Malaria resistance genes are associated with the levels of IgG subclasses directed against Plasmodium falciparum blood-stage antigens in Burkina Faso

ABSTRACT: BACKGROUND: HBB, IL4, IL12, TNF, LTA, NCR3 and FCGR2A polymorphisms have been associated with malaria resistance in humans, whereas cytophilic immunoglobulin G (IgG) antibodies are thought to play a critical role in immune protection against asexual blood stages of the parasite. Furthermore, HBB, IL4, TNF, and FCGR2A have been associated with both malaria resistance and IgG levels. This suggests that some malaria resistance genes influence the levels of IgG subclass antibodies. METHODS: In this study, the effect of HBB, IL4, IL12, TNF, LTA, NCR3 and FCGR2A polymorphisms on the levels of IgG responses against Plasmodium falciparum blood-stage extract was investigated in 220 individuals living in Burkina Faso. The Pearson's correlation coefficient among IgG subclasses was determined. A family-based approach was used to assess the association of polymorphisms with anti-P. falciparum IgG, IgG1, IgG2, IgG3 and IgG4 levels. RESULTS: After applying a multiple test correction, several polymorphisms were associated with IgG subclass or IgG levels. There was an association of i) haemoglobin C with IgG levels; ii) the FcgammaRIIa H/R131 with IgG2 and IgG3 levels; iii) TNF-863 with IgG3 levels; iv) TNF-857 with IgG levels; and, v) TNF1304 with IgG3, IgG4, and IgG levels. CONCLUSION: Taken together, the results support the hypothesis that some polymorphisms affect malaria resistance through their effect on the acquired immune response, and pave the way towards further comprehension of genetic control of an individual's humoral response against malaria.     

CoMFA/CoMSIA 3D-QSAR of pyrimidine inhibitors of Pneumocystis carinii dihydrofolate reductase

Pneumocystis carinii is typically a non-pathogenic fungus found in the respiratory tract of healthy humans. However, it may cause P. carinii pneumonia (PCP) in people with immune deficiency, affecting mainly premature babies, cancer patients and transplant recipients, and people with acquired immunodeficiency syndrome (AIDS). In the latter group, PCP occurs in approximately 80% of patients, a major cause of death. Currently, there are many available therapies to treat PCP patients, including P. carinii dihydrofolate reductase (PcDHFR) inhibitors, such as trimetrexate (TMX), piritrexim (PTX), trimethoprim (TMP), and pyrimethamine (PMT). Nevertheless, the high percentage of adverse side effects and the limited therapeutic success of the current drug therapy justify the search for new drugs rationally planned against PCP. This work focuses on the study of pyrimidine inhibitors of PcDHFR, using both CoMFA and CoMSIA 3D-QSAR methods.     

Structural analysis of ConBr reveals molecular correlation between the carbohydrate recognition domain and endothelial NO synthase activation

Diocleinae lectins are highly homologous in their primary structure which features metal binding sites and a carbohydrate recognition domain (CRD). Differences in the biological activity of legume lectins have been widely investigated using hemagglutination inhibition assays, isothermal titration microcalorimetry and co-crystallization with mono- and oligosaccharides. Here we report a new lectin crystal structure (ConBr) extracted from seeds of Canavalia brasiliensis, predict dimannoside binding by docking, identify the α-aminobutyric acid (Abu) binding pocket and compare the CRD of ConBr to that of homologous lectins. Based on the hypothesis that the carbohydrate affinity of lectins depends on CRD configuration, the relationship between tridimensional structure and endothelial NO synthase activation was used to clarify differences in biological activity. Our study established a correlation between the position of CRD amino acid side chains and the stimulation of NO release from endothelium.     

Müller Glia as an Active Compartment Modulating Nervous Activity in the Vertebrate Retina: Neurotransmitters and Trophic Factors

Müller cells represent the main type of glia present in the retina interacting with most, if not all neurons in this tissue. Müller cells have been claimed to function as optic fibers in the retina delivering light to photoreceptors with minimal distortion and low loss [Franze et al (2007) Proc Natl Acad Sci 104:8287–8292]. Most of the mediators found in the brain are also detected in the retinal tissue, and glia cells are active players in the synthesis, release, signaling and uptake of major mediators of synaptic function. Müller glia trophic factors may regulate many different aspects of neuronal circuitry during synaptogenesis, differentiation, neuroprotection and survival of photoreceptors, Retinal Ganglion Cells (RGCs) and other targets in the retina. Here we review the role of several transmitters and trophic factors that participate in the neuron-glia loop in the retina. Special issue article in honor of Dr. Ricardo Tapia.     

Genetic drift vs. natural selection in a long-term small isolated population: major histocompatibility complex class II variation in the Gulf of California endemic porpoise (Phocoena sinus)

Although many studies confirm long-term small isolated populations (e.g. island endemics) commonly sustain low neutral genetic variation as a result of genetic drift, it is less clear how selection on adaptive or detrimental genes interplay with random forces. We investigated sequence variation at two major histocompatibility complex (Mhc) class II loci on a porpoise endemic to the upper Gulf of California, México (Phocoena sinus, or vaquita). Its unique declining population is estimated around 500 individuals. Single-strand conformation polymorphism analysis revealed one putative functional allele fixed at the locus DQB (n = 25). At the DRB locus, we found two presumed functional alleles (n = 29), differing by a single nonsynonymous nucleotide substitution that could increase the stability at the dimer interface of alphabeta-heterodimers on heterozygous individuals. Identical trans-specific DQB1 and DRB1 alleles were identified between P. sinus and its closest relative, the Burmeister's porpoise (Phocoena spinipinnis). Comparison with studies on four island endemic mammals suggests fixation of one allele, due to genetic drift, commonly occurs at the DQA or DQB loci (effectively neutral). Similarly, deleterious alleles of small effect are also effectively neutral and can become fixed; a high frequency of anatomical malformations on vaquita gave empirical support to this prediction. In contrast, retention of low but functional polymorphism at the DRB locus was consistent with higher selection intensity. These observations indicated natural selection could maintain (and likely also purge) some crucial alleles even in the face of strong and prolonged genetic drift and inbreeding, suggesting long-term small populations should display low inbreeding depression. Low levels of Mhc variation warn about a high susceptibility to novel pathogens and diseases in vaquita.     

