Sublethal exposure, insecticide resistance, and community stress

Insecticides are an invaluable pest management tool and anthropogenic stressors of widespread environmental occurrence that are subject to biased perceptions based on the targeted application, market value of use, and regulatory requirements. As a result, short-term and simplistic efforts focusing on lethal effects toward individual species and populations prevail. Holistic and comprehensive studies exploring rather common sublethal insecticide exposures are rare, particularly considering their potential role in structuring populations and communities in diverse environmental settings and potentially interfering in a range of ecological interactions. Studies on insecticide resistance, for example, do not go beyond population-based studies, disregarding temporal and spatial effects in the associated community, and rarely considering the whole of sublethal exposure. Some of these knowledge gaps are here recognized and explored

Sublethal exposure, insecticide resistance, and community stress

Insecticides are an invaluable pest management tool and anthropogenic stressors of widespread environmental occurrence that are subject to biased perceptions based on the targeted application, market value of use, and regulatory requirements. As a result, short-term and simplistic efforts focusing on lethal effects toward individual species and populations prevail. Holistic and comprehensive studies exploring rather common sublethal insecticide exposures are rare, particularly considering their potential role in structuring populations and communities in diverse environmental settings and potentially interfering in a range of ecological interactions. Studies on insecticide resistance, for example, do not go beyond population-based studies, disregarding temporal and spatial effects in the associated community, and rarely considering the whole of sublethal exposure. Some of these knowledge gaps are here recognized and explored

A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage

ML, CD, IvL, GP, TM, SD, MS, APF, CT, DL, MAH, KL and SL: project grants from the Swedish Research Council, the Swedish Cancer Society and the Swedish Childhood Cancer Foundation. MHi and JC: Cancer Research UK (C8/A6613). MC, EP and WE: Wellcome Trust (073915). MN and BV: projects MEYS-NPS-LO1413 and GACR P206/12/G151. EMC, MP, MMS, ZF and PG: Norwegian Cancer Society (182735, 732200) and Helse Vest (911884, 911789). RB and SC: NIH (R01 CA95684), the Leukemia and Lymphoma Society and the Waxman Foundation. NW, AH, Ad’H: Cancer Research UK (C21383/A6950) and Engineering and Physical Sciences Research Council Doctoral Training Program. JL and YZ: Cancer Research UK (C240/A15751). MH and BW: SARomics Biostructures ABUY, KF: DDDP SciLife, Sweden. LJ, MHa, RS and A-LG: CBCS, Sweden. VP: SciLife fellowship. AT: Breast Cancer Research Scotland.The development of non-genotoxic therapies that activate wild-type p53 in tumors is of great interest since the discovery of p53 as a tumor suppressor. Here we report the identification of over 100 small-molecules activating p53 in cells. We elucidate the mechanism of action of a chiral tetrahydroindazole (HZ00), and through target deconvolution, we deduce that its active enantiomer (R)-HZ00, inhibits dihydroorotate dehydrogenase (DHODH). The chiral specificity of HZ05, a more potent analog, is revealed by the crystal structure of the (R)-HZ05/DHODH complex. Twelve other DHODH inhibitor chemotypes are detailed among the p53 activators, which identifies DHODH as a frequent target for structurally diverse compounds. We observe that HZ compounds accumulate cancer cells in S-phase, increase p53 synthesis, and synergize with an inhibitor of p53 degradation to reduce tumor growth in vivo. We, therefore, propose a strategy to promote cancer cell killing by p53 instead of its reversible cell cycle arresting effect.Publisher PDFPeer reviewe

Response of six European forest sites to decided and proposed air pollution emission reductions

Two acid deposition scenarios were simulated for six European forest sites situated in Germany, Denmark, Russia, Switzerland, Spain and Ireland. Three models were used in combination, the RAINS (Regional Acidification INformations and Simulation) model, the SAFE (Simulating Acidification in Forest Ecosystems) model and the MakeDep model. The scenarios used were based on results from international negotiations (the Oslo and Sofia protocols) and on calculations of what could be achieved using the best available technology at a reasonable cost. The parameters chosen for studying the course of acidification were base saturation, BC.Al molar ratio in soil solution and pH. Furthermore, the sites were compared with respect to deposition regimes as well as ion exchange and weathering rates, nutrient uptake and nutrient cycling. The results show, that all sites have undergone acidification. Three of the sites show BC.Al molar ratios below or very close to the threshold value of 1. Currently accepted reductions in S and N emissions will lead to a halt in acidification in all cases and a partial regeneration of the soil buffer capacity in some cases. Introducing maximum feasible reductions would improve soil conditions remarkably at all six sites. The differences in degree and course of acidification can be derived from differences in weathering rate and soil buffer capacity as well as from the deposition regimes. Detailed information on future anthropogenic base cation deposition is shown to be less important for the outcome of the scenarios than expected

