Novel AChE Inhibitors for Sustainable Insecticide Resistance Management

Resistance to insecticides has become a critical issue in pest management and it is particularly chronic in the control of human disease vectors. The gravity of this situation is being exacerbated since there has not been a new insecticide class produced for over twenty years. Reasoned strategies have been developed to limit resistance spread but have proven difficult to implement in the field. Here we propose a new conceptual strategy based on inhibitors that preferentially target mosquitoes already resistant to a currently used insecticide. Application of such inhibitors in rotation with the insecticide against which resistance has been selected initially is expected to restore vector control efficacy and reduce the odds of neo-resistance. We validated this strategy by screening for inhibitors of the G119S mutated acetylcholinesterase-1 (AChE1), which mediates insensitivity to the widely used organophosphates (OP) and carbamates (CX) insecticides. PyrimidineTrione Furan-substituted (PTF) compounds came out as best hits, acting biochemically as reversible and competitive inhibitors of mosquito AChE1 and preferentially inhibiting the mutated form, insensitive to OP and CX. PTF application in bioassays preferentially killed OP-resistant Culex pipiens and Anopheles gambiae larvae as a consequence of AChE1 inhibition. Modeling the evolution of frequencies of wild type and OP-insensitive AChE1 alleles in PTF-treated populations using the selectivity parameters estimated from bioassays predicts a rapid rise in the wild type allele frequency. This study identifies the first compound class that preferentially targets OP-resistant mosquitoes, thus restoring OP-susceptibility, which validates a new prospect of sustainable insecticide resistance management.     

Genome-wide programmable transcriptional memory by CRISPR-based epigenome editing

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Association between lesional or non lesional S. aureus strains from patients with impetigo and exfoliative toxin production. No association with SmaI PFGE patterns

Contrasting data are reported in the literature on the percent positivity rates (13.5%-100%) of exfoliative toxin (ET) production by S. aureus strains isolated from impetigo patients in Japan and in France. In the present study, by means of a recently available latex-test, toxin-A (ETA) or toxin-B (ETB) production was found in 67.6% of the 34 S. aureus strains isolated from 19 lesional (63.2%) and 15 non-lesional (nose or pharynx, 73.3%) areas of patients with impetigo (with no significant difference between the lesional and non-lesional isolates). ETA + ETB were produced by 44.1% of the strains, while 32.4% were non-producers. In contrast, the percent positivity rate observed in 40 [20 lesional and 20 non-lesional (nose or pharynx)] strains isolated in patients with atopic dermatitis was 15.0% (p < 0.001 both for the lesional and non-lesional strains versus impetigo, with no significant difference between lesional and non lesional strains). Finally, 26 strains from other types of specimens (abscesses, hemocultures, urine, central venous catheters, bronchoalveolar lavages) showed an 11.5% production rate of ETA or ETB (p < 0.001 versus impetigo strains, no significance versus atopic dermatitis). These data point to a significant association between exfoliative toxin production and S. aureus strains isolated in impetigo, both in lesional areas and in nasal/pharyngeal reservoirs. An attempt to correlate SmaI pulsed-field gel electrophoresis (PFGE) restriction patterns and exfoliative toxin production showed no significant association in either group.     

Interferons and oncogenes in the control of cell growth and differentiation: working hypothesis and experimental facts

This short review summarizes available evidence for (i) growth regulatory properties of exogenous as well as recently described autocrine IFNs, (ii) down-regulation of cellular oncogene expression with emphasis on c-myc and (iii) the possible involvement of the IFN-regulated 2-5A pathway at these levels. Initially described as a part of the IFN-induced antiviral mechanism, this double-stranded RNA-activated pathway leads to the preferential degradation of viral mRNAs in IFN-treated virus-infected cells probably through localized activation at the site of virus replication. Such mechanisms could be involved in the regulation of the stability of rapidly turning over mRNAs as for instance c-myc mRNA in IFN-treated cells. Whatever the elegance of the concept, however, experimental evidence is essentially circumstantial; tools developed in our group to strengthen the demonstration are briefly described.     

Nuclear location of synthetic oligonucleotides microinjected somatic cells: its implication in an antisense strategy.

Synthetic oligonucleotides are widely used to modulate gene expression. However their development as genetic tools and as molecule of therapeutic interest is restricted by the poor knowledge of their mechanism of action and of their uptake by cells. We recently found that microinjected oligonucleotides accumulates in the nucleus of the cells. These observations are described and their implications are discussed.     

The role of miRNA-221 and miRNA-126 in patients with benign metastasizing leiomyoma of the lung: an overview with new interesting scenarios

Molecular Biology Reports - Benign metastasizing leiomyoma (BML) is a rare disease characterized by extrauterine benign leiomyomatosis in patients with a previous or concomitant history of uterine...     

Epicardial adipose tissue extent: relationship with age, body fat distribution, and coronaropathy

Epicardial fat is a relatively neglected component of the heart and could be an important risk factor of cardiac disease. The objective of our study was to assess the relationship between epicardial adipose tissue (EAT) extent, fat distribution, and coronaropathy in a group of adult victims of accidental or suspicious sudden death. In 56 cadavers, we performed 34 measurements of EAT from five computerized photographs of the heart (anterior and posterior faces, and three ventricle transversal slices) and analyzed their relationship with anthropometric markers of adiposity (BMI, waist and leg circumference, thickness of abdominal and thigh subcutaneous adipose tissue (SAT)), with the presence and staging of coronary artery disease (CAD), and with markers of myocardial hypertrophy. Simple linear regressions showed that EAT measurements are highly intercorrelated (r from 0.4 to 0.6, P < 0.001), and correlate with age, waist circumference, and heart weight, and to a lesser extent, with BMI, abdominal SAT thickness, and leg SAT thickness. Multiple regression showed that age, waist circumference, and heart weight significantly and independently correlate with EAT (P < 0.0001). No other anthropometric measurement was found independently correlated with EAT. The EAT/myocardium ratios correlated positively with age and waist circumference. Anterior and posterior areas of EAT were found significantly increased in patients with CAD and correlated positively with CAD staging (P = 0.0034, r = 0.38). Anterior EAT surface was found positively associated with CAD (P = 0.01), independently of age and other adiposity measurements. Prospective studies are needed to assess the risk of occurrence/progression of CAD that relate to EAT excess.