Oxidative Pentose Phosphate Pathway Enzyme 6-Phosphogluconate Dehydrogenase Plays a Key Role in Breast Cancer Metabolism.

The pentose phosphate pathway (PPP) plays an essential role in the metabolism of breast cancer cells for the management of oxidative stress and the synthesis of nucleotides. 6-phosphogluconate dehydrogenase (6PGD) is one of the key enzymes of the oxidative branch of PPP and is involved in nucleotide biosynthesis and redox maintenance status. Here, we aimed to analyze the functional importance of 6PGD in a breast cancer cell model. Inhibition of 6PGD in MCF7 reduced cell proliferation and showed a significant decrease in glucose consumption and an increase in glutamine consumption, resulting in an important alteration in the metabolism of these cells. No difference in reactive oxygen species (ROS) production levels was observed after 6PGD inhibition, indicating that 6PGD, in contrast to glucose 6-phosphate dehydrogenase, is not involved in redox balance. We found that 6PGD inhibition also altered the stem cell characteristics and mammosphere formation capabilities of MCF7 cells, opening new avenues to prevent cancer recurrance after surgery or chemotherapy. Moreover, inhibition of 6PGD via chemical inhibitor S3 resulted in an induction of senescence, which, together with the cell cycle arrest and apoptosis induction, might be orchestrated by p53 activation. Therefore, we postulate 6PGD as a novel therapeutic target to treat breast cancer.

The landscape of tiered regulation of breast cancer cell metabolism.

Altered metabolism is a hallmark of cancer, but little is still known about its regulation. In this study, we measure transcriptomic, proteomic, phospho-proteomic and fluxomics data in a breast cancer cell-line (MCF7) across three different growth conditions. Integrating these multiomics data within a genome scale human metabolic model in combination with machine learning, we systematically chart the different layers of metabolic regulation in breast cancer cells, predicting which enzymes and pathways are regulated at which level. We distinguish between two types of reactions, directly and indirectly regulated. Directly-regulated reactions include those whose flux is regulated by transcriptomic alterations (~890) or via proteomic or phospho-proteomics alterations (~140) in the enzymes catalyzing them. We term the reactions that currently lack evidence for direct regulation as (putative) indirectly regulated (~930). Many metabolic pathways are predicted to be regulated at different levels, and those may change at different media conditions. Remarkably, we find that the flux of predicted indirectly regulated reactions is strongly coupled to the flux of the predicted directly regulated ones, uncovering a tiered hierarchical organization of breast cancer cell metabolism. Furthermore, the predicted indirectly regulated reactions are predominantly reversible. Taken together, this architecture may facilitate rapid and efficient metabolic reprogramming in response to the varying environmental conditions incurred by the tumor cells. The approach presented lays a conceptual and computational basis for mapping metabolic regulation in additional cancers.

Guidelines for Developing Successful Short Advanced Courses in Systems Medicine and Systems Biology.

Systems medicine and systems biology have inherent educational challenges. These have largely been addressed either by providing new masters programs or by redesigning undergraduate programs. In contrast, short courses can respond to a different need: they can provide condensed updates for professionals across academia, the clinic, and industry. These courses have received less attention. Here, we share our experiences in developing and providing such courses to current and future leaders in systems biology and systems medicine. We present guidelines for how to reproduce our courses, and we offer suggestions for how to select students who will nurture an interdisciplinary learning environment and thrive there.

Impact of Climate and Environmental Factors on West Nile Virus Circulation in Iran.

BACKGROUND: Geographic distribution of West Nile virus (WNV) is heterogeneous in Iran by a high circulation in the southern-western areas. The objective of our study was to determine environmental and climatic factors associated with the risk of WNV equine seropositivity in Iran. METHODS: Serological data were obtained from a serosurvey conducted in equine population in 260 districts in Iran. The climate and environmental parameters included in the models were distance to the nearest wetland area, type of stable, Normalized Difference Vegetation Index (NDVI), annual mean temperature, humidity and precipitation. RESULTS: The important risk factors included annual mean temperature, distance to wetlands, local and seasonal NDVI differences. The effect of local NDVI differences in spring was particularly notable. This was a normalized difference of average NDVI between two areas: a 5 km radius area centered on the stable and the 5-10 km surrounding area. CONCLUSION: The model indicated that local NDVI's contrast during spring is a major risk factor of the transmission of West-Nile virus in Iran. This so-called oasis effect consistent with the seasonal production of vegetation in spring, and is associated to the attractiveness of the local NDVI environment for WNV vectors and hosts.

