Statins (HMG-coenzyme A reductase inhibitors)-biomimetic membrane binding mechanism investigated by molecular chromatography

Many studies have demonstrated that the statin beneficial effects on cardiovascular diseases like coronary are linked to their hypocholesterolemic properties. These lipid-lowering drugs are the first-line pharmacologic therapy for hypercholesterolemia. In this paper, the interaction of a series of statin molecules STCOOH (pravastatin (prava), mevastatin (meva), simvastatin (simva) and fluvastatin (fluva)) with a phosphatidylcholine monolayer immobilized on to porous silica particles has been studied using a biochromatographic approach (molecular chromatography). The immobilized artificial membrane (IAM) provided a biophysical model system to study the binding of the statin molecules to a lipid membrane. For all the test statin molecules, linear retention plots were observed at all temperatures. An analysis of the thermodynamics (i.e., enthalpy (DeltaH(0)), entropy (DeltaS(0)*)) of the interaction of the statin molecules with the immobilized monolayer was also carried out. The DeltaH(0) and DeltaS(0)* values were negative due to van der Waals interactions and hydrogen bonding between the statin molecules with the polar head groups of the phospholipid monolayer (polar retention effect). The statin elution order was: Prava相似文献   

Safety and immunogenicity of an AMA-1 malaria vaccine in Malian adults: results of a phase 1 randomized controlled trial

Background

The objective was to evaluate the safety, reactogenicity and immunogenicity of the AMA-1-based blood-stage malaria vaccine FMP2.1/AS02A in adults exposed to seasonal malaria.

Methodology/Principal Findings

A phase 1 double blind randomized controlled dose escalation trial was conducted in Bandiagara, Mali, West Africa, a rural town with intense seasonal transmission of Plasmodium falciparum malaria. The malaria vaccine FMP2.1/AS02A is a recombinant protein (FMP2.1) based on apical membrane antigen-1 (AMA-1) from the 3D7 clone of P. falciparum, adjuvanted with AS02A. The comparator vaccine was a cell-culture rabies virus vaccine (RabAvert). Sixty healthy, malaria-experienced adults aged 18–55 y were recruited into 2 cohorts and randomized to receive either a half dose or full dose of the malaria vaccine (FMP2.1 25 µg/AS02A 0.25 mL or FMP2.1 50 µg/AS02A 0.5 mL) or rabies vaccine given in 3 doses at 0, 1 and 2 mo, and were followed for 1 y. Solicited symptoms were assessed for 7 d and unsolicited symptoms for 30 d after each vaccination. Serious adverse events were assessed throughout the study. Titers of anti-AMA-1 antibodies were measured by ELISA and P. falciparum growth inhibition assays were performed on sera collected at pre- and post-vaccination time points. Transient local pain and swelling were common and more frequent in both malaria vaccine dosage groups than in the comparator group. Anti-AMA-1 antibodies increased significantly in both malaria vaccine groups, peaking at nearly 5-fold and more than 6-fold higher than baseline in the half-dose and full-dose groups, respectively.

Conclusion/Significance

The FMP2.1/AS02A vaccine had a good safety profile, was well-tolerated, and was highly immunogenic in malaria-exposed adults. This malaria vaccine is being evaluated in Phase 1 and 2 trials in children at this site.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00308061","term_id":"NCT00308061"}}NCT00308061     

Hygienic quality of traditional processing and stability of tomato (Lycopersicon esculentum) puree in Togo

Microbiological and physicochemical qualities of a tomato (Lycopersicon esculentum) puree production line (ripe tomato, washing, cutting, pounding, bleaching, straining, bottling and pasteurization) and its preservation in Togo, West Africa, were studied using the HACCP method. Samples generated during the steps described previously were analyzed by determining sensory, chemical and microbiological characteristics. Samples were analyzed using MPN for coliform populations and plate count methodology for other bacteria. The microorganisms involved in spoilage of the opened products were moulds of genera Penicillium, Aspergillus, Fusarium, Geotrichum, Mucor and gram-positive Bacillus bacteria. The preserved tomato puree exhibited a pH value of 4.3, 90% water content, 0.98 water activity (aw) and an average ascorbic acid level of 27.3mg/100g. Results showed that the critical control point (CCP) of this tomato puree processing line is the pasteurization stage. The analysis of selected microbiological and physicochemical parameters during the preservation of bottled tomato puree indicated that this product was stable over 22 months at 29 degrees C. But the stability of the opened product stored at 29 degrees C did not exceed two months.     

