Recent Acquisition of Helicobacter pylori by Baka Pygmies

Both anatomically modern humans and the gastric pathogen Helicobacter pylori originated in Africa, and both species have been associated for at least 100,000 years. Seven geographically distinct H. pylori populations exist, three of which are indigenous to Africa: hpAfrica1, hpAfrica2, and hpNEAfrica. The oldest and most divergent population, hpAfrica2, evolved within San hunter-gatherers, who represent one of the deepest branches of the human population tree. Anticipating the presence of ancient H. pylori lineages within all hunter-gatherer populations, we investigated the prevalence and population structure of H. pylori within Baka Pygmies in Cameroon. Gastric biopsies were obtained by esophagogastroduodenoscopy from 77 Baka from two geographically separated populations, and from 101 non-Baka individuals from neighboring agriculturalist populations, and subsequently cultured for H. pylori. Unexpectedly, Baka Pygmies showed a significantly lower H. pylori infection rate (20.8%) than non-Baka (80.2%). We generated multilocus haplotypes for each H. pylori isolate by DNA sequencing, but were not able to identify Baka-specific lineages, and most isolates in our sample were assigned to hpNEAfrica or hpAfrica1. The population hpNEAfrica, a marker for the expansion of the Nilo-Saharan language family, was divided into East African and Central West African subpopulations. Similarly, a new hpAfrica1 subpopulation, identified mainly among Cameroonians, supports eastern and western expansions of Bantu languages. An age-structured transmission model shows that the low H. pylori prevalence among Baka Pygmies is achievable within the timeframe of a few hundred years and suggests that demographic factors such as small population size and unusually low life expectancy can lead to the eradication of H. pylori from individual human populations. The Baka were thus either H. pylori-free or lost their ancient lineages during past demographic fluctuations. Using coalescent simulations and phylogenetic inference, we show that Baka almost certainly acquired their extant H. pylori through secondary contact with their agriculturalist neighbors.     

The absence of fire can cause a lag phase: The invasion dynamics of Banksia ericifolia (Proteaceae)

The transition from a species introduction to an invasion often spans many decades (a lag phase). However, few studies have determined the mechanisms underlying lag phases. Such a mechanistic understanding is vital if the potential ecosystem‐level impacts are to be predicted and the invasion risks to be managed proactively. Here we examine Banksia ericifolia, introduced for floriculture to South Africa, as a case study. We found 18 sites where the species has been planted, with self‐sustaining (naturalized) populations at four sites, and an invasive population at one site. The invasion originated from around 100 individuals planted 35 years ago; after several fires this population has grown to approximately 10 000 plants covering about 127 ha. The current invasion of B. ericifolia already has ecosystem‐level impacts, for example the nectar available to bird pollinators has more than doubled, potentially disrupting native pollination networks. If fires occurred at the other naturalized sites we anticipate populations would rapidly spread and densify with invaded areas ultimately become banksia‐dominated woodlands. Indeed the only site other than the invasive site where fire has occurred regularly is already showing signs of rapid population growth and spread. However, recruitment is mainly immediately post fire and no seed bank accumulates in the soil, mechanical control of adult plants is cheap and effective, and immature plants are easily detected. This study is a first in illustrating the importance of fire in driving lag phases and provides a valuable example for why it is essential to determine the mechanisms that mediate lag phases in introduced plant species. Serotinous species that have been introduced to areas where fire is suppressed could easily be misinterpreted as low risk species whilst they remain in a lag phase, but they can represent a major invasion risk.     

The politics of race,culture and education

Mike Cole (ed.), EDUCATION FOR EQUALITY, London: Routledge, 1989, 237 pp., £9.95 (paper)

Peter Foster, POLICY AND PRACTICE IN MULICULTURAL AND ANTI‐RACIST EDUCATION, London: Routledge, 1990, 208 pp., £10.99 (paper)

Alrick X. Cambridge and Stephan Feuchtwang (eds), ANTI‐RACIST STRATEGIES, Avebury: Gower Publishing, 1990, 162 pp., £25.00

David Gillborn, ’RACE’, ETHNICITY AND EDUCATION, London: Unwin Hyman, 1990, 245 pp., £9.95 (paper)

Elizabeth Grugeon and Peter Woods, EDUCATING ALL: MULTICULTURAL PERSPECTIVES IN THE PRIMARY SCHOOL, London: Routledge, 1990, 244 pp., £9.95 (paper)

Barry Troyna and Bruce Carrington, EDUCATION, RACISM AND REFORM, London: Routledge, 1990, 139 pp., £30.00 and £8.99 (paper)

Kenneth J. Meier, Joseph Stewart Jr., Robert E. England, RACE, CLASS AND EDUCATION, Madison: University of Wisconsin Press, 1989, 194 pp., npl     