Workforce preparation: the Biohealth computing model for Master and PhD students.

The article addresses the strategic role of workforce preparation in the process of adoption of Systems Medicine as a driver of biomedical research in the new health paradigm. It reports on relevant initiatives, like CASyM, fostering Systems Medicine at EU level. The chapter focuses on the BioHealth Computing Program as a reference for multidisciplinary training of future systems-oriented researchers describing the productive interactions with the Synergy-COPD project.

Campylobacter infection in a cohort of rural children in Moramanga, Madagascar.

BACKGROUND: Campylobacter infection is the most common cause of bacterial gastroenteritis in developing countries, including Madagascar. Reports of pathogenicity have not been consistent and repeated exposures over time seem to lead to the development of protective immunity in developing areas. We conducted this study to support evidence for these hypotheses by exploring the association between infection and age, the reoccurrence of infection and the pathogenicity of Campylobacter. METHODS: We carried out a community-based longitudinal study of children under the age of 24 months in two rural villages in Moramanga, Madagascar. Children were visited twice a week and a stool specimen was collected in cases of diarrhoea. Stools specimens were collected bimonthly from all children enrolled, regardless of symptoms. Children were followed-up until the age of 36 months. RESULTS: Between January 2010 and May 31st 2012, 508 children were included in the cohort. We detected 319 episodes of Campylobacter infection in total, and 43.3% (n = 220) of the children had at least one episode of intestinal Campylobacter infection. The rate of Campylobacter isolation from stool specimens was 9.3%. The annual incidence rate for symptomatic Campylobacter infection was 0.05 episodes/child. The probability of Campylobacter infection was highest between the ages of six and 23 months. Taking children under six months of age as the reference group, the age-specific odds ratio for the association was 5.0 (95% CI: 2.9-8.6) for children aged six to 11 months, 5.7 (95% CI: 3.3-10.0) for children aged 12 to 17 months and 3.3 (95% CI: 1.8-5.8) for children aged 18 to 23 months. A second episode of infection occurred 63 days after the first episode in children with primary infections, and after 137 days in children with multiple infections (p < 0.01). First episodes of Campylobacter infection were associated with diarrhoea (odds ratio = 16.1; 95% CI: 1.8-140.8). CONCLUSION: Our findings suggest that protective immunity to Campylobacter may be acquired over time, following repeated exposures. However, Campylobacter infection prevention measures should be reinforced in the first year of life, as this age seems to be associated with the highest risk of diarrhoea during Campylobacter infection.

Anopheles gambiae resistance to pyrethroid-treated nets in cotton versus rice areas in Mali.

The rise and spread of Anopheles gambiae s.l. (the major malaria vector sub-Saharan Africa) resistance to pyrethroids is of great concern owing to the predominant role of pyrethroid-treated nets in the WHO global strategy for malaria control. Use of pyrethroids for agricultural purposes may exert a strong selection pressure, favouring the emergence of insecticide resistance. The objective of this study was to evaluate the efficacy of alpha-cypermethrin treated nets in settings where insecticides are used against pests. This was assessed in two ways, i.e. under laboratory conditions using the WHO standard cones test technique and in experimental huts, on Anopheles gambiae s.l. collected in two Malian rural sites, Koumantou characterised by cotton crops and high insecticide use and Sélingué, a rice field area with low insecticide use. According to the WHO standard cones test technique, there was no difference between mosquitoes collected in the two sites; KD50 time was less than 3 min and the KD95 time below 30 min. Nevertheless, in the experimental huts with alpha-cypermethrin treated bed nets, the mosquito mortality rate was significantly lower in Koumantou (102/361, 28.2%) than in Sélingué (122/233, 52.3%) (RR: 0.65, 95%CI: 0.56-0.76) (p<0.001). In addition, in Koumantou the percentage of unfed mosquitoes found in the veranda was much lower in the huts with untreated (26.0%, 33/127) than in those with treated nets (92.2%, 118/128) (p<0.01) while in Sélingué there was no difference between huts with treated and untreated bed nets. Alpha-cypermethrin treated bed nets had a significant effect on mortality and repelling behaviour of Anopheles gambiae s.l. though in Koumantou treated bed nets were less efficacious, possibly due to the intense use of pesticide for agriculture.

