Iceberg transport technologies in spatial competition. Hotelling reborn

Transport costs in address models of differentiation are usually modeled as separable of the consumption commodity and with a parametric price. However, there are many sectors in an economy where such modeling is not satisfactory either because transportation is supplied under oligopolistic conditions or because there is a difference (loss) between the amount delivered at the point of production and the amount received at the point of consumption. This paper is a first attempt to tackle these issues proposing to study competition in spatial models using an iceberg-like transport cost technology allowing for concave and convex melting functions.

Genetic analysis of the breeding system of an invasive subterranean termite, Reticulitermes santonensis, in urban and natural habitats.

Reticulitermes santonensis is a subterranean termite that invades urban areas in France and elsewhere where it causes damage to human-built structures. We investigated the breeding system, colony and population genetic structure, and mode of dispersal of two French populations of R. santonensis. Termite workers were sampled from 43 and 31 collection points, respectively, from a natural population in west-central France (in and around the island of Oleron) and an urban population (Paris). Ten to 20 workers per collection point were genotyped at nine variable microsatellite loci to determine colony identity and to infer colony breeding structure. There was a total of 26 colonies, some of which were spatially expansive, extending up to 320 linear metres. Altogether, the analysis of genotype distribution, F-statistics and relatedness coefficients suggested that all colonies were extended families headed by numerous neotenics (nonwinged precocious reproductives) probably descended from pairs of primary (winged) reproductives. Isolation by distance among collection points within two large colonies from both populations suggested spatially separated reproductive centres with restricted movement of workers and neotenics. There was a moderate level of genetic differentiation (F(ST) = 0.10) between the Oleron and Paris populations, and the number of alleles was significantly higher in Oleron than in Paris, as expected if the Paris population went through bottlenecks when it was introduced from western France. We hypothesize that the diverse and flexible breeding systems found in subterranean termites pre-adapt them to invade new or marginal habitats. Considering that R. santonensis may be an introduced population of the North American species R. flavipes, a breeding system consisting primarily of extended family colonies containing many neotenic reproductives may facilitate human-mediated spread and establishment of R. santonensis in urban areas with harsh climates.

Detecting epistasis with restricted response patterns in pairs of biallelic loci.

Well-established examples of genetic epistasis between a pair of loci typically show characteristic patterns of phenotypic distributions in joint genotype tables. However, inferring epistasis given such data is difficult due to the lack of power in commonly used approaches, which decompose the epistatic patterns into main plus interaction effects followed by testing the interaction term. Testing additive-only or all terms may have more power, but they are sensitive to nonepistatic patterns. Alternatively, the epistatic patterns of interest can be enumerated and the best matching one is found by searching through the possibilities. Although this approach requires multiple testing correction over possible patterns, each pattern can be fitted with a regression model with just one degree of freedom and thus the overall power can still be high, if the number of possible patterns is limited. Here we compare the power of the linear decomposition and pattern search methods, by applying them to simulated data generated under several patterns of joint genotype effects with simple biological interpretations. Interaction-only tests are the least powerful; while pattern search approach is the most powerful if the range of possibilities is restricted, but still includes the true pattern.

Dukes B colorectal cancer: distinct genetic categories and clinical outcome based on proximal or distal tumor location.

PURPOSE: The aim of this study was to determine whether tumor location proximal or distal to the splenic flexure is associated with distinct molecular patterns and can predict clinical outcome in a homogeneous group of patients with Dukes B (T3-T4, N0, M0) colorectal cancer. It has been hypothesized that proximal and distal colorectal cancer may arise through different pathogenetic mechanisms. Although p53 and Ki-ras gene mutations occur frequently in distal tumors, another form of genomic instability associated with defective DNA mismatch repair has been predominantly identified in the proximal colon. To date, however, the clinical usefulness of these molecular characteristics remains unproven. METHODS: A total of 126 patients with a lymph node-negative sporadic colon or rectum adenocarcinoma were prospectively assessed with the endpoint of death by cancer. No patient received either radiotherapy or chemotherapy. p53 protein was studied by immunohistochemistry using DO-7 monoclonal antibody, and p53 and Ki-ras gene mutations were detected by single strand conformation polymorphism assay. RESULTS: During a mean follow-up of 67 months, the overall five-year survival was 70 percent. Nuclear p53 staining was found in 57 tumors (47 percent), and was more frequent in distal than in proximal tumors (55 vs. 21 percent; chi-squared test, P < 0.001). For the whole group, p53 protein expression correlated with poor survival in univariate and multivariate analysis (log-rank test, P = 0.01; hazard ratio = 2.16; 95 percent confidence interval = 1.12-4.11, P = 0.02). Distal colon tumors and rectal tumors exhibited similar molecular patterns and showed no difference in clinical outcome. In comparison with distal colorectal cancer, proximal tumors were found to be statistically significantly different on the following factors: mucinous content (P = 0.008), degree of histologic differentiation (P = 0.012), p53 protein expression, and gene mutation (P = 0.001 and 0.01 respectively). Finally, patients with proximal tumors had a marginally better survival than those with distal colon or rectal cancers (log-rank test, P = 0.045). CONCLUSION: In this series of Dukes B colorectal cancers, p53 protein expression was an independent factor for survival, which also correlated with tumor location. Eighty-six percent of p53-positive tumors were located in the distal colon and rectum. Distal colon and rectum tumors had similar molecular and clinical characteristics. In contrast, proximal neoplasms seem to represent a distinct entity, with specific histopathologic characteristics, molecular patterns, and clinical outcome. Location of the neoplasm in reference to the splenic flexure should be considered before group stratification in future trials of adjuvant chemotherapy in patients with Dukes B tumors.