Control of human immunodeficiency virus type 1 is associated with HLA-B*13 and targeting of multiple gag-specific CD8+ T-cell epitopes

To better understand relationships between CD8+ T-cell specificity and the immune control of human immunodeficiency virus type 1 (HIV-1), we analyzed the role of HLA-B*13, an allele associated with low viremia, in a cohort of 578 C clade-infected individuals in Durban, South Africa. Six novel B*13-restricted cytotoxic T lymphocyte epitopes were defined from analyses of 37 B*13-positive subjects, including three Gag epitopes. These B*13-restricted epitopes contribute to a broad Gag-specific CD8+ response that is associated with the control of viremia. These data are consistent with data from studies of other HLA-class I alleles associated with HIV control that have shown that the targeting of multiple Gag epitopes is associated with relative suppression of viremia.     

Age of the Association between Helicobacter pylori and Man

When modern humans left Africa ca. 60,000 years ago (60 kya), they were already infected with Helicobacter pylori, and these bacteria have subsequently diversified in parallel with their human hosts. But how long were humans infected by H. pylori prior to the out-of-Africa event? Did this co-evolution predate the emergence of modern humans, spanning the species divide? To answer these questions, we investigated the diversity of H. pylori in Africa, where both humans and H. pylori originated. Three distinct H. pylori populations are native to Africa: hpNEAfrica in Afro-Asiatic and Nilo-Saharan speakers, hpAfrica1 in Niger-Congo speakers and hpAfrica2 in South Africa. Rather than representing a sustained co-evolution over millions of years, we find that the coalescent for all H. pylori plus its closest relative H. acinonychis dates to 88–116 kya. At that time the phylogeny split into two primary super-lineages, one of which is associated with the former hunter-gatherers in southern Africa known as the San. H. acinonychis, which infects large felines, resulted from a later host jump from the San, 43–56 kya. These dating estimates, together with striking phylogenetic and quantitative human-bacterial similarities show that H. pylori is approximately as old as are anatomically modern humans. They also suggest that H. pylori may have been acquired via a single host jump from an unknown, non-human host. We also find evidence for a second Out of Africa migration in the last 52,000 years, because hpEurope is a hybrid population between hpAsia2 and hpNEAfrica, the latter of which arose in northeast Africa 36–52 kya, after the Out of Africa migrations around 60 kya.     

Claudin 1 mediates TNFα-induced gene expression and cell migration in human lung carcinoma cells

Epithelial-mesenchymal transition (EMT) is an important mechanism in carcinogenesis. To determine the mechanisms that are involved in the regulation of EMT, it is crucial to develop new biomarkers and therapeutic targets towards cancers. In this study, when TGFβ1 and TNFα were used to induce EMT in human lung carcinoma A549 cells, we found an increase in an epithelial cell tight junction marker, Claudin 1. We further identified that it was the TNFα and not the TGFβ1 that induced the fibroblast-like morphology changes. TNFα also caused the increase in Claudin-1 gene expression and protein levels in Triton X-100 soluble cytoplasm fraction. Down-regulation of Claudin-1, using small interfering RNA (siRNA), inhibited 75% of TNFα-induced gene expression changes. Claudin-1 siRNA effectively blocked TNFα-induced molecular functional networks related to inflammation and cell movement. Claudin-1 siRNA was able to significantly reduce TNF-enhanced cell migration and fibroblast-like morphology. Furthermore, over expression of Claudin 1 with a Claudin 1-pcDNA3.1/V5-His vector enhanced cell migration. In conclusion, these observations indicate that Claudin 1 acts as a critical signal mediator in TNFα-induced gene expression and cell migration in human lung cancer cells. Further analyses of these cellular processes may be helpful in developing novel therapeutic strategies.     

Visualisation of transforming growth factor-beta 1, tissue kallikrein, and kinin and transforming growth factor-beta receptors on human clear-cell renal carcinoma cells

