Alien Registration- Bolduc, Edward L. (Lewiston, Androscoggin County)

https://digitalmaine.com/alien_docs/30686/thumbnail.jp

Alien Registration- Bolduc, Marie L. (Phillips, Franklin County)

https://digitalmaine.com/alien_docs/19375/thumbnail.jp

Alien Registration- Jalbert, Marie Eva L. (Auburn, Androscoggin County)

https://digitalmaine.com/alien_docs/30946/thumbnail.jp

Chemoenzymatic Synthesis of Cryptophycin Anticancer Agents by an Ester Bond-Forming Non-ribosomal Peptide Synthetase Module

Cryptophycins (Crp) are a group of cyanobacterial depsipeptides with activity against drug-resistant tumors. Although they have been shown to be promising, further efforts are required to return these highly potent compounds to the clinic through a new generation of analogues with improved medicinal properties. Herein, we report a chemosynthetic route relying on themultifunctional enzyme CrpD-M2 that incorporates a 2-hydroxy acid moiety (unit D) into Crp analogues. CrpD-M2 is a unique nonribosomal peptide synthetase (NRPS) module comprised of condensation-adenylation-ketoreduction-thiolation (C-A-KR-T) domains. We interrogated A-domain 2-keto and 2-hydroxy acid activation and loading, and KR domain activity in the presence of NADPH and NADH. The resulting 2-hydroxy acid was elongated with three synthetic Crp chain elongation intermediate analogues through ester bond formation catalyzed by CrpD-M2 C domain. Finally, the enzyme-bound seco-Crp products were macrolactonized by the Crp thioesterase. Analysis of these sequential steps was enabled through LC-FTICR-MS of enzyme-bound intermediates and products. This novel chemoenzymatic synthesis of Crp involves four sequential catalytic steps leading to the incorporation of a 2-hydroxy acid moiety in the final chain elongation intermediate. The presented work constitutes the first example where a NRPS-embedded KR domain is employed for assembly of a fully elaborated natural product, and serves as a proof-of-principle for chemoenzymatic synthesis of new Crp analogues

Une étude sur l'utilisation des roches stériles comme inclusions drainantes dans les résidus miniers

RÉSUMÉ L’industrie minière génère de grandes quantités de rejets solides tels les roches stériles et les rejets de concentrateur. La gestion sécuritaire de ces rejets est un enjeu important. Les roches stériles sont typiquement entreposées dans des haldes alors que les résidus issus du traitement du minerai sont pompés sous forme de boue à l’intérieur du parc à résidus qui est ceinturé de digues. Ces résidus lâches et saturés, à granulométrie fine, se consolident lentement sous leur propre poids, ce qui augmente leur densité et leur résistance. Pour réduire les risques de nature géotechnique reliés à l’entreposage de surface des résidus miniers, on peut modifier le design des bassins en y ajoutant des inclusions drainantes composées de roches stériles à granulométrie grossière. Cette technique engendre plusieurs avantages, incluant l’accélération de la consolidation des résidus miniers fins. Les inclusions drainantes offrent un chemin de drainage préférentiel pour la dissipation des pressions d’eau en excès puisque leur conductivité hydraulique est plus de 100 fois supérieure à celle des résidus en raison de leur granulométrie grossière très étalée. Cela permet d’augmenter plus rapidement le degré de consolidation et la résistance des résidus et ainsi réduire les risques géotechniques. Cette technique de codisposition est un nouveau domaine de recherche. Des travaux récents de modélisation conceptuelle ainsi que des essais sur table sismique avec des inclusions de sable ont démontré la validité du concept. L’objectif de ce projet est de poursuivre ces travaux en abordant l’effet des inclusions de roches stériles sur la consolidation des résidus miniers en se basant sur un cas réel. Un programme d’essais a été mené pour caractériser les propriétés des résidus et des stériles provenant de la mine Osisko située à Malartic, au Québec. Ces propriétés ont ensuite été utilisées pour simuler l’influence d’inclusions drainantes ajoutées dans un parc à résidus. Cette analyse permet de dégager les éléments importants qui affectent la consolidation de résidus miniers à proximité d’inclusions drainantes.----------ABSTRACT The mining industry generates large quantity of waste materials such as waste rock and tailings. Those by-products may potentially be harmful to the environment and need to be safely contained. Waste rock is conventionally stored in piles on the surface while the tailings produced by the milling facilities are pumped as slurry inside an impoundment surrounded by dikes. Such saturated tailings tend to consolidate under their own weight after their deposition, increasing their density and resistance with time. Mine tailings can be problematic to manage as they contain a high proportion of fine particles, which give them complex geotechnical properties that can lead to dike failure in extreme cases. The design of a tailings impoundment can be modified to reduce the geotechnical risks by placing inclusions of coarse grained waste rock inside the pond. This technique offers many advantages such as increasing the consolidation rate of fine tailings. The inclusions of waste rock offer preferential drainage pathways to dissipate the excess pore water pressure inside the impoundment, as their saturated hydraulic conductivity is 100 to 1000 higher than that of tailings due to their coarser grain size. This phenomenon increases the consolidation rates and the resistance of the tailings, thus decreasing geotechnical risks. The co-disposition of waste rock and tailings is a recent research domain. Previous work on tailings tested on a seismic table and conceptual numerical modeling with simplified material properties has demonstrated the validity of this concept. The objective of this research project was to investigate the effects of waste rock inclusions on the consolidation of tailings using data coming from an actual mine site. Tailings and waste rock samples were obtained from the Osisko Malartic mine located in the province of Quebec, and characterized in the laboratory. The measured properties were used to simulate the use of waste rock inclusions in a tailings impoundment. This analysis increases our understanding of the parameters affecting the consolidation of tailings near a waste rock inclusion