Genetic survey of "spinturnix sp" (Acari, Mesostigmata) and their bat hosts in Western Palearctic

SUMMARY : The coevolution between two intimately associated organisms, like host and parasite, is a widely investigated theme in evolutionary biology. Recently, the use of genetic data in the study of host-parasite systems evidences that the genetic information from some parasites can complement genetic data from their hosts and thus may help to better understand their host's evolutionary history. Phylogenetic and population genetic aspects of bat parasites have been poorly investigated. Spinturnicid mites are highly specialized ectoparasites, exclusively associated with bats and therefore represent an ideal model to extant our knowledge on bat and parasite biology and on their coevolutionary history. In this thesis, I developed several molecular markers (mitochondrial DNA) to compare the genetic patterns of Spinturnix mites with their bat hosts at different levels. The molecular co-phylogeny between Spinturnix sp. and their bat hosts suggests a partial cospeciation and the occurrence of failure to speciate events and multiple host switches. Thus, Spinturnix mites do not exactly mirror the phylogenetic pattern of their hosts, despite their intimate association. Similar roosting habits of the hosts seem to promote host switches between different species, as far as ecological conditions are favourable. The phylogeographic study of the Maghrebian bat M. punicus in the Mediterranean area confirms the presence of M. punicus in North Africa, Corsica and Sardinia and highlights that islands and mainland are genetically highly divergent. The comparison between the parasitic mite S. myoti and the Maghrebian bat suggests that the phylogeographic pattern of the mite is moulded by its host, with open water as main barrier for host and parasite dispersal. Moreover, the unique presence of a European S. myoti lineage on M. punicus from Corsica strongly suggests the former presence of mouse-eared bats (M. myotis and/or M. blythii) in Corsica. By highlighting the probable presence of a nowadays locally extinct host species, S. myoti may represent a good proxy for inferring complex evolutionary history of bat hosts. Finally, population genetic surveys of S. myoti and S. bechsteinii suggest that these mites benefit from close contacts between individuals during the mating season and/or hibernation to disperse among remote colonies. The contrasted genetic patterns of these two distinct bat-mite systems evidence that bat social structure is a determinant factor of the genetic structure of mite populations. Altogether, this PhD thesis demonstrates the usefulness of parasites to gather information about their bat hosts. In addition, my results illustrate how different ecological and biological characteristics of bat species allow the emergence of a surprising diversity in the genetic patterns of the parasites, which may contribute to the diversification and speciation of parasites. RESUME : La co-évolution entre deux organismes intimement liés, comme un parasite et son hôte, fait partie des questions largement étudiées en biologie évolutive. Récemment, l'utilisation de données génétique dans l'étude des interactions hôte-parasite a montré que l'information génétique de certains parasites peut compléter les données génétiques de l'hôte et ainsi peut éclairer l'histoire évolutive de leur hôte. Très peu études ont étudié les interactions entre les chauves-souris et leurs parasites d'un point de vue moléculaire. Les acariens du genre Spinturnix sont des ectoparasites très spécialisés exclusivement associés aux chauves-souris. Ils représentent donc un model idéal pour élargir nos connaissances tant sur l'écologie des parasites de chauves-souris que sur leur coévolution. Durant cette thèse, plusieurs marqueurs moléculaires (ADN mitochondrial) ont été développés pour ainsi comparer la distribution de la variation génétique des parasites du genre Spinturnix avec celle de leurs hôtes, et ceci à différents niveaux. Tout d'abord, la co-phylogénie moléculaire entre les espèces de Spinturnix et les leurs hôtes révèle une co-spéciation partielle ainsi que la présence d'événement de non spéciation et de transferts horizontaux. Ces parasites ne reflètent donc pas entièrement l'histoire évolutive de leurs hôtes, malgré leurs intimes associations. La cohabitation de plusieurs espèces de chauves-souris dans un même gîte permet aux parasites un transfert entre différentes espèces, atténuant ainsi leur degré de co-spéciation. Deuxièmement, l'étude phylogéographique du marin du Maghreb dans le bassin Méditerranéen confirme sa présence en Afrique du Nord, en Corse et en Sardaigne. La comparaison avec un de ses parasites S. myoti suggère que la répartition génétique de S. myoti est façonnée par celle de leurs hôtes, avec les étendues d'eau comme barrière principale tant à la dispersion de l'hôte que de son parasite. De plus, la présence unique d'une lignée européenne de ces parasites sur des marins du Maghreb de Corse suggère fortement la présence du grand ou petit marin en Corse dans le passé. En reflétant la présence potentielle à un endroit donné d'une espèce de chauve-souris actuellement disparue, S. myoti peut représenter une bonne alternative pour comprendre l'histoire évolutive complexe des chauves-souris. Finalement, l'étude des structures génétiques des populations des parasites S. myoti et S. bechsteinii suggère que les contacts corporels entre chauves-souris durant la saison de reproduction ou l'hibernation peuvent permettre la dispersion des parasites entre des colonies éloignées géographiquement. La différence de structure génétique entre ces deux associations particulières montre que la structure génétique des populations de parasites dépend fortement des traits d'histoire de vie de son hôte. Dans l'ensemble, cette thèse démontre l'importance des parasites pour amener des informations sur leurs hôtes, les chauves-souris. Elle illustre aussi comment les différences écologique et biologique des différentes espèces de chauves-souris peuvent amener une étonnante diversité de structure génétique au sein de populations de parasites, ce qui peut peut-être contribuer à la diversification et à la spéciation des parasites.

