Sulfonamide Synthesis through Electrochemical Oxidative Coupling of Amines and Thiols

Sulfonamides are key motifs in pharmaceuticals and agrochemicals, spurring the continuous development of novel and efficient synthetic methods to access these functional groups. Herein, we report an environmentally benign electrochemical method which enables the oxidative coupling between thiols and amines, two readily available and inexpensive commodity chemicals. The transformation is completely driven by electricity, does not require any sacrificial reagent or additional catalysts and can be carried out in only 5 min. Hydrogen is formed as a benign byproduct at the counter electrode. Owing to the mild reaction conditions, the reaction displays a broad substrate scope and functional group compatibility

Neural Decision Boundaries for Maximal Information Transmission

We consider here how to separate multidimensional signals into two categories, such that the binary decision transmits the maximum possible information transmitted about those signals. Our motivation comes from the nervous system, where neurons process multidimensional signals into a binary sequence of responses (spikes). In a small noise limit, we derive a general equation for the decision boundary that locally relates its curvature to the probability distribution of inputs. We show that for Gaussian inputs the optimal boundaries are planar, but for non-Gaussian inputs the curvature is nonzero. As an example, we consider exponentially distributed inputs, which are known to approximate a variety of signals from natural environment.Comment: 5 pages, 3 figure

Generation of Humoral Immune Responses to Multi-Allele PfAMA1 Vaccines; Effect of Adjuvant and Number of Component Alleles on the Breadth of Response

There is increasing interest in multi-allele vaccines to overcome strain-specificity against polymorphic vaccine targets such as Apical Membrane Antigen 1 (AMA1). These have been shown to induce broad inhibitory antibodies in vitro and formed the basis for the design of three Diversity-Covering (DiCo) proteins with similar immunological effects. The antibodies produced are to epitopes that are shared between vaccine alleles and theoretically, increasing the number of component AMA1 alleles is expected to broaden the antibody response. A plateau effect could however impose a limit on the number of alleles needed to achieve the broadest specificity. Moreover, production cost and the vaccine formulation process would limit the number of component alleles. In this paper, we compare rabbit antibody responses elicited with multi-allele vaccines incorporating seven (three DiCos and four natural AMA1 alleles) and three (DiCo mix) antigens for gains in broadened specificity. We also investigate the effect of three adjuvant platforms on antigen specificity and antibody functionality. Our data confirms a broadened response after immunisation with DiCo mix in all three adjuvants. Higher antibody titres were elicited with either CoVaccine HT™ or Montanide ISA 51, resulting in similar in vitro inhibition (65–82%) of five out of six culture-adapted P. falciparum strains. The antigen binding specificities of elicited antibodies were also similar and independent of the adjuvant used or the number of vaccine component alleles. Thus neither the four extra antigens nor adjuvant had any observable benefits with respect to specificity broadening, although adjuvant choice influenced the absolute antibody levels and thus the extent of parasite inhibition. Our data confirms the feasibility and potential of multi-allele PfAMA1 formulations, and highlights the need for adjuvants with improved antibody potentiation properties for AMA1-based vaccines

Measurement of the plasma levels of antibodies against the polymorphic vaccine candidate apical membrane antigen 1 in a malaria-exposed population

<p>Abstract</p> <p>Background</p> <p>Establishing antibody correlates of protection against malaria in human field studies and clinical trials requires, amongst others, an accurate estimation of antibody levels. For polymorphic antigens such as apical membrane antigen 1 (AMA1), this may be confounded by the occurrence of a large number of allelic variants in nature.</p> <p>Methods</p> <p>To test this hypothesis, plasma antibody levels in an age-stratified cohort of naturally exposed children from a malaria-endemic area in Southern Ghana were determined by indirect ELISA. Titres against four single <it>Pf</it>AMA1 alleles were compared with those against three different allele mixtures presumed to have a wider repertoire of epitope specificities. Associations of antibody levels with the incidence of clinical malaria as well as with previous exposure to parasites were also examined.</p> <p>Results</p> <p>Antibody titres against <it>Pf</it>AMA1 alleles generally increased with age/exposure while antibody specificity for <it>Pf</it>AMA1 variants decreased, implying that younger children (≤ 5 years) elicit a more strain-specific antibody response compared to older children. Antibody titre measurements against the FVO and 3D7 AMA1 alleles gave the best titre estimates as these varied least in pair-wise comparisons with titres against all <it>Pf</it>AMA1 allele mixtures. There was no association between antibody levels against any capture antigen and either clinical malaria incidence or parasite density.</p> <p>Conclusions</p> <p>The current data shows that levels of naturally acquired antigen-specific antibodies, especially in infants and young children, are dependent on the antigenic allele used for measurement. This may be relevant to the interpretation of antibody titre data from measurements against single <it>Pf</it>AMA1 alleles, especially in studies involving infants and young children who have experienced fewer infections.</p

