Polyparasite Helminth Infections and Their Association to Anaemia and Undernutrition in Northern Rwanda

Background

Intestinal schistosomiasis and soil-transmitted helminth (STH) infections constitute major public health problems in many parts of sub-Saharan Africa. In this study we examined the functional significance of such polyparasite infections in anemia and undernutrition in Rwandan individuals.

Methods

Three polyparasite infection profiles were defined, in addition to a reference profile that consisted of either no infections or low-intensity infection with only one of the focal parasite species. Logistic regression models were applied to data of 1,605 individuals from 6 schools in 2 districts of the Northern Province before chemotherapeutic treatment in order to correctly identify individuals who were at higher odds of being anaemic and/or undernourished.

Findings

Stunted relative to nonstunted, and males compared to females, were found to be at higher odds of being anaemic independently of polyparasite infection profile. The odds of being wasted were 2-fold greater for children with concurrent infection of at least 2 parasites at M+ intensity compared to those children with the reference profile. Males compared to females and anaemic compared to nonanaemic children were significantly more likely to be stunted. None of the three polyparasite infection profiles were found to have significant effects on stunting.

Conclusion

The present data suggest that the levels of polyparasitism, and infection intensities in the Rwandan individuals examined here may be lower as compared to other recent similar epidemiological studies in different regions across sub-Saharan Africa. Neither the odds of anaemia nor the odds of stunting were found to be significantly different in the three-polyparasite infection profiles. However, the odds of wasting were higher in those children with at least two parasites at M+ intensity compared to those children with the reference profile. Nevertheless, despite the low morbidity levels indicated in the population under study here, we recommend sustainable efforts for the deworming of affected populations to be continued in order to support the economic development of the country.     

Origin and Phylogeny of Microbes Living in Permanent Antarctic Lake Ice

Abstract The phylogenetic diversity of bacteria and cyanobacteria colonizing sediment particles in the permanent ice cover of an Antarctic lake was characterized by analyses of 16S rRNA genes amplified from environmental DNA. Samples of mineral particles were collected from a depth of 2.5 m in the 4-m-thick ice cover of Lake Bonney, McMurdo Dry Valleys, Antarctica. A rRNA gene clone library of 198 clones was made and characterized by sequencing and oligonucleotide probe hybridization. The library was dominated by representatives of the cyanobacteria, proteobacteria, and Planctomycetales, but also contained diverse clones representing many other microbial groups, including the Acidobacterium/Holophaga division, the Green Non-Sulfur division, and the Actinobacteria. Six oligonucleotide probes were made for the most abundant clades recovered in the library. To determine whether the ice microbial community might originate from wind dispersal of the algal mats found elsewhere in Taylor Valley, the probes were hybridized to 16S rDNAs amplified from three samples of terrestrial cyanobacterial mats collected at nearby sites, as well as to bacterial 16S rDNAs from the lake ice community. The results demonstrate the presence of a diverse microbial community dominated by cyanobacteria in the lake ice, and also show that the dominant members of the lake ice microbial community are found in terrestrial mats elsewhere in the area. The lake ice microbial community appears to be dominated by organisms that are not uniquely adapted to the lake ice ecosystem, but instead are species that originate elsewhere in the surrounding region and opportunistically colonize the unusual habitat provided by the sediments suspended in lake ice. Received: 16 August 1999; Accepted: 28 December 1999; Online Publication: 28 April 2000     

Mutations in SLC2A2 Gene Reveal hGLUT2 Function in Pancreatic β Cell Development

The structure-function relationships of sugar transporter-receptor hGLUT2 coded by SLC2A2 and their impact on insulin secretion and β cell differentiation were investigated through the detailed characterization of a panel of mutations along the protein. We studied naturally occurring SLC2A2 variants or mutants: two single-nucleotide polymorphisms and four proposed inactivating mutations associated to Fanconi-Bickel syndrome. We also engineered mutations based on sequence alignment and conserved amino acids in selected domains. The single-nucleotide polymorphisms P68L and T110I did not impact on sugar transport as assayed in Xenopus oocytes. All the Fanconi-Bickel syndrome-associated mutations invalidated glucose transport by hGLUT2 either through absence of protein at the plasma membrane (G20D and S242R) or through loss of transport capacity despite membrane targeting (P417L and W444R), pointing out crucial amino acids for hGLUT2 transport function. In contrast, engineered mutants were located at the plasma membrane and able to transport sugar, albeit with modified kinetic parameters. Notably, these mutations resulted in gain of function. G20S and L368P mutations increased insulin secretion in the absence of glucose. In addition, these mutants increased insulin-positive cell differentiation when expressed in cultured rat embryonic pancreas. F295Y mutation induced β cell differentiation even in the absence of glucose, suggesting that mutated GLUT2, as a sugar receptor, triggers a signaling pathway independently of glucose transport and metabolism. Our results describe the first gain of function mutations for hGLUT2, revealing the importance of its receptor versus transporter function in pancreatic β cell development and insulin secretion.     