Theoretical formulation for mosquito host-feeding patterns: application to a West Nile virus focus of southern France.

Host-feeding patterns play a key role in the transmission of vector-borne diseases such as West Nile fever, which involves two kinds of vertebrates, birds and mammals. In this study, we propose a theoretical formulation for mosquito host-feeding patterns using three quantities, as follows: the apparent attractiveness/contact probabilities, the conditional host(-feeding) preferences, and the enzootic versus bridge probabilities. Using results from host-baited trap collections, the quantities defined above were assessed for the most abundant mosquito species in the main West Nile virus focus of southern France. We found that host availability is important in determining the efficiency of bridge vectors, and that even ornithophilic mosquitoes like Culex species, classically classified as enzootic vectors, may turn out to be efficient bridge vectors in certain contexts of host abundance. Our developed theoretical framework can easily be adapted and applied to other experimental data and other vector-borne diseases.

Bayesian mapping of pulmonary tuberculosis in Antananarivo, Madagascar.

BACKGROUND: Tuberculosis (TB), an infectious disease caused by the Mycobacterium tuberculosis is endemic in Madagascar. The capital, Antananarivo is the most seriously affected area. TB had a non-random spatial distribution in this setting, with clustering in the poorer areas. The aim of this study was to explore this pattern further by a Bayesian approach, and to measure the associations between the spatial variation of TB risk and national control program indicators for all neighbourhoods. METHODS: Combination of a Bayesian approach and a generalized linear mixed model (GLMM) was developed to produce smooth risk maps of TB and to model relationships between TB new cases and national TB control program indicators. The TB new cases were collected from records of the 16 Tuberculosis Diagnostic and Treatment Centres (DTC) of the city from 2004 to 2006. And five TB indicators were considered in the analysis: number of cases undergoing retreatment, number of patients with treatment failure and those suffering relapse after the completion of treatment, number of households with more than one case, number of patients lost to follow-up, and proximity to a DTC. RESULTS: In Antananarivo, 43.23% of the neighbourhoods had a standardized incidence ratio (SIR) above 1, of which 19.28% with a TB risk significantly higher than the average. Identified high TB risk areas were clustered and the distribution of TB was found to be associated mainly with the number of patients lost to follow-up (SIR: 1.10, CI 95%: 1.02-1.19) and the number of households with more than one case (SIR: 1.13, CI 95%: 1.03-1.24). CONCLUSION: The spatial pattern of TB in Antananarivo and the contribution of national control program indicators to this pattern highlight the importance of the data recorded in the TB registry and the use of spatial approaches for assessing the epidemiological situation for TB. Including these variables into the model increases the reproducibility, as these data are already available for individual DTCs. These findings may also be useful for guiding decisions related to disease control strategies.

Spatial clustering of pulmonary tuberculosis and impact of the care factors in Antananarivo City.

OBJECTIVE: To analyse the spatial distribution of TB in Antananarivo and investigate risk factors. METHODS: Pulmonary TB data were collected through passive case detection in 16 Tuberculosis Diagnostic and Treatment Centers (DTC). New cases listed in the DTC registers from 2004 to 2006 and resident in Antananarivo were included in the study. Field workers of the national control program conducted household surveys of all cases to collect complementary information on socio-economic status. TB spatial organization and risk factors were analysed over two successive periods (August 2004-July 2005, August 2005-July 2006); analysis was done at the neighbourhood level, by searching for spatial clusters with the spatial scan test. RESULTS: 3075 pulmonary tuberculosis new cases were reported in Antananarivo from 2004 to 2006. The average incidence during the study period was 74/100,000 inhabitants (95% CI: 64.9-84.5). Spatial clusters occurred in three of the six arrondissements (districts) of the city (192 neighbourhoods). A decrease in clustering was observed with movement towards the southern neighbourhood. CONCLUSION: The change in risk of a TB cluster was linked to socio-economic (e.g. household amount of ownership of tap water) and patient care factors (e.g. patients lost to follow-up).

