Haemoglobin S and haemoglobin C: 'quick but costly' versus 'slow but gratis' genetic adaptations to Plasmodium falciparum malaria

Haemoglobin S (HbS; beta 6Glu -> Val) and HbC (beta 6Glu -> Lys) strongly protect against clinical Plasmodium falciparum malaria. HbS, which is lethal in homozygosity, has a multi-foci origin and a widespread geographic distribution in sub-Saharan Africa and Asia whereas HbC, which has no obvious CC segregational load, occurs only in a small area of central West-Africa. To address this apparent paradox, we adopted two partially independent haplotypic approaches in the Mossi population of Burkina Faso where both the local S (S-Benin) and the C alleles are common (0.05 and 0.13). Here we show that: both C and S-Benin are monophyletic; C has accumulated a 4-fold higher recombinational and DNA slippage haplotypic variability than the S-Benin allele (P = 0.003) implying higher antiquity; for a long initial lag period, the C alleles did apparently remain very few. These results, consistent with epidemiological evidences, imply that the C allele has been accumulated mainly through a recessive rather than a semidominant mechanism of selection. This evidence explains the apparent paradox of the uni-epicentric geographic distribution of HbC, representing a 'slow but gratis' genetic adaptation to malaria through a transient polymorphism, compared to the polycentric 'quick but costly' adaptation through balanced polymorphism of HbS

Max-weight scheduling in networks with heavy-tailed traffic

We consider the problem of packet scheduling in a single-hop network with a mix of heavy-tailed and light-tailed traffic, and analyze the impact of heavy-tailed traffic on the performance of Max-Weight scheduling. As a performance metric we use the delay stability of traffic flows: a traffic flow is delay stable if its expected steady-state delay is finite, and delay unstable otherwise. First, we show that a heavy-tailed traffic flow is delay unstable under any scheduling policy. Then, we focus on the celebrated Max-Weight scheduling policy, and show that a light-tailed flow that conflicts with a heavy-tailed flow is also delay unstable. This is true irrespective of the rate or the tail distribution of the light-tailed flow, or other scheduling constraints in the network. Surprisingly, we show that a light-tailed flow can be delay unstable, even when it does not conflict with heavy-tailed traffic. Furthermore, delay stability in this case may depend on the rate of the light-tailed flow. Finally, we turn our attention to the class of Max-Weight-α scheduling policies; we show that if the α-parameters are chosen suitably, then the sum of the α-moments of the steady-state queue lengths is finite. We provide an explicit upper bound for the latter quantity, from which we derive results related to the delay stability of traffic flows, and the scaling of moments of steady-state queue lengths with traffic intensity

VISTAS DE LA CIUDAD DE AGRIGENTO EN SICILIA [Material gráfico]

MILÁN (ITALIA)Copia digital. Madrid : Ministerio de Educación, Cultura y Deporte, 201

Throughput Optimal Scheduling Over Time-Varying Channels in the Presence of Heavy-Tailed Traffic

We study the problem of scheduling over time varying links in a network that serves both heavy-tailed and light tailed traffic. We consider a system consisting of two parallel queues, served by a single server. One of the queues receives heavy-tailed traffic (the heavy queue), and the other receives light-tailed traffic (the light queue). The queues are connected to the server through time-varying ON/OFF links, which model fading wireless channels. We first show that the policy that gives complete priority to the light-tailed traffic guarantees the best possible tail behavior of both queue backlog distributions, whenever the queues are stable. However, the priority policy is not throughput maximizing, and can cause undesirable instability effects in the heavy queue. Next, we study the class of throughput optimal max-weight-α scheduling policies. We discover a threshold phenomenon, and show that the steady state light queue backlog distribution is heavy-tailed for arrival rates above a threshold value, and light-tailed otherwise. We also obtain the exact tail coefficient of the light queue backlog distribution under max-weight-α scheduling. Finally, we study a log-max-weight scheduling policy, which is throughput optimal, and ensures that the light queue backlog distribution is light-tailed.National Science Foundation (U.S.) (Grant CNS-1217048)National Science Foundation (U.S.) (Grant CNS-0915988)National Science Foundation (U.S.) (CMMI-1234062)United States. Army Research Office. Multidisciplinary University Research Initiative (Grant W911NF-08-1-0238

Differential antibody response to the Anopheles gambiae gSG6 and cE5 salivary proteins in individuals naturally exposed to bites of malaria vectors.