Genetic linkage of Bietti crystallin corneoretinal dystrophy to chromosome 4q35.

Bietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessive retinal degeneration characterized by multiple glistening intraretinal dots scattered over the fundus, degeneration of the retina, and sclerosis of the choroidal vessels, ultimately resulting in progressive night blindness and constriction of the visual field. Although BCD has been associated with abnormalities in fatty-acid metabolism and absence of fatty-acid binding by two cytosolic proteins, the genetic basis of BCD is unknown. We report linkage of the BCD locus to D4S426 (maximum LOD score [Z(max)] 4.81; recombination fraction [straight theta] 0), D4S2688 (Zmax=3.97; straight theta=0), and D4S2299 (Zmax=5.31; straight theta=0), on chromosome 4q35-4qtel. Multipoint analysis confirmed linkage to the region telomeric of D4S1652 with a Z(max) of 5.3 located 4 cM telomeric of marker D4S2930.

DNA polymorphism of schistosomes and their snail hosts

Analysis of the genomes of schistosomes and one of their intermediate hosts, Biomphalaria glabrata, using Random Amplified Polymorphic DNA (RAPD) demonstrated that intraspecific genetic polymorphism in the parasite is limited but in the snail is highly pronounced. This suggests an important role for the snail in the determination of the epidemiology of the disease. In addition to their intraspecific stability, schistosome derived RAPDs exhibit a high level of interspecific polymorphism and are thus ideal for the construction of phylogenetic trees. For the detection of intraspecific polymorphisms extensive variation in the mitochondrial DNA is being exploited for the development of a PCR based test for Schistosoma mansoni. Gene level polymorphisms are being analyzed by Low Stringency Single Specific Primer PCR.

A molecular genetic study of the variations in metabolic function during schistosome development

During their complex life cycle schistosomes alternate between the use of stored glycogen and reliance on host glucose to provide for their energy needs. In addition, there is dramatic variation between the relative contribution of aerobic versus anaerobic glucose metabolism during development. We have cloned a set of representative cDNAs that encode proteins involved in glucose uptake, glycolysis, Kreb's cycle and oxidative phosphorylation. The different cDNAs were used as probes to examine the expression of glucose metabolism genes during the schistosome life cycle. Steady state mRNA levels from whole cercariae, isolated cercarial tails, schistosomula and adult worms were analysed on Northern blots and dot blots which were quantified using storage phosphor technology. These studies reveal: (1) Transcripts encoding glycogen metabolic enzymes are expressed to much higher levels in cercarial tails than whole cercariae or schistosomula while the opposite pattern is found for glucose transporters and hexokinase transcripts; (2) Schistosomula contain low levels of transcripts encoding respiratory enzymes but regain the capacity for aerobic glucose metabolism as they mature to adulthood; (3) Male and female adults contain similar levels of the different transcripts involved in glucose metabolism.