Prevalence of West Nile virus neutralizing antibodies in wild birds from the Camargue area, southern France.

The Camargue area of southern France experienced the re-emergence of West Nile Virus (WNV) in the late summer of 2000 and 2004. Immediately preceding the 2004 outbreak, samples were collected from 432 birds of 32 different species captured in mist nets and from 201 Cattle Egret (Bubulcus ibis) nestlings sampled in their nests between 1 April and 12 June 2004. West Nile virus neutralizing titers of >/=40 were detected in 4.8% (95% confidence limit, 2.9-7.5%) of the adult birds and in 1.6% (0.3-4.6%) of the egret nestlings. Migratory passerines had a higher prevalence of WNV neutralizing antibodies (7.0%) than did resident and short-distance migratory passerines (0.8%), suggesting exposure to WNV or a related flavivirus during overwintering in Africa.

Vector competence of some French Culex and Aedes mosquitoes for West Nile virus.

To identify the mosquito species able to sustain the transmission of West Nile Virus (WNV) in the Camargue region (the main WNV focus of southern France), we assessed the vector competence of Culex modestus and Culex pipiens, the most abundant bird-feeders, and Aedes caspius, the most abundant mammophilic species occasionally found engorged with avian blood. Female mosquitoes were exposed to the infectious meal (10(10.3) plaque forming units (PFU)/mL) by membrane feeding, and hold at 26 degrees C. After the incubation period, disseminated infection was assessed by WNV detection using an indirect fluorescent antibody assay (IFA) on head squashes, and the transmission rate was assessed by the presence of WNV RNA in salivary secretions with a real-time reverse transcriptase-polymerase chain reaction (RT-PCR). After 14 incubation days, the disseminated infection and the transmission rates were 89.2% and 54.5% for Cx. modestus, 38.5% and 15.8% for Cx. pipiens, and 0.8% and 0 for Ae. caspius. Culex modestus was found to be an extremely efficient laboratory WNV vector and could thus be considered the main WNV vector in wetlands of the Camargue. Culex pipiens was a moderately efficient laboratory WNV vector, but in dry areas of the region it could play the main role in WNV transmission between birds and from birds to mammals. Aedes caspius was an inefficient vector of WNV in the laboratory, and despite its high densities, its role in WNV transmission may be minor in southern France.

Magpies as hosts for West Nile virus, southern France.

European magpies (Pica pica) from southern France were tested for antibodies to West Nile virus (WNV) and viral shedding in feces during spring-autumn 2005. Results suggest that this peridomestic species may be a suitable sentinel species and a relevant target for additional investigations on WNV ecology in Europe.

Bird migration routes and risk for pathogen dispersion into western Mediterranean wetlands.

Wild birds share with humans the capacity for moving fast over large distances. During migratory movements, birds carry pathogens that can be transmitted between species at breeding, wintering, and stopover places where numerous birds of various species are concentrated. We consider the area of the Camargue (southern France) as an example to highlight how ad hoc information already available on birds' movements, abundance, and diversity can help assess the introduction and transmission risk for birdborne diseases in the western Mediterranean wetlands. Avian influenza and West Nile viruses are used as examples because birds are central to the epidemiology of these viruses.

Rift Valley fever in West Africa: the role of space in endemicity.

Rift Valley fever is an endemic vector-borne disease in West Africa, which mainly affects domestic ruminants and occasionally humans. The aetiological mechanisms of its endemicity remain under debate. We used a simple spatially explicit model to assess the possibility of endemicity without wild animals providing a permanent virus reservoir. Our model takes into account the vertical transmission in some mosquito species, the rainfall-driven emergence of their eggs and local and distant contacts because of herd migration. Endemicity without such a permanent virus reservoir would be impossible in a single site except when there is a strictly periodic rainfall pattern; but it would be possible when there are herd movements and sufficient inter-site variability in rainfall, which drives mosquito emergence.

