Deltamethrin Resistance Mechanisms in Aedes aegypti Populations from Three French Overseas Territories Worldwide

BACKGROUND:Aedes aegypti is a cosmopolite mosquito, vector of arboviruses. The worldwide studies of its insecticide resistance have demonstrated a strong loss of susceptibility to pyrethroids, the major class of insecticide used for vector control. French overseas territories such as French Guiana (South America), Guadeloupe islands (Lesser Antilles) as well as New Caledonia (Pacific Ocean), have encountered such resistance. METHODOLOGY/PRINCIPAL FINDINGS:We initiated a research program on the pyrethroid resistance in French Guiana, Guadeloupe and New Caledonia. Aedes aegypti populations were tested for their deltamethrin resistance level then screened by an improved microarray developed to specifically study metabolic resistance mechanisms. Cytochrome P450 genes were implicated in conferring resistance. CYP6BB2, CYP6M11, CYP6N12, CYP9J9, CYP9J10 and CCE3 genes were upregulated in the resistant populations and were common to other populations at a regional scale. The implication of these genes in resistance phenomenon is therefore strongly suggested. Other genes from detoxification pathways were also differentially regulated. Screening for target site mutations on the voltage-gated sodium channel gene demonstrated the presence of I1016 and C1534. CONCLUSION /SIGNIFICANCE:This study highlighted the presence of a common set of differentially up-regulated detoxifying genes, mainly cytochrome P450 genes in all three populations. GUA and GUY populations shared a higher number of those genes compared to CAL. Two kdr mutations well known to be associated to pyrethroid resistance were also detected in those two populations but not in CAL. Different selective pressures and genetic backgrounds can explain such differences. These results are also compared with those obtained from other parts of the world and are discussed in the context of integrative research on vector competence

Longitudinal Association between Late-Life Depression (LLD) and Frailty:Findings from a Prospective Cohort Study (MiMiCS-FRAIL)

OBJECTIVES: The aim of the present study was to investigate whether late-life depression (LLD) is associated with incident frailty over time. DESIGN: Prospective cohort study, one-year follow-up. SETTING: Geriatric outpatient clinic, Southwestern of Brazil. PARTICIPANTS: 181 follow-up participants aged 60 years or over. MEASUREMENTS: Depressive disorders were classified as Major Depressive disorder (MDD) or Subthreshold Depression (STD) according to DSM-5 criteria. Depressive symptoms were assessed with validated versions of 15-item Geriatric Depression Scale (GDS-15) and 9-item Patient Health Questionnaire (PHQ-9). We performed binary logistic regressions to estimate the odds ratio (OR) for frailty in LLD adjusting for multiple confounders. Participants who were frail at baseline were excluded from the analyses according to measures of frailty (FRAIL questionnaire and 36-item Frailty Index, FI-36). We also estimated the risk ratio or relative risk (RR) and the risk difference (RD) for incident frailty. RESULTS: We observed a 2 to 4-fold increased risk for incident frailty among participants with LLD. The presence of a depressive disorder was significantly associated with the onset of frailty (adjusted OR for FRAIL and FI-36: 3.07 [95% CI = 1.03 - 9.17] and 3.76 [95% CI = 1.09 - 12.97], respectively. Notably, the risk for frailty due to LLD was significantly higher with the FI-36 compared to the FRAIL (RR: 3.03 versus 2.23). RD was of 17.3% and 12.7% with the FRAIL and the FI-36, respectively. CONCLUSION: Our data support the association between LLD and incident frailty over one year among geriatric outpatients, reinforcing longitudinal evidence from population-based studies

Incorporation of DPP6a and DPP6K Variants in Ternary Kv4 Channel Complex Reconstitutes Properties of A-type K Current in Rat Cerebellar Granule Cells

Dipeptidyl peptidase-like protein 6 (DPP6) proteins co-assemble with Kv4 channel α-subunits and Kv channel-interacting proteins (KChIPs) to form channel protein complexes underlying neuronal somatodendritic A-type potassium current (ISA). DPP6 proteins are expressed as N-terminal variants (DPP6a, DPP6K, DPP6S, DPP6L) that result from alternative mRNA initiation and exhibit overlapping expression patterns. Here, we study the role DPP6 variants play in shaping the functional properties of ISA found in cerebellar granule (CG) cells using quantitative RT-PCR and voltage-clamp recordings of whole-cell currents from reconstituted channel complexes and native ISA channels. Differential expression of DPP6 variants was detected in rat CG cells, with DPP6K (41±3%)>DPP6a (33±3%)>>DPP6S (18±2%)>DPP6L (8±3%). To better understand how DPP6 variants shape native neuronal ISA, we focused on studying interactions between the two dominant variants, DPP6K and DPP6a. Although previous studies did not identify unique functional effects of DPP6K, we find that the unique N-terminus of DPP6K modulates the effects of KChIP proteins, slowing recovery and producing a negative shift in the steady-state inactivation curve. By contrast, DPP6a uses its distinct N-terminus to directly confer rapid N-type inactivation independently of KChIP3a. When DPP6a and DPP6K are co-expressed in ratios similar to those found in CG cells, their distinct effects compete in modulating channel function. The more rapid inactivation from DPP6a dominates during strong depolarization; however, DPP6K produces a negative shift in the steady-state inactivation curve and introduces a slow phase of recovery from inactivation. A direct comparison to the native CG cell ISA shows that these mixed effects are present in the native channels. Our results support the hypothesis that the precise expression and co-assembly of different auxiliary subunit variants are important factors in shaping the ISA functional properties in specific neuronal populations