Reducing the Time Requirement of k-Means Algorithm

Traditional k-means and most k-means variants are still computationally expensive for large datasets, such as microarray data, which have large datasets with large dimension size d. In k-means clustering, we are given a set of n data points in d-dimensional space R^d and an integer k. The problem is to determine a set of k points in R^d, called centers, so as to minimize the mean squared distance from each data point to its nearest center. In this work, we develop a novel k-means algorithm, which is simple but more efficient than the traditional k-means and the recent enhanced k-means. Our new algorithm is based on the recently established relationship between principal component analysis and the k-means clustering. We provided the correctness proof for this algorithm. Results obtained from testing the algorithm on three biological data and six non-biological data (three of these data are real, while the other three are simulated) also indicate that our algorithm is empirically faster than other known k-means algorithms. We assessed the quality of our algorithm clusters against the clusters of a known structure using the Hubert-Arabie Adjusted Rand index (ARI_HA). We found that when k is close to d, the quality is good (ARI_HA>0.8) and when k is not close to d, the quality of our new k-means algorithm is excellent (ARI_HA>0.9). In this paper, emphases are on the reduction of the time requirement of the k-means algorithm and its application to microarray data due to the desire to create a tool for clustering and malaria research. However, the new clustering algorithm can be used for other clustering needs as long as an appropriate measure of distance between the centroids and the members is used. This has been demonstrated in this work on six non-biological data.     

Prevalence of trypanosomes,salivary gland hypertrophy virus and <Emphasis Type="Italic">Wolbachia</Emphasis> in wild populations of tsetse flies from West Africa

Background

Tsetse flies are vectors of African trypanosomes, protozoan parasites that cause sleeping sickness (or human African trypanosomosis) in humans and nagana (or animal African trypanosomosis) in livestock. In addition to trypanosomes, four symbiotic bacteria Wigglesworthia glossinidia, Sodalis glossinidius, Wolbachia, Spiroplasma and one pathogen, the salivary gland hypertrophy virus (SGHV), have been reported in different tsetse species. We evaluated the prevalence and coinfection dynamics between Wolbachia, trypanosomes, and SGHV in four tsetse species (Glossina palpalis gambiensis, G. tachinoides, G. morsitans submorsitans, and G. medicorum) that were collected between 2008 and 2015 from 46 geographical locations in West Africa, i.e. Burkina Faso, Mali, Ghana, Guinea, and Senegal.

Results

The results indicated an overall low prevalence of SGHV and Wolbachia and a high prevalence of trypanosomes in the sampled wild tsetse populations. The prevalence of all three infections varied among tsetse species and sample origin. The highest trypanosome prevalence was found in Glossina tachinoides (61.1%) from Ghana and in Glossina palpalis gambiensis (43.7%) from Senegal. The trypanosome prevalence in the four species from Burkina Faso was lower, i.e. 39.6% in Glossina medicorum, 18.08%; in Glossina morsitans submorsitans, 16.8%; in Glossina tachinoides and 10.5% in Glossina palpalis gambiensis. The trypanosome prevalence in Glossina palpalis gambiensis was lowest in Mali (6.9%) and Guinea (2.2%). The prevalence of SGHV and Wolbachia was very low irrespective of location or tsetse species with an average of 1.7% for SGHV and 1.0% for Wolbachia. In some cases, mixed infections with different trypanosome species were detected. The highest prevalence of coinfection was Trypanosoma vivax and other Trypanosoma species (9.5%) followed by coinfection of T. congolense with other trypanosomes (7.5%). The prevalence of coinfection of T. vivax and T. congolense was (1.0%) and no mixed infection of trypanosomes, SGHV and Wolbachia was detected.

Conclusion

The results indicated a high rate of trypanosome infection in tsetse wild populations in West African countries but lower infection rate of both Wolbachia and SGHV. Double or triple mixed trypanosome infections were found. In addition, mixed trypanosome and SGHV infections existed however no mixed infections of trypanosome and/or SGHV with Wolbachia were found.

     

Chromosomal inversions and ecotypic differentiation in Anopheles gambiae: the perspective from whole‐genome sequencing

The molecular mechanisms and genetic architecture that facilitate adaptive radiation of lineages remain elusive. Polymorphic chromosomal inversions, due to their recombination‐reducing effect, are proposed instruments of ecotypic differentiation. Here, we study an ecologically diversifying lineage of Anopheles gambiae, known as the Bamako chromosomal form based on its unique complement of three chromosomal inversions, to explore the impact of these inversions on ecotypic differentiation. We used pooled and individual genome sequencing of Bamako, typical (non‐Bamako) An. gambiae and the sister species Anopheles coluzzii to investigate evolutionary relationships and genomewide patterns of nucleotide diversity and differentiation among lineages. Despite extensive shared polymorphism and limited differentiation from the other taxa, Bamako clusters apart from the other taxa, and forms a maximally supported clade in neighbour‐joining trees based on whole‐genome data (including inversions) or solely on collinear regions. Nevertheless, F_ST outlier analysis reveals that the majority of differentiated regions between Bamako and typical An. gambiae are located inside chromosomal inversions, consistent with their role in the ecological isolation of Bamako. Exceptionally differentiated genomic regions were enriched for genes implicated in nervous system development and signalling. Candidate genes associated with a selective sweep unique to Bamako contain substitutions not observed in sympatric samples of the other taxa, and several insecticide resistance gene alleles shared between Bamako and other taxa segregate at sharply different frequencies in these samples. Bamako represents a useful window into the initial stages of ecological and genomic differentiation from sympatric populations in this important group of malaria vectors.     