Transforming growth factor-beta1 (TGF-beta1) has a biphasic effect on the growth of renal epithelial cells. In transformed cells, TGF-beta1 appears to accelerate the proliferation of malignant cells. The diverse cellular functions of TGF-beta1 are regulated by three high-affinity serine/threonine kinase receptors, namely TbetaRI, TbetaRII and TbetaRIII. The renal serine protease tissue kallikrein acts on its endogenous protein substrate kininogen to form kinin peptides. The cellular actions of kinins are mediated through B1 and B2 G protein-coupled rhodopsin receptors. Both kinin peptides and TGF-beta1 are mitogenic, and therefore may play an important role in carcinogenesis. Experiments were designed to immunolabel tissue kallikrein, TGF-beta1, TbetaRII, TbetaRIII and kinin receptors using specific antibodies on serial sections of normal kidney and clear-cell renal carcinoma (CCRC) tissue, which included both the tumour and the adjacent renal parenchyma. The essential result was the localisation of tissue kallikrein, kinin B 1 and B 2 receptors and TGF-beta1 primarily on the cell membranes of CCRC cells. In the distal and proximal tubules of the renal parenchyma adjacent to the carcinoma (RPTAC), immunolabelling for tissue kallikrein was reduced, but the expression of kinin B1 and B2 receptors was enhanced. Immunolabelling for TbetaRII and TbetaRIII was more pronounced in the proximal tubules of the tissue adjacent to the carcinoma when compared to the normal kidney. The expression of tissue kallikrein, kinin receptors, and TbetaRII and TbetaRIII may be relevant to the parenchymal invasion and metastasis of clear-cell renal carcinoma.     

Unique acquisition of cytotoxic T-lymphocyte escape mutants in infant human immunodeficiency virus type 1 infection

The role of cytotoxic T-lymphocyte (CTL) escape in rapidly progressive infant human immunodeficiency virus type 1 (HIV-1) infection is undefined. The data presented here demonstrate that infant HIV-1-specific CTL can select for viral escape variants very early in life. These variants, furthermore, may be selected specifically in the infant, despite the same CTL specificity being present in the mother. Additionally, pediatric CTL activity may be compromised both by the transmission of maternal escape variants and by mother-to-child transmission of escape variants that originally arose in the father. The unique acquisition of these CTL escape forms may help to explain the severe nature of some pediatric HIV infections.     

Characterisation of worldwide Helicobacter pylori strains reveals genetic conservation and essentiality of serine protease HtrA

HtrA proteases and chaperones exhibit important roles in periplasmic protein quality control and stress responses. The genetic inactivation of htrA has been described for many bacterial pathogens. However, in some cases such as the gastric pathogen Helicobacter pylori, HtrA is secreted where it cleaves the tumour‐suppressor E‐cadherin interfering with gastric disease development, but the generation of htrA mutants is still lacking. Here, we show that the htrA gene locus is highly conserved in worldwide strains. HtrA presence was confirmed in 992 H. pylori isolates in gastric biopsy material from infected patients. Differential RNA‐sequencing (dRNA‐seq) indicated that htrA is encoded in an operon with two subsequent genes, HP1020 and HP1021. Genetic mutagenesis and complementation studies revealed that HP1020 and HP1021, but not htrA, can be mutated. In addition, we demonstrate that suppression of HtrA proteolytic activity with a newly developed inhibitor is sufficient to effectively kill H. pylori, but not other bacteria. We show that Helicobacter htrA is an essential bifunctional gene with crucial intracellular and extracellular functions. Thus, we describe here the first microbe in which htrA is an indispensable gene, a situation unique in the bacterial kingdom. HtrA can therefore be considered a promising new target for anti‐bacterial therapy.     

ClassTR: Classifying Within-Host Heterogeneity Based on Tandem Repeats with Application to Mycobacterium tuberculosis Infections

Genomic tools have revealed genetically diverse pathogens within some hosts. Within-host pathogen diversity, which we refer to as “complex infection”, is increasingly recognized as a determinant of treatment outcome for infections like tuberculosis. Complex infection arises through two mechanisms: within-host mutation (which results in clonal heterogeneity) and reinfection (which results in mixed infections). Estimates of the frequency of within-host mutation and reinfection in populations are critical for understanding the natural history of disease. These estimates influence projections of disease trends and effects of interventions. The genotyping technique MLVA (multiple loci variable-number tandem repeats analysis) can identify complex infections, but the current method to distinguish clonal heterogeneity from mixed infections is based on a rather simple rule. Here we describe ClassTR, a method which leverages MLVA information from isolates collected in a population to distinguish mixed infections from clonal heterogeneity. We formulate the resolution of complex infections into their constituent strains as an optimization problem, and show its NP-completeness. We solve it efficiently by using mixed integer linear programming and graph decomposition. Once the complex infections are resolved into their constituent strains, ClassTR probabilistically classifies isolates as clonally heterogeneous or mixed by using a model of tandem repeat evolution. We first compare ClassTR with the standard rule-based classification on 100 simulated datasets. ClassTR outperforms the standard method, improving classification accuracy from 48% to 80%. We then apply ClassTR to a sample of 436 strains collected from tuberculosis patients in a South African community, of which 92 had complex infections. We find that ClassTR assigns an alternate classification to 18 of the 92 complex infections, suggesting important differences in practice. By explicitly modeling tandem repeat evolution, ClassTR helps to improve our understanding of the mechanisms driving within-host diversity of pathogens like Mycobacterium tuberculosis.