Genetic variability and differentiation between populations of Rhodnius prolixus and R. pallescens, vectors of Chagas' Disease in Colombia

Enzyme polymorphism in Rhodnius prolixus and R. pallescens (Hemiptera, Reduviidae), principal vectors of Chagas' disease in Colombia, was analyzed using starch gel electrophoresis. Three geographic locations were sampled in order to determine gene flow between populations and to characterize intra- and interspecific differences. Of 25 enzymes assayed 10 were successfully resolved and then used to score the genetic variation. The enzymes PEPD, GPI, PGM and ICD were useful to differentiate these species and PGD, PGM and MDH distinguished between sylvatic and domiciliary populations of R. prolixus. Both polymorphism and heterozygosity indicated greater genetic variability in sylvatic habitats (H = 0.021) compared to domiciliary habitats (H = 0.006) in both species. Gene flow between sylvatic and domiciliary populations in R. prolixus was found to be minimal. This fact and the genetic distance between them suggest a process of genetic isolation in the domiciliary population.

A possible correlation between the host genetic background in the epidemiology of Hepatitis B virus in the Amazon region of Brazil

The Amazon region of Brazil is an area of great interest because of the large distribution of hepatitis B virus in specific Western areas. Seven urban communities and 24 Indian groups were visited in a total of 4,244 persons. Each individual was interviewed in order to obtain demographic and familial information. Whole blood was collected for serology and genetic determinations. Eleven genetic markers and three HBV markers were tested. Among the most relevant results it was possible to show that (i) there was a large variation of previous exposure to HBV in both urban and non-urban groups ranging from 0 to 59.2%; (ii) there was a different pattern of epidemiological distribution of HBV that was present even among a same linguistic Indian group, with mixed patterns of correlation between HBsAg and anti-HBs and (iii) the prevalence of HBV markers (HBsAg and anti-HBs) were significantly higher (P=0.0001) among the Indian population (18.8%) than the urban groups (12.5%). Its possible that the host genetic background could influence and modulate the replication of the virus in order to generate HB carrier state.

Genetic identity of the critically endangered Wimmer's shrew Crocidura wimmeri

Coastal primary rainforests have suffered damage in Côte d'Ivoire as a result of a lack of protection and urban pressures. Consequently, the highly endemic and critically endangered Wimmer's shrew, Crocidura wimmeri, known only from its type locality, Adiopodoumé, near Abidjan, was considered to have been extinct since 1976. Shrew species assignment is often problematic because of strong phenotypic similarities among many species. The phylogenetic position of C. wimmeri within the African Crocidura species should thus be clarified. In light of its recent rediscovery in the nearby small Banco National Park (34 km2), we investigated the genetic identity of seven specimens of C. wimmeri, based on 1020 bp of the mitochondrial DNA cytochrome b gene compared to other species sampled in the same region and published sequences from GenBank. Crocidura wimmeri formed a well-defined clade, the closest-related species being Crocidura sp., with a distance of 9.3%, a yet unknown species from Taï and Ziama forests. These results thus confirmed the validity of this species. This genetic characterization not only contributes to our knowledge of the evolution of West African shrews, but also may help in the discovery of additional populations of this critically endangered species.

Data bases for the assessment of medical technologies: examples from Europe.

The assessment of medical technologies has to answer several questions ranging from safety and effectiveness to complex economical, social, and health policy issues. The type of data needed to carry out such evaluation depends on the specific questions to be answered, as well as on the stage of development of a technology. Basically two types of data may be distinguished: (a) general demographic, administrative, or financial data which has been collected not specifically for technology assessment; (b) the data collected with respect either to a specific technology or to a disease or medical problem. On the basis of a pilot inquiry in Europe and bibliographic research, the following categories of type (b) data bases have been identified: registries, clinical data bases, banks of factual and bibliographic knowledge, and expert systems. Examples of each category are discussed briefly. The following aims for further research and practical goals are proposed: criteria for the minimal data set required, improvement to the registries and clinical data banks, and development of an international clearinghouse to enhance information diffusion on both existing data bases and available reports on medical technology assessments.