Background Mosquito saliva plays crucial roles in blood feeding but also evokes in hosts an anti-saliva antibody response. The IgG response to the Anopheles gambiae salivary protein gSG6 was previously shown to be a reliable indicator of human exposure to Afrotropical malaria vectors. We analyzed here the humoral response to the salivary anti-thrombin cE5 in a group of individuals from a malaria hyperendemic area of Burkina Faso. Methods ELISA was used to measure the anti-cE5 IgG, IgG1 and IgG4 antibody levels in plasma samples collected in the village of Barkoumbilen (Burkina Faso) among individuals of the Rimaibé ethnic group. Anti-gSG6 IgG levels were also determined for comparison. Anopheles vector density in the study area was evaluated by indoor pyrethrum spray catches. Results The cE5 protein was highly immunogenic and triggered in exposed individuals a relatively long-lasting antibody response, as shown by its unchanged persistence after a few months of absent or very low exposure (dry season). In addition cE5 did not induce immune tolerance, as previously suggested for the gSG6 antigen. Finally, IgG subclass analysis suggested that exposed individuals may mount a Th1-type immune response against the cE5 protein. Conclusions The anti-cE5 IgG response is shown here to be a sensitive indicator of human exposure to anopheline vectors and to represent an additional tool for malaria epidemiological studies. It may be especially useful in conditions of low vector density, to monitor transiently exposed individuals (i.e. travellers/workers/soldiers spending a few months in tropical Africa) and to evaluate the impact of insecticide treated nets on vector control. Moreover, the gSG6 and cE5 salivary proteins were shown to trigger in exposed individuals a strikingly different immune response with (i) gSG6 evoking a short-lived IgG response, characterized by high IgG4 levels and most likely induction of immune tolerance, and (ii) cE5 eliciting a longer-living IgG response, dominated by anti-cE5 IgG1 antibodies and not inducing tolerance mechanisms. We believe that these two antigens may represent useful reagents to further investigate the so far overlooked role of Anopheles saliva and salivary proteins in host early immune response to Plasmodium parasites

A clonal Plasmodium falciparum population in an isolated outbreak of malaria in the Republic of Cabo Verde

We present the first parasitological, molecular and longitudinal analysis of an isolated outbreak of malaria. This outbreak occurred on Santiago Island (Republic of Cabo Verde), a region where malaria is hypoendemic and controlled, and thus the population is considered non-immune. Blood samples were collected from the inhabitants over 1 month and during cross-sectional surveys in the following year. The presence and nature of the parasites was determined by PCR. Plasmodium falciparum was the only species detected. Genetic analysis revealed that the circulating parasites were genetically homogeneous, and probably clonal. Gametocytes were found throughout this period. Our data suggest that this represented a focal outbreak, resulting in the infection of at least 40% of the villagers with a clonal parasite line. Thus, P. falciparum infections can persist for at least 1 year in a substantial proportion (10%) of the hosts. Implications for malaria control and the interpretation of epidemiological data are discussed

Human candidate gene polymorphisms and risk of severe malaria in children in Kilifi, Kenya: a case-control association study