Activation of Calcitonin Receptor and Calcitonin Receptor-like Receptor by Membrane-anchored Ligands

G protein-coupled receptors (GPCRs) are the most important pharmaceutical targets, and more than 40% of drugs in use today modulate GPCR signaling. A major hurdle in the development of therapies targeting GPCRs is the drug candidate''s nonselective actions in multiple tissues. The ability to spatially control GPCR signaling would provide a venue for developing therapies that require targeted GPCR signaling. Here, we show that the fusion of a RAMP1 co-receptor with the calcitonin gene-related peptide (CGRP), or calcitonin, transforms the RAMP1 from a co-receptor to bona fide membrane-anchored ligands (CGRP-RAMP1 and CAL-RAMP1). The CAL-RAMP1 selectively activates the calcitonin receptor (CR), whereas, the CGRP-RAMP1 activates both the calcitonin receptor-like receptor (CLR) and CR. Unlike a free peptide, which moves freely in the extracellular space and differentiates targets based on molecular affinity, the anchored CGRP-RAMP1 and CAL-RAMP1 ligands confine their activities to individual cells. In addition, our study showed that a CGRP8–37-RAMP1 chimera, but not RAMP1, functions as an antagonist for CGRP-RAMP1-mediated signaling, suggesting that the activation of CLR by CGRP-RAMP1 shares similar molecular mechanisms with the CGRP-mediated activation of CLR/RAMP1 receptor complexes. Taken together, our finding thus provides a novel class of ligands that activate CR and CLR exclusively in an autocrine manner and a proof-of-concept demonstration for future development of targeted therapies aimed at these receptors in specific cell populations.     

GPCR genes are preferentially retained after whole genome duplication

One of the most interesting questions in biology is whether certain pathways have been favored during evolution, and if so, what properties could cause such a preference. Due to the lack of experimental evidence, whether select gene families have been preferentially retained over time after duplication in metazoan organisms remains unclear. Here, by syntenic mapping of nonchemosensory G protein-coupled receptor genes (nGPCRs which represent half the receptome for transmembrane signaling) in the vertebrate genomes, we found that, as opposed to the 8-15% retention rate for whole genome duplication (WGD)-derived gene duplicates in the entire genome of pufferfish, greater than 27.8% of WGD-derived nGPCRs which interact with a nonpeptide ligand were retained after WGD in pufferfish Tetraodon nigroviridis. In addition, we show that concurrent duplication of cognate ligand genes by WGD could impose selection of nGPCRs that interact with a polypeptide ligand. Against less than 2.25% probability for parallel retention of a pair of WGD-derived ligands and a pair of cognate receptor duplicates, we found a more than 8.9% retention of WGD-derived ligand-nGPCR pairs--threefold greater than one would surmise. These results demonstrate that gene retention is not uniform after WGD in vertebrates, and suggest a Darwinian selection of GPCR-mediated intercellular communication in metazoan organisms.     

Regulation of oocyte and cumulus cell interactions by intermedin/adrenomedullin 2

Ovarian folliculogenesis has been studied as a model of hormonal regulation of development and differentiation, cell death, and cell-cell communication. In addition to gonadotropins from the pituitary and follicular paracrine factors, oocyte secreted factors have been shown to play critical roles in the regulation of follicular cell functions. Except for the well characterized BMP family proteins, including GDF9 and BMP15, oocytes are known to secrete oocyte secreted factors that are important for the regulation of cumulus cell survival and the maintenance of tertiary structure of cumulus cell-enclosed oocyte complexes (COCs). Based on genomic screening and studies of COCs cultured in vitro, we showed that intermedin (IMD)/adrenomedullin 2 (ADM2) is a novel oocyte-derived ligand important for the regulation of cell interactions in COCs that functions, in part, by suppressing cumulus cell apoptosis. Consistently, we showed that suppression of IMD/ADM2 signaling in growing rat ovaries in vivo leads to oocyte atresia and aberrant cell cycle progression in follicular cells. Together, our studies indicated that mammalian oocytes deploy a G protein-coupled receptor ligand to coordinate normal interactions of oocytes and cumulus cells and provided a better understanding of how the tertiary structure of a COC is maintained as follicles undergo exponential growth during the late stages of folliculogenesis.     

Neural crest invasion is a spatially-ordered progression into the head with higher cell proliferation at the migratory front as revealed by the photoactivatable protein, KikGR

Neural crest cell (NCC) invasion is a complex sculpting of individual cells into organized migratory streams that lead to organ development along the vertebrate axis. Key to our understanding of how molecular mechanisms modulate the NCC migratory pattern is information about cell behaviors, yet it has been challenging to selectively mark and analyze migratory NCCs in a living embryo. Here, we apply an innovative in vivo strategy to investigate chick NCC behaviors within the rhombomere 4 (r4) migratory stream by combining photoactivation of KikGR and confocal time-lapse analysis of H2B-mRFP1 transfected NCCs. We find that the spatial order of r4 NCC emergence translates into a distal-to-proximal invasion of the 2nd branchial arch. Lead and trailing NCCs display similar average cell speeds and directionalities. Surprisingly, we find that lead NCCs proliferate along the migratory route and grow to outnumber trailing NCCs by nearly 3 to 1. A simple, cell-based computational model reproduces the r4 NCC migratory pattern and predicts the invasion order can be disrupted by slower, less directional lead cells or by environmental noise. Our results suggest a model in which NCC behaviors maintain a spatially-ordered invasion of the branchial arches with differences in cell proliferation between the migratory front and trailing NCCs.