Estimated resistance of the malaria mosquito Anopheles messeae s.l. to the insecticide malathion

Resistance to agricultural pesticides is an important and insufficiently studied concern for pest and disease vector research. We determined the malathion resistance of species in the Anopheles maculipennis mosquito group in a habitat near Novosibirsk, Russia. Most of the 851 individuals we measured were members of the Anopheles messeae s.l. complex (An. messeae and An. daciae species). The LC₅₀ value for malathion was 0.052 mg/L for the mixed specimens, and we failed to find any differences between species. The LC₅₀ value was within the range of values for malathion resistance of Anopheles stephensi and Culex quinquefasciatus. As the main resistance mechanism to organophosphate and carbamate insecticides is a single mononucleotide substitution in the ace‐1 gene, we searched for this mutation in An. messeae s.l. and An. beklemishevi by restriction analysis. This mutation was not found in 347 of the specimens. We sequenced the ace‐1 gene fragment for 24 specimens from four species of the Anopheles maculipennis group, including An. messeae, An. daciae, An. atroparvus, and An. beklemishevi. These specimens harbored a nucleotide substitution in the triplet where a mutation can lead to insecticide resistance, but this substitution would make it difficult for the resistance to develop. Since the studied specimens belong to branches of the Palearctic portion of the Anopheles maculipennis group, we suspect that all other Palearctic species of this group would have difficulties harboring the ace‐1 mutation that would lead to organophosphate and carbamate resistance.     

Effects of grandmothers' smoking in pregnancy on birth weight: intergenerational cohort study

Objective To investigate the influences on birth weight of maternal smoking during pregnancy across generations.Design Intergenerational cohort study.Participants Members of the 1958 birth cohort and their offspring and mothers.Setting England, Scotland, and Wales.Main outcome measure Birth weight.Results Information on grandmothers'' smoking during pregnancy was available for 9028 singleton offspring of 4302 female cohort members. Assuming heritable transmission through the intergenerational association, grandmothers'' smoking was predicted to result in a 34 g reduction (95% confidence interval -41 g to -28 g) in the birth weight of grandchildren. Random effects models showed a negative association between grandmothers'' smoking and birth weight of grandchildren (β regression coefficient -24 g, -50 g to 3 g), but this effect was eliminated after adjustment for maternal smoking (0 g, -26 g to 26 g).No association was evident among the offspring of non-smoking mothers (n = 6105; 14 g, -17 g to 46 g), and after adjustment for maternal birth weight, adult height and body mass index, grandmothers'' smoking was positively associated with the birth weight of grandchildren (45 g, 10 g to 80 g).Conclusion Deficits in mothers'' birth weight attributable to their mother smoking was not evident in the grandchildren.     

Molecular mechanism of T-cell protein tyrosine phosphatase (TCPTP) activation by mitoxantrone

T-cell protein tyrosine phosphatase (TCPTP) is a ubiquitously expressed non-receptor protein tyrosine phosphatase. It is involved in the negative regulation of many cellular signaling pathways. Thus, activation of TCPTP could have important therapeutic applications in diseases such as cancer and inflammation. We have previously shown that the α-cytoplasmic tail of integrin α₁β₁ directly binds and activates TCPTP. In addition, we have identified in a large-scale high-throughput screen six small molecules that activate TCPTP. These small molecule activators include mitoxantrone and spermidine. In this study, we have investigated the molecular mechanism behind agonist-induced TCPTP activation. By combining several molecular modeling and biochemical techniques, we demonstrate that α₁-peptide and mitoxantrone activate TCPTP via direct binding to the catalytic domain, whereas spermidine does not interact with the catalytic domain of TCPTP in vitro. Furthermore, we have identified a hydrophobic groove surrounded by negatively charged residues on the surface of TCPTP as a putative binding site for the α₁-peptide and mitoxantrone. Importantly, these data have allowed us to identify a new molecule that binds to TCPTP, but interestingly cannot activate its phosphatase activity. Accordingly, we describe here mechanism of TCPTP activation by mitoxantrone, the cytoplasmic tail of α₁-integrin, and a mitoxantrone-like molecule at the atomic level. These data provide invaluable insight into the development of novel TCPTP activators, and may facilitate the rational discovery of small-molecule cancer therapeutics.     

Seipin traps triacylglycerols to facilitate their nanoscale clustering in the endoplasmic reticulum membrane

Seipin is a disk-like oligomeric endoplasmic reticulum (ER) protein important for lipid droplet (LD) biogenesis and triacylglycerol (TAG) delivery to growing LDs. Here we show through biomolecular simulations bridged to experiments that seipin can trap TAGs in the ER bilayer via the luminal hydrophobic helices of the protomers delineating the inner opening of the seipin disk. This promotes the nanoscale sequestration of TAGs at a concentration that by itself is insufficient to induce TAG clustering in a lipid membrane. We identify Ser166 in the α3 helix as a favored TAG occupancy site and show that mutating it compromises the ability of seipin complexes to sequester TAG in silico and to promote TAG transfer to LDs in cells. While the S166D-seipin mutant colocalizes poorly with promethin, the association of nascent wild-type seipin complexes with promethin is promoted by TAGs. Together, these results suggest that seipin traps TAGs via its luminal hydrophobic helices, serving as a catalyst for seeding the TAG cluster from dissolved monomers inside the seipin ring, thereby generating a favorable promethin binding interface.

A combination of biomolecular simulations and experiments reveals that the disc-like oligomeric lipodystrophy protein seipin interacts with and traps triglycerides in the endoplasmic reticulum, thus facilitating the formation and growth of lipid droplets.     

Plasticized xyloglucan for improved toughness—Thermal and mechanical behaviour

Tamarind seed xyloglucan is an interesting polysaccharide of high molar mass with excellent thermomechanical properties. Several plasticizers were studied in order to facilitate thermal processing and improve toughness (work to fracture) of xyloglucan film materials: sorbitol, urea, glycerol and polyethylene oxide. Films of different compositions were cast and studied by thermogravimetric analysis (TGA), calorimetry (DSC), dynamic mechanical thermal analysis (DMA) and tensile tests. Results are analysed and discussed based on mechanisms and practical considerations. Highly favourable characteristics were found with XG/sorbitol combinations, and the thermomechanical properties motivate further work on this material system, for instance as a matrix in biocomposite materials.