Comparison of macrofauna communities in sediments of the beds of vertical flow constructed wetlands planted with Panicum maximum (Jacq.) treating domestic wastewater

To improve our understanding of the ecological functioning of constructed wetlands, the macrofauna structure in the sediments of a constructed wetland planted with Panicum maximum treating domestic wastewater was studied. Two beds were planted with young P. maximum and two unplanted beds were used as controls. After 150 days of wastewater treatment on the beds, macrofauna was collected by taking five cores of sediment samples at the corners and the centre of each bed following three layers in the vertical profile. Globally, the planted beds removed COD, NH₄⁺, and PO₄^3? more (p < 0.05) than the control. Eleven taxa belonging to 6 classes and 11 orders were recorded. Macrofauna was significantly more diversified (Mann–Whitney test: p < 0.05) in terms of Shannon index of diversity in the planted beds (0.25–0.44 bits/ind.) than in the control (0.08–0.23 bits/ind.). But macrofauna settlement presents a relative homogeneity between the beds (index Jaccard = 0.63). Its abundance was three times higher in the planted bed than in the control. From the surface to the bottom of the beds, macrofauna diversity and abundance decreased and were heavily dominated by Annelida. The significant relationships were only observed between Insecta and Myriapoda in the control.     

Plasmodium falciparum signal peptide peptidase is a promising drug target against blood stage malaria

The resistance of malaria parasites to current anti-malarial drugs is an issue of major concern globally. Recently we identified a Plasmodium falciparum cell membrane aspartyl protease, which binds to erythrocyte band 3, and is involved in merozoite invasion. Here we report the complete primary structure of P. falciparum signal peptide peptidase (PfSPP), and demonstrate that it is essential for parasite invasion and growth in human erythrocytes. Gene silencing suggests that PfSPP may be essential for parasite survival in human erythrocytes. Remarkably, mammalian signal peptide peptidase inhibitors (Z-LL)₂-ketone and L-685,458 effectively inhibited malaria parasite invasion as well as growth in human erythrocytes. In contrast, DAPT, an inhibitor of a related γ-secretase/presenilin-1, was ineffective. Thus, SPP inhibitors specific for PfSPP may function as potent anti-malarial drugs against the blood stage malaria.     

Development of Real-Time PCR Methods for the Detection of Bacterial Meningitis Pathogens without DNA Extraction

Neisseria meningitidis (Nm), Haemophilus influenzae (Hi), and Streptococcus pneumoniae (Sp) are the lead causes of bacterial meningitis. Detection of these pathogens from clinical specimens using traditional real-time PCR (rt-PCR) requires DNA extraction to remove the PCR inhibitors prior to testing, which is time consuming and labor intensive. In this study, five species-specific (Nm-sodC and -ctrA, Hi-hpd#1 and -hpd#3 and Sp-lytA) and six serogroup-specific rt-PCR tests (A, B, C, W, X, Y) targeting Nm capsular genes were evaluated in the two direct rt-PCR methods using PerfeCTa and 5x Omni that do not require DNA extraction. The sensitivity and specify of the two direct rt-PCR methods were compared to TaqMan traditional rt-PCR, the current standard rt-PCR method for the detection of meningitis pathogens. The LLD for all 11 rt-PCR tests ranged from 6,227 to 272,229 CFU/ml for TaqMan, 1,824–135,982 for 5x Omni, and 168–6,836 CFU/ml for PerfeCTa. The diagnostic sensitivity using TaqMan ranged from 89.2%-99.6%, except for NmB-csb, which was 69.7%. For 5x Omni, the sensitivity varied from 67.1% to 99.8%, with three tests below 90%. The sensitivity of these tests using PerfeCTa varied from 89.4% to 99.8%. The specificity ranges of the 11 tests were 98.0–99.9%, 97.5–99.9%, and 92.9–99.9% for TaqMan, 5x Omni, and PerfeCTa, respectively. PerfeCTa direct rt-PCR demonstrated similar or better sensitivity compared to 5x Omni direct rt-PCR or TaqMan traditional rt-PCR. Since the direct rt-PCR method does not require DNA extraction, it reduces the time and cost for processing CSF specimens, increases testing throughput, decreases the risk of cross-contamination, and conserves precious CSF. The direct rt-PCR method will be beneficial to laboratories with high testing volume.