Background: Human genetic factors are important determinants of malaria risk. We investigated associations between multiple candidate polymorphisms—many related to the structure or function of red blood cells—and risk for severe Plasmodium falciparum malaria and its specific phenotypes, including cerebral malaria, severe malaria anaemia, and respiratory distress. Methods: We did a case-control study in Kilifi County, Kenya. We recruited as cases children presenting with severe malaria to the high-dependency ward of Kilifi County Hospital. We included as controls infants born in the local community between Aug 1, 2006, and Sept 30, 2010, who were part of a genetics study. We tested for associations between a range of candidate malaria-protective genes and risk for severe malaria and its specific phenotypes. We used a permutation approach to account for multiple comparisons between polymorphisms and severe malaria. We judged p values less than 0·005 significant for the primary analysis of the association between candidate genes and severe malaria. Findings: Between June 11, 1995, and June 12, 2008, 2244 children with severe malaria were recruited to the study, and 3949 infants were included as controls. Overall, 263 (12%) of 2244 children with severe malaria died in hospital, including 196 (16%) of 1233 with cerebral malaria. We investigated 121 polymorphisms in 70 candidate severe malaria-associated genes. We found significant associations between risk for severe malaria overall and polymorphisms in 15 genes or locations, of which most were related to red blood cells: ABO, ATP2B4, ARL14, CD40LG, FREM3, INPP4B, G6PD, HBA (both HBA1 and HBA2), HBB, IL10, LPHN2 (also known as ADGRL2), LOC727982, RPS6KL1, CAND1, and GNAS. Combined, these genetic associations accounted for 5·2% of the variance in risk for developing severe malaria among individuals in the general population. We confirmed established associations between severe malaria and sickle-cell trait (odds ratio [OR] 0·15, 95% CI 0·11–0·20; p=2·61 × 10−58), blood group O (0·74, 0·66–0·82; p=6·26 × 10−8), and –α3·7-thalassaemia (0·83, 0·76–0·90; p=2·06 × 10−6). We also found strong associations between overall risk of severe malaria and polymorphisms in both ATP2B4 (OR 0·76, 95% CI 0·63–0·92; p=0·001) and FREM3 (0·64, 0·53–0·79; p=3·18 × 10−14). The association with FREM3 could be accounted for by linkage disequilibrium with a complex structural mutation within the glycophorin gene region (comprising GYPA, GYPB, and GYPE) that encodes for the rare Dantu blood group antigen. Heterozygosity for Dantu was associated with risk for severe malaria (OR 0·57, 95% CI 0·49–0·68; p=3·22 × 10−11), as was homozygosity (0·26, 0·11–0·62; p=0·002). Interpretation: Both ATP2B4 and the Dantu blood group antigen are associated with the structure and function of red blood cells. ATP2B4 codes for plasma membrane calcium-transporting ATPase 4 (the major calcium pump on red blood cells) and the glycophorins are ligands for parasites to invade red blood cells. Future work should aim at uncovering the mechanisms by which these polymorphisms can result in severe malaria protection and investigate the implications of these associations for wider health. Funding: Wellcome Trust, UK Medical Research Council, European Union, and Foundation for the National Institutes of Health as part of the Bill & Melinda Gates Grand Challenges in Global Health Initiative

Highly preferential association of NonF508del CF mutations with the M470 allele

AbstractBackgroundOn the basis of previous findings on random individuals, we hypothesized a preferential association of CF causing mutations with the M allele of the M470V polymorphic site of the CFTR gene.MethodsWe have determined the M/V-CF mutation haplotype in a series of 201 North East Italian and 73 Czech CF patients who were not F508del homozygotes, as F508del was already known to be fully associated with the M allele.ResultsOut of 358 not F508del CF genes, 84 carried the V allele and 274 the less common M allele. In the N-E Italian population, MM subjects have a risk of carrying a CF causing mutation 6.9× greater than VV subjects when F508del is excluded and 15.4× when F508del is included. In the Czech population a similar, although less pronounced, association is observed.ConclusionsBesides the possible biological significance of this association, the possibility of exploiting it for a pilot screening program has been explored in a local North East Italian population for which CF patients were characterized for their CF mutation. General M470V genotyping followed by common CF mutation screening limited to couples in which each partner carries at least one M allele would need testing only 39% of the couples, which contribute 89% of the total risk, with a cost benefit