Economic evaluations of interventions to optimize medication use in older adults with polypharmacy and multimorbidity: A systematic review

Purpose: To conduct a systematic review of the economic impact of interventions intended at optimizing medication use in older adults with multimorbidity and polypharmacy. Methods: We searched Ovid-Medline, Embase, CINAHL, Ageline, Cochrane, and Web of Science, for articles published between 2004 and 2020 that studied older adults with multi-morbidity and polypharmacy. The intervention studied had to be aimed at optimizing medication use and present results on costs. Results: Out of 3,871 studies identified by the search strategy, eleven studies were included. The interventions involved different provider types, with a majority described as a multidisciplinary team involving a pharmacist and a general practitioner, in the decision-making process. Interventions were generally associated with a reduction in medication expenditure. The benefits of the intervention in terms of clinical outcomes remain limited. Five studies were cost-benefit analyses, which had a net benefit that was either null or positive. Cost-utility and cost-effectiveness analyses resulted in incremental cost-effectiveness ratios that were generally within the willingness-to-pay thresholds of the countries in which the studies were conducted. However, the quality of the studies was generally low. Omission of key cost elements of economic evaluations, including intervention cost and payer perspective, limited interpretability. Conclusion: Interventions to optimize medication use may provide benefits that outweigh their implementation costs, but the evidence remains limited. There is a need to identify and address barriers to the scaling-up of such interventions, starting with the current incentive structures for pharmacists, physicians, and patients

Present day challenges in understanding the geomagnetic hazard to national power grids

Power grids and pipeline networks at all latitudes are known to be at risk from the natural hazard of geomagnetically induced currents. At a recent workshop in South Africa, UK and South African scientists and engineers discussed the current understanding of this hazard, as it affects major power systems in Europe and Africa. They also summarised, to better inform the public and industry, what can be said with some certainty about the hazard and what research is yet required to develop useful tools for geomagnetic hazard mitigation

efam: an expanded, metaproteome-supported HMM profile database of viral protein families

Motivation: Viruses infect, reprogram and kill microbes, leading to profound ecosystem consequences, from elemental cycling in oceans and soils to microbiome-modulated diseases in plants and animals. Although metagenomic datasets are increasingly available, identifying viruses in them is challenging due to poor representation and annotation of viral sequences in databases. Results: Here, we establish efam, an expanded collection of Hidden Markov Model (HMM) profiles that represent viral protein families conservatively identified from the Global Ocean Virome 2.0 dataset. This resulted in 240 311 HMM profiles, each with at least 2 protein sequences, making efam >7-fold larger than the next largest, panecosystem viral HMM profile database. Adjusting the criteria for viral contig confidence from 'conservative' to 'eXtremely Conservative' resulted in 37 841 HMM profiles in our efam-XC database. To assess the value of this resource, we integrated efam-XC into VirSorter viral discovery software to discover viruses from less-studied, ecologically distinct oxygen minimum zone (OMZ) marine habitats. This expanded database led to an increase in viruses recovered from every tested OMZ virome by similar to 24% on average (up to similar to 42%) and especially improved the recovery of often-missed shorter contigs (<5 kb). Additionally, to help elucidate lesser-known viral protein functions, we annotated the profiles using multiple databases from the DRAM pipeline and virion-associated metaproteomic data, which doubled the number of annotations obtainable by standard, single-database annotation approaches. Together, these marine resources (efam and efam-XC) are provided as searchable, compressed HMM databases that will be updated bi-annually to help maximize viral sequence discovery and study from any ecosystem

Structural basis of nSH2 regulation and lipid binding in PI3Kα

We report two crystal structures of the wild-type phosphatidylinositol 3-kinase α (PI3Kα) heterodimer refined to 2.9 Å and 3.4 Å resolution: the first as the free enzyme, the second in complex with the lipid substrate, diC4-PIP2, respectively. The first structure shows key interactions of the N-terminal SH2 domain (nSH2) and iSH2 with the activation loop that suggest a mechanism by which the enzyme is inhibited in its basal state. In the second structure, the lipid substrate binds in a positively charged pocket adjacent to the ATP-binding site, bordered by the P-loop, the activation loop and the iSH2 domain. An additional lipid-binding site was identified at the interface of the ABD, iSH2 and kinase domains. The ability of PI3Kα to bind an additional PIP2 molecule was confirmed in vitro by fluorescence quenching experiments. The crystal structures reveal key differences in the way the nSH2 domain interacts with wild-type p110α and with the oncogenic mutant p110αH1047R. Increased buried surface area and two unique salt-bridges observed only in the wild-type structure suggest tighter inhibition in the wild-type PI3Kα than in the oncogenic mutant. These differences may be partially responsible for the increased basal lipid kinase activity and increased membrane binding of the oncogenic mutant