Acidic biphenyl derivatives: Synthesis and biological activity of a new series of potent 5-HT4 receptor antagonists

Serotonin (5-hydroxytryptamine, 5-HT) is an important signaling molecule in the central nervous system (CNS) and in non-neuronal tissues and organs. Serotonin mediates a positive chronotropic and inotropic response through 5-HT₄ receptors in the atrium and ventricle of the heart. Recent investigations have revealed increased expression of the 5-HT_4(b) isoform in cardiomyocytes of chronic arrhythmic and failing hearts, and that the use of 5-HT₄ receptor antagonists may be beneficial for treating these conditions. The 5-HT₄ receptor possesses a transmembrane (TM) binding site important for ligand affinity and recognition, as well as a capacity to accommodate bulky ligands. A new series of peripherally-acting 5-HT₄ receptor antagonists were prepared by combining the acidic biphenyl group from the class of angiotensin II receptor blockers (ARBs) with the SB207266 (piboserod) scaffold. The new compounds were pharmacologically evaluated and carboxylic acid 21 was identified as a potent and promising 5-HT₄ receptor antagonist with moderate affinity for the AT₁ receptor. The permeability of carboxylic acid 21 in a Caco-2 assay was low and the corresponding prodrug esters 23a–f were therefore prepared. The pharmacokinetics of methyl ester 20 and n-butyl ester 23c were evaluated in a rat model, revealing incomplete metabolism to carboxylic acid 21. However, methyl ester 20 is a potent 5-HT₄ receptor antagonist with binding affinities in the low picomolar range. Methyl ester 20 has promising oral bioavailability and pharmacokinetics and may target 5-HT₄ receptors in both CNS and peripheral organs.     

Eumelanin‐based colouration reflects local survival of juvenile feral pigeons in an urban pigeon house

Urbanisation introduces deep changes in habitats, eventually creating new urban ecosystems where ecological functions are driven by human activities. The higher frequency of some phenotypes in urban vs rural/wild areas has led to the assumption that directional selection in urban habitats occurs, which may thereby favour some behavioural and physiological traits in urban animal populations compared to rural ones. However, empirical evidence of directional selection on phenotypic traits in urban areas remains scarce. In this study we tested whether eumelanin‐based colouration could be linked to survival in two urban populations of the feral pigeon Columba livia. A number of studies in different cities pointed out a higher frequency of darker individuals in more urbanised areas compared to rural ones. To investigate whether directional selection through survival on this highly heritable trait could explain such patterns, we conducted mark–recapture studies on two populations of feral pigeons in highly urbanized areas. We predicted that darker coloured individuals would exhibit higher survival and/or philopatry (integrated into ‘local survival’) than paler coloured ones. No difference in local survival was found between adults of different colouration intensities. However, on one site, we found that darker juveniles had a higher local survival probability than light ones. Juvenile local survival on that site was also negatively correlated with the number of chicks born. This suggests the existence of colour‐ and/or density‐dependent selection processes acting on juvenile feral pigeons in urban environments, acting through differential mortality and/or dispersal.     

High Burden of Human Papillomavirus (HPV) Infection among Young Women in KwaZulu-Natal,South Africa

Objectives

HPV infection causes cervical cancer, yet information on prevalence and risk factors for HPV in Africa remain sparse. This study describes the prevalence of HPV genotypes and risk factors associated with HPV among young women ≤ 30 years of age in KwaZulu-Natal (KZN), South Africa.

Methods

Cervicovaginal lavage samples were tested for HPV genotypes in 224 women enrolled in a prospective cohort study. Clinical, behavioural and demographic data were collected. We measured prevalence of HPV genotypes and using logistic regression, examined for factors associated with HPV.

