Synthesis of norbornanepentols: analogues of inositols

The synthesis of endo-5,6-exo-2,3-syn-7-norbornanepentol (5), endo-5-exo-2,3,6-syn-7-norbornanepentol (14), and 7-exo-2,3,5,6-norbornanepentol (16) are described. cis-Hydroxylation of 7-tert-butoxynorbornadiene (1) gave the exo-diol 2, endo-diol 3, and tetrol 4. The latter was deprotected to give pentol 5. Oxidation of alkene 6 afforded diacid 7 and two minor products: the exo-diol 8 and alpha-hydroxyketone 9. cis-Hydroxylation of 6 gave the endo- and exo-diols 10 and 8. Acetalation of 8 furnished the bis(dioxolane) 11. Reduction of ketone 9 gave the trans-diol 12. Deblocking of 8 and 12 led the tetrol 15 or pentols 16 and 14. The structure of tetrol 4 was confirmed by X-ray diffraction. Compounds 4, 5 and 16 were devoid of antitumor or antiviral activity.     

Global Stability of Reversible Enzymatic Metabolic Chains

We consider metabolic networks with reversible enzymatic reactions. The model is written as a system of ordinary differential equations, possibly with inputs and outputs. We prove the global stability of the equilibrium (if it exists), using techniques of monotone systems and compartmental matrices. We show that the equilibrium does not always exist. Finally, we consider a metabolic system coupled with a genetic network, and we study the dependence of the metabolic equilibrium (if it exists) with respect to concentrations of enzymes. We give some conclusions concerning the dynamical behavior of coupled genetic/metabolic systems.     

Micro-Geographical Heterogeneity in Schistosoma mansoni and S. haematobium Infection and Morbidity in a Co-Endemic Community in Northern Senegal

Background

Schistosoma mansoni and S. haematobium are co-endemic in many areas in Africa. Yet, little is known about the micro-geographical distribution of these two infections or associated disease within such foci. Such knowledge could give important insights into the drivers of infection and disease and as such better tailor schistosomiasis control and elimination efforts.

Methodology

In a co-endemic farming community in northern Senegal (346 children (0–19 y) and 253 adults (20–85 y); n = 599 in total), we studied the spatial distribution of S. mansoni and S. haematobium single and mixed infections (by microscopy), S. mansoni-specific hepatic fibrosis, S. haematobium-specific urinary tract morbidity (by ultrasound) and water contact behavior (by questionnaire). The Kulldorff''s scan statistic was used to detect spatial clusters of infection and morbidity, adjusted for the spatial distribution of gender and age.

Principal Findings

Schistosoma mansoni and S. haematobium infection densities clustered in different sections of the community (p = 0.002 and p = 0.023, respectively), possibly related to heterogeneities in the use of different water contact sites. While the distribution of urinary tract morbidity was homogeneous, a strong geospatial cluster was found for severe hepatic fibrosis (p = 0.001). Particularly those people living adjacent to the most frequently used water contact site were more at risk for more advanced morbidity (RR = 6.3; p = 0.043).

Conclusions/Significance

Schistosoma infection and associated disease showed important micro-geographical heterogeneities with divergent patterns for S. mansoni and S. haematobium in this Senegalese community. Further in depth investigations are needed to confirm and explain our observations. The present study indicates that local geospatial patterns should be taken into account in both research and control of schistosomiasis. The observed extreme focality of schistosomiasis even at community level, suggests that current strategies may not suffice to move from morbidity control to elimination of schistosomiasis, and calls for less uniform measures at a finer scale.     

Selection of antimalarial drug resistance after intermittent preventive treatment of infants and children (IPTi/c) in Senegal

Senegal has since 2003 used sulphadoxine-pyrimethamine (SP) for Intermittent Preventive Treatment (IPT) of malaria in risk groups. However, the large-scale IPT strategy may result in increasing drug resistance. Our study investigated the possible impact of SP-IPT given to infants and children on the prevalence of SP-resistant haplotypes in the Plasmodium falciparum genes Pfdhfr and Pfdhps, comparing sites with and without IPTi/c. P. falciparum positives samples (n = 352) were collected from children under 5 years of age during two cross-sectional surveys in 2010 and 2011 in three health districts (two on IPTi/c and one without IPTi/c intervention) located in the southern part of Senegal. The prevalence of SP-resistance-related haplotypes in Pfdhfr and Pfdhps was determined by nested PCR followed by sequence-specific oligonucleotide probe (SSOP)–ELISA. The prevalence of the Pfdhfr double mutant haplotypes (CNRN and CICN) was stable between years at < 10% in the control group (P = 0.69), while it rose significantly in the IPTi/c group from 2% in 2010 to 20% in 2011 (P = 0.008). The prevalence of the Pfdhfr triple mutant haplotype (CIRN) increased in both groups, but only significantly in the IPTi/c group from 41% to 65% in 2011 (P = 0.005). Conversely, the Pfdhps 437G mutation decreased in both groups from 44.6% to 28.6% (P = 0.07) and from 66.7% to 47.5% (P = 0.02) between 2010 and 2011 in the control and the IPTi/c groups, respectively. Combined with Pfdhfr, there was a weak trend for decreasing prevalence of quadruple mutants (triple Pfdhfr + Pfdhps 437G) in both groups (P = 0.15 and P = 0.34). During the two cross-sectional surveys, some significant changes were observed in the SP-resistance-related genes. However, since these changes were observed in the two groups, the IPTi/c strategy does only seem to have limited impact on resistance development and other factors as well. However, continuous monitoring will be needed, due to the up-scaling of the IPTi/c strategy in Senegal according to WHO recommendations.     

