3 research outputs found
Host age and Plasmodium falciparum multiclonality are associated with gametocyte prevalence: a 1-year prospective cohort study
Abstract Background Since Plasmodium falciparum transmission relies exclusively on sexual-stage parasites, several malaria control strategies aim to disrupt this step of the life cycle. Thus, a better understanding of which individuals constitute the primary gametocyte reservoir within an endemic population, and the temporal dynamics of gametocyte carriage, especially in seasonal transmission settings, will not only support the effective implementation of current transmission control programmes, but also inform the design of more targeted strategies. Methods A 1-year prospective cohort study was initiated in June 2013 with the goal of assessing the longitudinal dynamics of P. falciparum gametocyte carriage in a village in Mali with intense seasonal malaria transmission. A cohort of 500 individuals aged 1–65 years was recruited for this study. Gametocyte prevalence was measured monthly using Pfs25-specific RT-PCR, and analysed for the effects of host age and gender, seasonality, and multiclonality of P. falciparum infection over 1 year. Results Most P. falciparum infections (51–89%) in this population were accompanied by gametocytaemia throughout the 1-year period. Gametocyte prevalence among P. falciparum-positive individuals (proportion of gametocyte positive infections) was associated with age (p = 0.003) but not with seasonality (wet vs. dry) or gender. The proportion of gametocyte positive infections were similarly high in children aged 1–17 years (74–82% on median among 5 age groups), while older individuals had relatively lower proportion, and those aged > 35 years (median of 43%) had significantly lower than those aged 1–17 years (p < 0.05). Plasmodium falciparum-positive individuals with gametocytaemia were found to have significantly higher P. falciparum multiclonality than those without gametocytaemia (p < 0.033 in two different analyses). Conclusions Taken together, these results suggest that a substantial proportion of Pf-positive individuals carries gametocytes throughout the year, and that age is a significant determinant of gametocyte prevalence among these P. falciparum-positive individuals. Furthermore, the presence of multiple P. falciparum genotypes in an infection, a common feature of P. falciparum infections in high transmission areas, is associated with gametocyte prevalence
Functional Characterization of a Novel Series of Biased Signaling Dopamine D3 Receptor Agonists
Dopamine
receptors play an integral role in controlling brain physiology.
Importantly, subtype selective agonists and antagonists of dopamine
receptors with biased signaling properties have been successful in
treating psychiatric disorders with a low incidence of side effects.
To this end, we recently designed and developed SK609, a dopamine
D3 receptor (D3R) selective agonist that has atypical signaling properties.
SK609 has shown efficacy in reversing akinesia and reducing L-dopa-induced
dyskinesia in a hemiparkinsonian rats. In the current study, we demonstrate
that SK609 has high selectivity for D3R with no binding affinity on
D2R high- or low-affinity state when tested at a concentration of
10 ÎĽM. In addition, SK609 and its analogues do not induce desensitization
of D3R as determined by repeated agonist treatment response in phosphorylation
of ERK1/2 functional assay. Most significantly, SK609 and its analogues
preferentially signal through the G-protein-dependent pathway and
do not recruit β-arrestin-2, suggesting a functional bias toward
the G-protein-dependent pathway. Structure–activity relationship
(SAR) studies using analogues of SK609 demonstrate that the molecules
bind at the orthosteric site by maintaining the conserved salt bridge
interactions with aspartate 110 on transmembrane 3 and aryl interactions
with histidine 349 on transmembrane 6, in addition to several hydrophobic
interactions with residues from transmembranes 5 and 6. The compounds
follow a strict SAR with reference to the three pharmacophore elements:
substituted phenyl ring, length of the linker connecting phenyl ring
and amine group, and orientation and hydrophobic branching groups
at the amine among SK609 analogues for efficacy and functional selectivity.
These features of SK609 and the analogues suggest that biased signaling
is an inherent property of this series of molecules