Modelling ''clean rain'' treatments in acidified soils - EXMAN project results

The SAFE dynamic model was applied to a ''clean rain'' roof experiment performed within the EXMAN project. In the experiment ambient throughfall was removed and replaced with artificial ''clean throughfall''. Input of S, N and H to the forest ecosystem was reduced by 75-100%. The results of the modelling show, that the time scales of model predictions and experiments are the same. The change in base cation flux was well reproduced, while the simulation of changes in aluminum flux was less successful. pH stayed constant in the experiment as well as in the calculations

Spinosad-induced stress on the maize weevil Sitophilus zeamais: Presentation

Although seldom considered, sublethal insecticide exposure may lead to harmful, neutral, or even beneficial responses that may affect (or not) the behavior and fitness of the exposed insects. Intriguingly, little is known about such effects on stored product insect pests and even less is available regarding the bioinsecticide, spinosad. Thus, we assessed the sublethal effects of spinosad on walking, feeding, drinking and mating behaviors of maize weevils (Sitophilus zeamais), also assessing their survival, reproductive output, and grain loss compared with maize weevils exposed to the pyrethroid deltamethrin (as positive control), and water only (negative control). Both spinosad and deltamethrin were able to effectively control the insects, although the latter caused a faster mortality than the former. Behavioral pattern changes were caused by both insecticides, especially deltamethrin, triggering irritability (i.e., avoidance after contact). Different feeding and drinking responses were also detected with significant avoidance to deltamethrin, but not to spinosad. Maize weevil couples sublethally exposed to deltamethrin and spinosad exhibited altered reproductive behavior, a likely consequence of their altered activity, but deltamethrin caused greater behavioral changes. Curiously, higher progeny emergence and grain loss were observed in deltamethrin-exposed insects, suggesting that this pyrethroid insecticide elicits hormesis in maize weevils that may compromise control efficacy by this compound. In contrast, such effect was not detected with spinosad, which did not elicit avoidance allowing the intended weevil exposure and control.Although seldom considered, sublethal insecticide exposure may lead to harmful, neutral, or even beneficial responses that may affect (or not) the behavior and fitness of the exposed insects. Intriguingly, little is known about such effects on stored product insect pests and even less is available regarding the bioinsecticide, spinosad. Thus, we assessed the sublethal effects of spinosad on walking, feeding, drinking and mating behaviors of maize weevils (Sitophilus zeamais), also assessing their survival, reproductive output, and grain loss compared with maize weevils exposed to the pyrethroid deltamethrin (as positive control), and water only (negative control). Both spinosad and deltamethrin were able to effectively control the insects, although the latter caused a faster mortality than the former. Behavioral pattern changes were caused by both insecticides, especially deltamethrin, triggering irritability (i.e., avoidance after contact). Different feeding and drinking responses were also detected with significant avoidance to deltamethrin, but not to spinosad. Maize weevil couples sublethally exposed to deltamethrin and spinosad exhibited altered reproductive behavior, a likely consequence of their altered activity, but deltamethrin caused greater behavioral changes. Curiously, higher progeny emergence and grain loss were observed in deltamethrin-exposed insects, suggesting that this pyrethroid insecticide elicits hormesis in maize weevils that may compromise control efficacy by this compound. In contrast, such effect was not detected with spinosad, which did not elicit avoidance allowing the intended weevil exposure and control

Intact Protein Analysis at 21 Tesla and X-Ray Crystallography Define Structural Differences in Single Amino Acid Variants of Human Mitochondrial Branched-Chain Amino Acid Aminotransferase 2 (BCAT2)

Structural technologies are an essential component in the design of precision therapeutics. Precision medicine entails the development of therapeutics directed toward a designated target protein, with the goal to deliver the right drug to the right patient at the right time. In the field of oncology, protein structural variants are often associated with oncogenic potential. In a previous proteogenomic screen of patient-derived glioblastoma (GBM) tumor materials, we identified a sequence variant of human mitochondrial branched-chain amino acid aminotransferase 2 as a putative factor of resistance of GBM to standard-of-care-treatments. The enzyme generates glutamate, which is neurotoxic. To elucidate structural coordinates that may confer altered substrate binding or activity of the variant BCAT2 T186R, a ~45 kDa protein, we applied combined ETD and CID top-down mass spectrometry in a LC-FT-ICR MS at 21 T, and X-Ray crystallography in the study of both the variant and non-variant intact proteins. The combined ETD/CID fragmentation pattern allowed for not only extensive sequence coverage but also confident localization of the amino acid variant to its position in the sequence. The crystallographic experiments confirmed the hypothesis generated by in silico structural homology modeling, that the Lys59 side-chain of BCAT2 may repulse the Arg186 in the variant protein (PDB code: 5MPR), leading to destabilization of the protein dimer and altered enzyme kinetics. Taken together, the MS and novel 3D structural data give us reason to further pursue BCAT2 T186R as a precision drug target in GBM. [Figure not available: see fulltext.]