Distribution of equine infectious anemia in horses in the north of Minas Gerais State, Brazil.

The paper examines the prevalence of equine infectious anemia (EIA) in horse populations in the northern part (comprising 89 cities) of Minas Gerais State, Brazil, from January 2002 to December 2004. Data on 8,981 agar gel immunodiffusion test results from the region were used as input for a statistical and autoregressive analysis model to construct a city-level map of the distribution of EIA prevalence. The following EIA prevalence (P) levels were found: 49 cities with 0 < P < or = 0.5%, 26 with 0.5% < P < or = 1.5%, 10 with 1.5% < P < or = 5%, and 4 with 5% < P < or = 25%.

Impact of urban atmospheric pollution on coronary disease.

Recent epidemiological findings have suggested that urban atmospheric pollution may have adverse effects on the cardiovascular system as well as on the respiratory system. We carried out an exhaustive search of published studies investigating links between coronary heart disease and urban atmospheric pollution. The review was conducted on cited articles published between 1994 and 2005 and whose main objective was to measure the risk of ischaemic heart diseases related to urban pollution. Of the 236 references identified, 46 epidemiological studies were selected for analysis on the basis of pre-defined criteria. The studies were analysed according to short-term effects (time series and case-crossover designs) and long-term effects (case-control and cohort studies). A link between coronary heart disease and at least one of the pollutants studied (PM10, O3, NOx, CO, SO2) emerged in 40 publications. Particulate matter, nitrogen oxides, and carbon monoxide were the pollutants most often linked with coronary heart disease. The association was inconstant for O3. Although the mean mortality or morbidity risk related to urban atmospheric pollution is low compared with that associated with other better-known risk factors, its impact on health is nevertheless major because of the large number of people who are exposed. This exhaustive review supports the possibility that urban pollution is indeed an environmental cardiovascular risk factor and should be considered as such by the cardiologists.

Aedes aegypti survival and dengue transmission patterns in French Guiana.

Field survival of Aedes aegypti females is a key parameter for estimating the dengue transmission potential of a mosquito population. The objectives of this study were to explore the dynamics of these survival rates at different times of the year in French Guiana and to analyze the results from the perspective of dengue patterns. The mosquitoes were captured, marked, released, and recaptured during four consecutive days in six houses every month, for three to 24 months, from January 1997 to December 1998. Laboratory experiments showed no effects on female survival but some effect on the survival of males. Females' daily survival in the field varied from 0.525 to 1 but was mostly between 0.8 and 0.95 during the entire year, with a mean value of 0.913. The field survival of Ae. aegypti females in French Guiana was thus in agreement with the likely transmission of dengue and the dengue endemic patterns throughout the year. On the other hand, heavy rainfalls during this time were less favorable to Ae. aegypti survival, which may explain part of the El Niño effect on dengue epidemics in French Guiana. The methods and results on Ae. aegypti survival will be implemented in a global dengue surveillance network in French Guiana.

Time-delay dynamics for contagious bovine pleuropneumonia.

Modelling of contagious disease usually employs compartmental SEIR-like models where the waiting times in respective compartments are exponentially distributed. In this paper, we are interested in investigating how the distributions of sojourn times in infective compartments affect the dynamics and persistence of the contagious bovine pleuropneumonia, a chronic respiratory disease of cattle. Two kinds of extreme distributions of the sojourn times are considered: a Dirac delta-function and truncated Gaussian function leading to a model with (non-constant) delay and the classical exponential distribution that stands for a model without delay. Expressions of the basic reproductive numbers are derived and dynamical behaviours are discussed for the three models. It is found that the spreading of disease exhibits wave-like oscillations for the time-delay dynamics. In contrast, the disease appears to last longer when the spreading is described by the classical dynamics without delay. Subsequently, the time-delay dynamics turns out to be more appropriate for the description of an experimental epidemic of CBPP.