Bayesian multisensory integration and cross-modal spatial links.

Our perception of the word is the result of combining information between several senses, such as vision, audition and proprioception. These sensory modalities use widely different frames of reference to represent the properties and locations of object. Moreover, multisensory cues come with different degrees of reliability, and the reliability of a given cue can change in different contexts. The Bayesian framework--which we describe in this review--provides an optimal solution to deal with this issue of combining cues that are not equally reliable. However, this approach does not address the issue of frames of references. We show that this problem can be solved by creating cross-modal spatial links in basis function networks. Finally, we show how the basis function approach can be combined with the Bayesian framework to yield networks that can perform optimal multisensory combination. On the basis of this theory, we argue that multisensory integration is a dialogue between sensory modalities rather that the convergence of all sensory information onto a supra-modal area.     

Towards biocompatible vaccine delivery systems: interactions of colloidal PECs based on polysaccharides with HIV-1 p24 antigen

This work reports on the interactions of a model protein (p24, the capside protein of HIV-1 virus) with colloids obtained from polyelectrolyte complexes (PECs) involving two polysaccharides: chitosan and dextran sulfate (DS). The PECs were elaborated by a one-shot addition of default amounts of one counterpart to the polymer in excess. Depending on the nature of the excess polyelectrolyte, the submicrometric colloid was either positively or negatively charged. HIV-1 capsid p24 protein was chosen as antigen, the ultrapure form, lipopolysaccharide-free (endotoxin-, vaccine grade) was used in most experiments, as the level of purity of the protein had a great impact on the immobilization process. p24 sorption kinetics, isotherms, and loading capacities were investigated for positively and negatively charged particles of chitosans and dextran sulfates differing in degrees of polymerization (DP) or acetylation (DA). Compared with the positive particles, negatively charged colloids had higher binding capacities, faster kinetics, and a better stability of the adsorbed p24. Capacities up to 600 mg x g(-1) (protein-colloid) were obtained, suggesting that the protein interacted within the shell of the particles. Small-angle X-rays scattering experiments confirmed this hypothesis. Finally, the immunogenicity of the p24-covered particles was assessed for vaccine purposes in mice. The antibody titers obtained with immobilized p24 was dose dependent and in the same range as for Freund's adjuvant, a gold standard for humoral responses.     

Does the niche breadth or trade‐off hypothesis explain the abundance–occupancy relationship in avian Haemosporidia?

Two hypotheses have been proposed to explain the abundance–occupancy relationship (AOR) in parasites. The niche breadth hypothesis suggests that host generalists are more abundant and efficient at colonizing different host communities than specialists. The trade‐off hypothesis argues that host specialists achieve high density across their hosts' ranges, whereas generalists incur the high cost of adaptation to diverse immuno‐defence systems. We tested these hypotheses using 386 haemosporidian cytochrome‐b lineages (1894 sequences) recovered from 2318 birds of 103 species sampled in NW Africa, NW Iberia, W Greater Caucasus and Transcaucasia. The number of regions occupied by lineages was associated with their frequency suggesting the presence of AOR in avian Haemosporidia. However, neither hypothesis provided a better explanation for the AOR. Although the host generalist Plasmodium SGS1 was over three times more abundant than other widespread lineages, both host specialists and generalists were successful in colonizing all study regions and achieved high overall prevalence.     

Patterns and drivers of Araucaria araucana forest growth along a biophysical gradient in the northern Patagonian Andes: Linking tree rings with satellite observations of soil moisture

Araucaria araucana (Araucaria) is a long‐lived conifer growing along a sharp west–east biophysical gradient in the Patagonian Andes. The patterns and climate drivers of Araucaria growth have typically been documented on the driest part of the gradient relying on correlations with meteorological records, but the lack of in situ soil moisture observations has precluded an assessment of the growth responses to soil moisture variability. Here, we use a network of 21 tree‐ring width chronologies to investigate the spatiotemporal patterns of tree growth through the entire gradient and evaluate their linkages with regional climate and satellite‐observed surface soil moisture variability. We found that temporal variations in tree growth are remarkably similar throughout the gradient and largely driven by soil moisture variability. The regional spatiotemporal pattern of tree growth was positively correlated with precipitation (r = 0.35 for January 1920–1974; P < 0.01) and predominantly negatively correlated with temperature (r = ?0.38 for January–March 1920–1974; P < 0.01) during the previous growing season. These correlations suggest a temporally lagged growth response to summer moisture that could be associated with known physiological carry‐over processes in conifers and to a response to moisture variability at deeper layers of the rooting zone. Notably, satellite observations revealed a previously unobserved response of Araucaria growth to summer surface soil moisture during the current rather than the previous growing season (r = 0.65 for 1979–2000; P < 0.05). This new response has a large spatial footprint across the mid‐latitudes of the South American continent (35°–45°S) and highlights the potential of Araucaria tree rings for palaeoclimatic applications. The strong moisture constraint on tree growth revealed by satellite observations suggests that projected summer drying during the coming decades may result in regional growth declines in Araucaria forests and other water‐limited ecosystems in the Patagonian Andes.