QTL Analysis of Shading Sensitive Related Traits in Maize under Two Shading Treatments

During maize development and reproduction, shading stress is an important abiotic factor influencing grain yield. To elucidate the genetic basis of shading stress in maize, an F2:3 population derived from two inbred lines, Zhong72 and 502, was used to evaluate the performance of six traits under shading treatment and full-light treatment at two locations. The results showed that shading treatment significantly decreased plant height and ear height, reduced stem diameter, delayed day-to-tassel (DTT) and day-to-silk (DTS), and increased anthesis-silking interval (ASI). Forty-three different QTLs were identified for the six measured traits under shading and full light treatment at two locations, including seven QTL for plant height, nine QTL for ear height, six QTL for stem diameter, seven QTL for day-to-tassel, six QTL for day-to-silk, and eight QTL for ASI. Interestingly, three QTLs, qPH4, qEH4a, and qDTT1b were detected under full sunlight and shading treatment at two locations simultaneously, these QTL could be used for selecting elite hybrids with high tolerance to shading and high plant density. And the two QTL, qPH10 and qDTS1a, were only detected under shading treatment at two locations, should be quit for selecting insensitive inbred line in maize breeding procedure by using MAS method

Longevity and Composition of Cellular Immune Responses Following Experimental Plasmodium falciparum Malaria Infection in Humans

Cellular responses to Plasmodium falciparum parasites, in particular interferon-gamma (IFNγ) production, play an important role in anti-malarial immunity. However, clinical immunity to malaria develops slowly amongst naturally exposed populations, the dynamics of cellular responses in relation to exposure are difficult to study and data about the persistence of such responses are controversial. Here we assess the longevity and composition of cellular immune responses following experimental malaria infection in human volunteers. We conducted a longitudinal study of cellular immunological responses to sporozoites (PfSpz) and asexual blood-stage (PfRBC) malaria parasites in naïve human volunteers undergoing single (n = 5) or multiple (n = 10) experimental P. falciparum infections under highly controlled conditions. IFNγ and interleukin-2 (IL-2) responses following in vitro re-stimulation were measured by flow-cytometry prior to, during and more than one year post infection. We show that cellular responses to both PfSpz and PfRBC are induced and remain almost undiminished up to 14 months after even a single malaria episode. Remarkably, not only ‘adaptive’ but also ‘innate’ lymphocyte subsets contribute to the increased IFNγ response, including αβT cells, γδT cells and NK cells. Furthermore, results from depletion and autologous recombination experiments of lymphocyte subsets suggest that immunological memory for PfRBC is carried within both the αβT cells and γδT compartments. Indeed, the majority of cytokine producing T lymphocytes express an CD45RO+ CD62L- effector memory (EM) phenotype both early and late post infection. Finally, we demonstrate that malaria infection induces and maintains polyfunctional (IFNγ+IL-2+) EM responses against both PfRBC and PfSpz, previously found to be associated with protection. These data demonstrate that cellular responses can be readily induced and are long-lived following infection with P. falciparum, with a persisting contribution by not only adaptive but also (semi-)innate lymphocyte subsets. The implications hereof are positive for malaria vaccine development, but focus attention on those factors potentially inhibiting such responses in the field

Gender differences in the use of cardiovascular interventions in HIV-positive persons; the D:A:D Study

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