Results

Median age of participants was 21 years [interquartile range (IQR):18–23]. The overall prevalence of HPV was 76.3% (171/224) with multiple and single genotypes prevalent in 56.3% and 20.1% of women respectively. Proportion of women with high-risk genotypes (16, 18, 31, 33, 35, 39, 45, 51, 52, 56 and 58) was 54.5%. Women not living with their partner [adjusted odds ratio (aOR)] = 3.42 95% CI1.22–9.60; p = 0.019), was significantly associated with HPV infection and high-risk HPV genotype infection.

Conclusion

The high burden of HPV and associated risk behaviours highlight the need to intensify behavioural interventions to prevent HPV acquisition in young women. The large scale delivery of HPV vaccine should be prioritised to prevent HPV acquisition and reduce HPV-related morbidity.     

Deciphering structure-activity relationships in a series of Tat/TAR inhibitors

A series of pentameric “Polyamide Amino Acids” (PAAs) compounds derived from the same trimeric precursor have been synthesized and investigated as HIV TAR RNA ligands, in the absence and in the presence of a Tat fragment. All PAAs bind TAR with similar sub-micromolar affinities but their ability to compete efficiently with the Tat fragment strongly differs, IC₅₀ ranging from 35 nM to >2 μM. While NMR and CD studies reveal that all PAA interact with TAR at the same site and induce globally the same RNA conformational change upon binding, a comparative thermodynamic study of PAA/TAR equilibria highlights distinct TAR binding modes for Tat competitor and non-competitor PAAs. This led us to suggest two distinct interaction modes that have been further validated by molecular modeling studies. While the binding of Tat competitor PAAs induces a contraction at the TAR bulge region, the binding of non-competitor ones widens it. This could account for the distinct PAA ability to compete with Tat fragment. Our work illustrates how comparative thermodynamic studies of a series of RNA ligands of same chemical family are of value for understanding their binding modes and for rationalizing structure-activity relationships.     

EDTA/gelatin zymography method to identify C1s versus activated MMP‐9 in plasma and immune complexes of patients with systemic lupus erythematosus

Gelatin zymography analysis is a sensitive method and commonly used to characterize and quantify the presence of the gelatinases (MMP‐2 and MMP‐9) in biological samples. In human plasma samples from healthy controls and systemic lupus erythematosus (SLE) patients, we observed a gelatinolytic molecule at 80 kDa, suggestive for activated human MMP‐9. However, by developing and using the EDTA/gelatin zymography method and after purification of the 80 kDa entity, we proved that this molecule was the C1s subunit of the complement system. The zymolytic capacity of C1s was validated and found to be enhanced, in the absence of calcium and in the presence of EDTA. Our findings indicate that for correct identification of gelatinolytic proteins in complex biological samples the use of EDTA/gelatin zymography for enzyme development is advised. In addition, by quantification of EDTA/gelatin zymography analysis and ELISA, we observed that the levels of C1s were higher in plasma and immune complexes of SLE patients than of healthy individuals. Therefore, our data imply that C1s may become a marker for the diagnosis of SLE.     

Mechanisms Preserving Insulin Action during High Dietary Fat Intake

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Identification of human skin bacteria attractive to the Asian Tiger mosquito

Aedes albopictus is a vector of arboviruses and filarial nematodes. Originating from Asia, this mosquito has rapidly expanded its geographical distribution and colonized areas across both temperate and tropical regions. Due to the increase in insecticide resistance, the use of environmentally friendly vector control methods is encouraged worldwide. Using methods based on semiochemicals in baited traps are promising for management of mosquito populations. Interestingly, human skin microbiota was shown to generate volatile compounds that attract the mosquito species Anopheles gambiae and Aedes aegypti. Here, we investigated the composition of skin bacteria from different volunteers and the attractive potential of individual isolates to nulliparous Ae. albopictus females. We showed that three out of 16 tested isolates were more attractive and two were more repulsive. We identified dodecenol as being preferentially produced by attractive isolates and 2-methyl-1-butanol (and to a lesser extent 3-methyl-1-butanol) as being overproduced by these isolates compared with the other ones. Those bacterial volatile organic compounds represent promising candidates but further studies are needed to evaluate their potential application for baited traps improvement.