Molecular dynamics and combined docking studies for the identification of Zaire ebola virus inhibitors

Ebola virus (EBOV) is a lethal human pathogen with a risk of global spread of its zoonotic infections, and Ebolavirus Zaire specifically has the highest fatality rate amongst other species. There is a need for continuous effort towards having therapies, as a single licensed treatment to neutralize the EBOV is yet to come into reality. This present study virtually screened the MCULE database containing almost 36 million compounds against the structure of a Zaire Ebola viral protein (VP) 35 and a consensus scoring of both MCULE and CLCDDW docking programs remarked five compounds as potential hits. These compounds, with binding energies ranging from –7.9 to –8.9?kcal/mol, were assessed for predictions of their physicochemical and bioactivity properties, as well as absorption, distribution, metabolism, excretion, and toxicity (ADMET) criteria. The results of the 50?ns molecular dynamics simulations showed the presence of dynamic stability between ligand and protein complexes, and the structures remained significantly unchanged at the ligand-binding site throughout the simulation period. Both docking analysis and molecular dynamics simulation studies suggested strong binding affinity towards the receptor cavity and these selected compounds as potential inhibitors against the Zaire Ebola VP 35. With respect to inhibition constant values, bioavailability radar and other physicochemical properties, compound A (MCULE-1018045960-0-1) appeared to be the most promising hit compound. However, the ligand efficiency and ligand efficiency scale need improvement during optimization, and also validation via in vitro and in vivo studies are necessary to finally make a lead compound in treating Ebola virus diseases.

Communicated by Ramaswamy H. Sarma     

Influence of exogenous corticosterone on testicular function and mating behavior of Nigerian indigenous cocks

In bridging the knowledge gap on stress physiology of Nigerian indigenous chickens, this study investigated the effect of exogenous corticosterone (eCORT) as stress inducing agent on the testicular function and mating behavior of Nigerian indigenous cocks. Twenty-four (24) cocks and one hundred and forty four (144) hens (mating ratio of 1 cock: 6 hens) were grouped into four and assigned to each of the four eCORT treatments (0, 2, 4 and 6 mgeCORT/KgBW) daily for 14 days. Semen samples were collected on days 0, 7 and 14 and analyzed for semen volume (SV), progressive sperm motility (PSM), membrane integrity (MI) and sperm abnormality (SA). Mating behaviors were monitored on days 3, 5 and 8. Blood samples, for hormonal (Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH) Testosterone (TEST) and stress analysis (heterophil/lymphocyte ratio, H/L) were collected from brachial vein on days 7 and 14. On day 15, cocks were euthanized and testes harvested for histomorphometry. Data were analyzed using multivariate analysis, one–way ANOVA and Kruskal-Wallis tests all in SPSS 23. Administration of 4 mgeCORT/KgBW declined (P<0.05) PSM while 4 mgeCORT/KgBW and 6 mgeCORT/KgBW cocks had reduced (P<0.05) SV and MI with increased SA. Compared to baseline values, progressive sperm motility of cocks administered 6 mgeCORT for 7 and 14 days decreased (P<0.05) by 57.5% and 52.4%, respectively. Exogenous CORT had no significant (P>0.05) influence on the mating behaviors, H/L ratio, FSH and TEST. However, 2 mgeCORT/KgBW enhanced LH levels. Administration of eCORT did not affect the testicular epithelial height and seminiferous tubular diameter. In conclusion, optimal stress induced by eCORT impaired semen quality but with less impact on reproductive hormones, H/L and mating behaviors of intensively raised Nigerian indigenous cocks.     

Brief communication: Emergence chronology of permanent teeth in Nigerian children

This study measured the mean age, duration, and sequence of the emergence of permanent dentition in Nigerian children and compared the findings with other population groups. The cross‐sectional study involved 1,078 Nigerian children, aged 4–16 years old, from selected primary and secondary schools in the Ife Central local government area in Ile‐Ife, Osun State. In general, compared to boys, girls had an earlier mean age of emergence of all the permanent teeth. Children from high socioeconomic class had an earlier mean age of emergence for the maxillary incisors (6.43 and 7.58 years) and mandibular incisors (5.28 and 6.44 years) compared to children from middle and low socioeconomic classes, although socioeconomic effects were more mixed for premolars and molars. Compared to their counterparts in the USA, Australia, Belgium, and Iran, Nigerian children showed an earlier mean age of emergence of all the permanent teeth studied except for Pakistani boys, who had an earlier mean age of emergence of the maxillary premolars and second molar. Poorer economic status has been associated with delayed dental development; however, when compared to other populations, the Nigerian children in this study have earlier mean emergence ages than children from wealthier countries such as the USA and Australia. Am J Phys Anthropol 153:506–511, 2014. © 2013 Wiley Periodicals, Inc.     

New baseline environmental assessment of mosquito ecology in northern Haiti during increased urbanization

The catastrophic 2010 earthquake in Port‐au‐Prince, Haiti, led to the large‐scale displacement of over 2.3 million people, resulting in rapid and unplanned urbanization in northern Haiti. This study evaluated the impact of this unplanned urbanization on mosquito ecology and vector‐borne diseases by assessing land use and change patterns. Land‐use classification and change detection were carried out on remotely sensed images of the area for 2010 and 2013. Change detection identified areas that went from agricultural, forest, or bare‐land pre‐earthquake to newly developed and urbanized areas post‐earthquake. Areas to be sampled for mosquito larvae were subsequently identified. Mosquito collections comprised five genera and ten species, with the most abundant species being Culex quinquefasciatus 35% (304/876), Aedes albopictus 27% (238/876), and Aedes aegypti 20% (174/876). All three species were more prevalent in urbanized and newly urbanized areas. Anopheles albimanus, the predominate malaria vector, accounted for less than 1% (8/876) of the collection. A set of spectral indices derived from the recently launched Landsat 8 satellite was used as covariates in a species distribution model. The indices were used to produce probability surfaces maps depicting the likelihood of presence of the three most abundant species within 30 m pixels. Our findings suggest that the rapid urbanization following the 2010 earthquake has increased the amount of area with suitable habitats for urban mosquitoes, likely influencing mosquito ecology and posing a major risk of introducing and establishing emerging vector‐borne diseases.     

