necrosis factor (TNF)-α, represents a biphasic response, an early phase dependent on p38 mitogen activated protein kinase (MAPK) activation and a later phase, possible dependent on protein synthesis. Many of the factors involved in the early modulation of LTP by TNF-α have yet to be elucidated. This study investigated if metabotropic glutamate receptors (mGluRs) are functionally linked to the inhibitory effect of TNF-α on LTP in the rat dentate gyrus in vitro. We report that the impairment of early-LTP by TNF-α is significantly attenuated by prior application of the group I/II mGluR antagonist MCPG and more specifically the mGluR5 antagonist MPEP. Since TNF-α is now known to cause transient increases in intracellular Ca2+ levels from ryanodine-sensitive stores, we explored the possibility that disruption of intracellular Ca2+ homeostasis could be involved. Ryanodine was found to significantly reverse the inhibition of LTP by TNF-α. From these studies we propose that the TNF-α inhibition of LTP is dependent upon the activation of TNFR1 and mGlu5-receptors. Importantly this study provides the first proof of the involvement of ryanodine-sensitive intracellular Ca2+ stores in TNF-α mediated inhibition of LTP