Risk Factors for Plasmodium falciparum Gametocyte Positivity in a Longitudinal Cohort

Malaria transmission intensity is highly heterogeneous even at a very small scale. Implementing targeted intervention in malaria transmission hotspots offers the potential to reduce the burden of disease both locally and in adjacent areas. Transmission of malaria parasites from man to mosquito requires the production of gametocyte stage parasites. Cluster analysis of a 19-year long cohort study for gametocyte carriage revealed spatially defined gametocyte hotspots that occurred during the time when chloroquine was the drug used for clinical case treatment. In addition to known risk factors for gametocyte carriage, notably young age (<15 years old) and associated with a clinical episode, blood groups B and O increased risk compared to groups A and AB. A hotspot of clinical P. falciparum clinical episodes that overlapped the gametocyte hotspots was also identified. Gametocyte positivity was found to be increased in individuals who had been treated with chloroquine, as opposed to other drug treatment regimens, for a clinical P. falciparum episode up to 30 days previously. It seems likely the hotspots were generated by a vicious circle of ineffective treatment of clinical cases and concomitant gametocyte production in a sub-population characterized by an increased prevalence of all the identified risk factors. While rapid access to treatment with an effective anti-malarial can reduce the duration of gametocyte carriage and onward parasite transmission, localised hotspots represent a challenge to malaria control and eventual eradication.     

Epidemiology and Genetic Characterization of Measles Strains in Senegal, 2004-2013

BackgroundIn Senegal, with the variable routine vaccination coverage, the risk for illness and death from measles still exists as evidenced by the measles epidemic episode in 2009. Since 2002 a laboratory-based surveillance system of measles was established by the Ministry of Health and the Institut Pasteur de Dakar. The present study analysed the data collected over the 10 years inclusive between 2004-2013 in order to define a measles epidemiological profile in Senegal, and we carried out a phylogenetic analysis of measles virus circulating in Senegal over the period 2009-2012.ConclusionImprovements in the measles surveillance in Senegal are required and the introduction of oral fluid and FTA cards as an alternative to transportation of sera should be investigated to improve surveillance. The introduction of a national vaccine database including number of doses of measles-containing vaccine will greatly improve efforts to interrupt and ultimately eliminate measles virus transmission in Senegal.     

The effect of the soil-feeding termite Cubitermes niokoloensis on soil microbial activity in a semi-arid savanna in West Africa

Plant and Soil - Soil-feeding termite mounds are an important, highly specific soil microbial compartment in semi-arid savannas. The aim of this study was to determine the role of these mounds in...     

Expression profile of SIRT2 in human melanoma and implications for sirtuin-based chemotherapy

Melanoma is cancer of melanin-containing melanocyte cells. This neoplasm is one of the most deadly forms of skin cancer, and currently available therapeutic options are insufficient in significantly improve outcomes for many patients. Therefore, novel targets are required to effectively manage this neoplasm. Several sirtuins have previously been found to be upregulated in melanoma, so in this study, the expression profile of SIRT2 was determined. Employing a tissue microarray containing benign nevi, primary melanomas, and lymph node metastases, we have found that the tissue from lymph node metastases appears to have a significant upregulation of SIRT2 relative to primary tumors across the nuclear, cytoplasmic, and whole cell data. Additionally, SIRT2 staining was found to be higher in the nucleus of metastatic melanomas compared to cytoplasmic staining. As SIRT2 is considered to be a predominantly cytoplasmic protein, this is a novel and very interesting finding. This, combined with previous studies that show other sirtuins are increased in melanoma and involved in cellular proliferation and survival, leads to the suggestion that exploring pan-sirtuin inhibitors may be the best target for the next iteration of melanoma chemotherapeutics.