Molecular analysis of the luminal- and mucosal-associated intestinal microbiota in diarrhea-predominant irritable bowel syndrome

Alterations in the intestinal microbiota have been suggested as an etiological factor in the pathogenesis of irritable bowel syndrome (IBS). This study used a molecular fingerprinting technique to compare the composition and biodiversity of the microbiota within fecal and mucosal niches between patients with diarrhea-predominant IBS (D-IBS) and healthy controls. Terminal-restriction fragment (T-RF) length polymorphism (T-RFLP) fingerprinting of the bacterial 16S rRNA gene was used to perform microbial community composition analyses on fecal and mucosal samples from patients with D-IBS (n = 16) and healthy controls (n = 21). Molecular fingerprinting of the microbiota from fecal and colonic mucosal samples revealed differences in the contribution of T-RFs to the microbiota between D-IBS patients and healthy controls. Further analysis revealed a significantly lower (1.2-fold) biodiversity of microbes within fecal samples from D-IBS patients than healthy controls (P = 0.008). No difference in biodiversity in mucosal samples was detected between D-IBS patients and healthy controls. Multivariate analysis of T-RFLP profiles demonstrated distinct microbial communities between luminal and mucosal niches in all samples. Our findings of compositional differences in the luminal- and mucosal-associated microbiota between D-IBS patients and healthy controls and diminished microbial biodiversity in D-IBS fecal samples further support the hypothesis that alterations in the intestinal microbiota may have an etiological role in the pathogenesis of D-IBS and suggest that luminal and mucosal niches need to be investigated.     

Deciphering Combinations of PI3K/AKT/mTOR Pathway Drugs Augmenting Anti-Angiogenic Efficacy In Vivo

Ocular neovascularization is a common pathology associated with human eye diseases e.g. age-related macular degeneration and proliferative diabetic retinopathy. Blindness represents one of the most feared disabilities and remains a major burden to health-care systems. Current approaches to treat ocular neovascularisation include laser photocoagulation, photodynamic therapy and anti-VEGF therapies: Ranibizumab (Lucentis) and Aflibercept (Eylea). However, high clinical costs, frequent intraocular injections, and increased risk of infections are challenges related with these standards of care. Thus, there is a clinical need to develop more effective drugs that overcome these challenges. Here, we focus on an alternative approach by quantifying the in vivo anti-angiogenic efficacy of combinations of phosphatidylinositol-3-kinase (PI3K) pathway inhibitors. The PI3K/AKT/mTOR pathway is a complex signalling pathway involved in crucial cellular functions such as cell proliferation, migration and angiogenesis. RT-PCR confirms the expression of PI3K target genes (pik3ca, pik3r1, mtor and akt1) in zebrafish trunks from 6 hours post fertilisation (hpf) and in eyes from 2 days post fertilisation (dpf). Using both the zebrafish intersegmental vessel and hyaloid vessel assays to measure the in vivo anti-angiogenic efficacy of PI3K/Akt/mTOR pathway inhibitors, we identified 5 µM combinations of i) NVP-BEZ235 (dual PI3K-mTOR inhibitor) + PI-103 (dual PI3K-mTOR inhibitor); or ii) LY-294002 (pan-PI3K inhibitor) + NVP-BEZ235; or iii) NVP-BEZ235 + rapamycin (mTOR inhibitor); or iv) LY-294002 + rapamycin as the most anti-angiogenic. Treatment of developing larvae from 2–5 dpf with 5 µM NVP-BEZ235 plus PI-103 resulted in an essentially intact ocular morphology and visual behaviour, whereas other combinations severely disrupted the developing retinal morphology and visual function. In human ARPE19 retinal pigment epithelium cells, however, no significant difference in cell number was observed following treatment with the inhibitor combinations. Collectively, these results highlight the potential of combinations of PI3K/AKT/mTOR pathway inhibitors to safely and effectively treat ocular neovascularization.     

Organic farming promotes bee abundance in vineyards in Italy but not in South Africa

Although grapevine is a crop that produces fruit without insect pollination, vineyards may provide resources for bees and other pollinators. Flower resources such as pollen and nectar are provided by the vine plants as well as other flowering plants including cover crops grown between the vine rows. Little is known about how management and landscape context affects bee communities in pollinator-independent crop systems such as grapevine. This study investigates the effect of organic versus conventional management on bee species richness and abundance in vineyards in Italy and South Africa both having a Mediterranean climate. In each country, six pairs of organic and conventional vineyards were studied in simplified and complex agricultural landscapes. A total of 433 bee individuals from 25 species and 1049 individuals from 15 species were recovered in pan traps from Italy and South Africa respectively. Bee abundance showed region specific response to the effects of vineyard management. Flowering plants and proportion of uncultivated land mediated differences in bee abundance. Higher flowering plant species richness and flower density were found in organic vineyards compared to conventional vineyards in South Africa but these flowering plant indices were not significantly different between the two vineyard management types in Italy. This emphasizes the necessity for local and region specific studies for informing conservation, as even in the same crop system with a similar climate, the effects of farm management differed between countries.