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Strategically replacing hydrogen with deuterium at sites of metabolism in small molecule drugs can significantly alter clearance and potentially enhance clinical safety. Bupropion is an antidepressant and smoking cessation medication with the potential to cause seizures. We hypothesized that incorporating deuterium at specific sites in bupropion may greatly reduce epimerization, potentially slow metabolism, and reduce the formation of toxic metabolites, namely hydroxybupropion which has been associated with bupropion's toxicity. Four deuterated analogues were synthesized incorporating deuterium at sites of metabolism and epimerization with the aim of altering the metabolic profile of bupropion. Spectroscopic binding and metabolism studies with bupropion and R-or S-d4 and R-or S-d10 analogs were performed with recombinant CYP2B6, human liver microsomes, and human hepatocytes. Results demonstrate that deuterated bupropion analogues exhibited 20-25% decrease in racemization and displayed a significant decrease in the formation of CYP2B6-mediated R,R - or S,S-hydroxybupropion with recombinant protein and human liver microsomes. In primary human hepatocytes, metabolism of deuterated analogs to R,R - and S,S-hydroxybupropion and threo- and erythro-hydrobupropion was significantly less than R/S-d0 bupropion. Selective deuterium substitution at metabolic soft spots in bupropion has the potential to provide a drug with a simplified pharmacokinetic profile, reduced toxicity and improved tolerability in patients.

This article is protected by copyright. All rights reserved. With the accelerating pace of global change, it is imperative that we obtain rapid inventories of the status and distribution of wildlife for ecological inferences and conservation planning. To address this challenge, we launched the SNAPSHOT USA project, a collaborative survey of terrestrial wildlife populations using camera traps across the United States. For our first annual survey, we compiled data across all 50 states during a 14-week period (17 August - 24 November of 2019). We sampled wildlife at 1509 camera trap sites from 110 camera trap arrays covering 12 different ecoregions across four development zones. This effort resulted in 166,036 unique detections of 83 species of mammals and 17 species of birds. All images were processed through the Smithsonian's eMammal camera trap data repository and included an expert review phase to ensure taxonomic accuracy of data, resulting in each picture being reviewed at least twice. The results represent a timely and standardized camera trap survey of the USA. All of the 2019 survey data are made available herein. We are currently repeating surveys in fall 2020, opening up the opportunity to other institutions and cooperators to expand coverage of all the urban-wild gradients and ecophysiographic regions of the country. Future data will be available as the database is updated at eMammal.si.edu/snapshot-usa, as well as future data paper submissions. These data will be useful for local and macroecological research including the examination of community assembly, effects of environmental and anthropogenic landscape variables, effects of fragmentation and extinction debt dynamics, as well as species-specific population dynamics and conservation action plans. There are no copyright restrictions; please cite this paper when using the data for publication. Publisher PDF

Introduction: MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) is a key mediator of the NF-κB signaling pathway, the main driver of a subset of B-cell lymphomas and functions by forming a complex with CARMA1 and BCL10 to mediate antigen receptor-induced lymphocyte activation. MALT1 is considered a potential therapeutic target for several subtypes of non-Hodgkin B-cell lymphomas and chronic lymphocytic leukemia (CLL). Previously, we described the discovery of novel and potent MALT1 inhibitors with anti-proliferative effects in non-Hodgkin B-cell lymphoma cells. Here, we highlight the strong anti-tumor activity of our MALT1 inhibitors across multiple tumor models and the combination potential with agents including standard-of-care. Results: Novel small molecule MALT1 inhibitors were identified using Schrodinger's proprietary physics-based free energy perturbation (FEP+) modeling technology. These molecules demonstrate strong MALT1 protein binding affinity, potent inhibition of MALT1 enzymatic activity and anti-proliferative activity in the activated B-cell (ABC) subtype of diffuse large B cell lymphoma (DLBCL) cell lines such as OCI-LY3 and OCI-LY10. In combination with approved agents, these inhibitors demonstrate strong combination potential with Bruton's tyrosine kinase (BTK) inhibitors such as ibrutinib in ABC-DLBCL cell lines. In ABC-DLBCL CDX models, our representative MALT1 inhibitor induces tumor regression as a single agent and complete tumor regression in combination with ibrutinib. Our representative MALT1 inhibitor, when tested in LY2298 PDX models, demonstrates similar results. In addition, our representative MALT1 inhibitor was explored in a CDX model derived from a Mantle cell lymphoma REC-1 cell line, and demonstrates strong anti-tumor activity of ~78% tumor growth inhibition (TGI) as a single agent. Conclusions: Schrodinger's novel, potent MALT1 protease small molecule inhibitors are efficacious in in vitro B-cell lymphoma cell proliferation assays and in in vivo B-cell lymphoma xenograft models. These data suggest that targeting MALT1 may expand therapeutic options for patients with selected B-cell lymphomas, such as ABC-DLBCL, with the possibility of expanding into other B-cell lymphomas such as MCL. Furthermore, these small molecule MALT1 inhibitors demonstrate potential in combination with BTKi to overcome drug-induced resistance in patients with relapsed/refractory B-cell lymphomas. Taken together, the data presented here strongly underscore the therapeutic potential of our MALT1 inhibitor and support further evaluation in clinical trials. Disclosures Weiss: Schrodinger: Current Employment; ARTham Therapeutics: Membership on an entity's Board of Directors or advisory committees.

This paper describes the preliminary design result of the Monorail Crane System (MCS), which is a subsystem of the ITER Neutral Beam Remote Handling System. Since the concept design of the MCS, the design is elaborated further detail considering new maintenance requirements, updated interfaces with the components to be maintained, and the latest configurations in the NB cell. The main design updates are described as follows. First, the railway is changed from the one monorail with two side reaction rails to a dual rail system, which has better load distribution within the crane trolley and the building mountings. Second, additional railway and a switching mechanism are added between the HNB#1 and #2 to access to the VVPSS components, which are newly added in the NB cell. Third, the mounting of the transversal beams supporting the dual rails onto the embedded plates are updated and further elaborated. Forth, the crane trolley is designed to have independent redundant kinematic chains so that it is recoverable from a single point failure. Fifth, series of braking systems such as a service brake, an auxiliary brake, and an emergency brake are integrated in each kinematic chain to cope with normal and accidental loads. Sixth, seismic uncoupling devices are integrated to protect the mechanical components of the crane itself and the building structure. Lastly, detailed cabling design is implemented from the control cubicle to the locations where the subcomponents are located.

Introduction: MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1), was identified as a translocation protein fused with cIAP2 in mucosa-associated lymphoid tissue (MALT) B cell lymphomas. MALT1, a key mediator of NF-κB signaling and the main driver of a subset of B-cell lymphomas, functions via formation of a complex with CARMA1 and BCL10 to mediate antigen receptor-induced lymphocyte activation. MALT1 has been considered as a potential therapeutic target for several non-Hodgkin B cell lymphomas as well as chronic lymphocytic leukemia (CLL). Here, we describe the discovery of novel, potent MALT1 inhibitors that result in antiproliferative effects in non-Hodgkin B-cell lymphoma cells. Results: We have identified novel small molecule MALT1 inhibitors using our proprietary physics-based Free Energy Perturbation (FEP+) modeling technology. Our compounds show potent (sub nM) inhibition of MALT1 enzymatic activity, as well as high binding affinity (sub nM) to MALT1 protein measured by Surface Plasmon Resonance (SPR). BCL10 is a binding partner of MALT1 that is cleaved by MALT1 at the C-terminus. Our inhibitors were efficacious in a target engagement assay showing prevention of BCL10 cleavage in Activated B-cell (ABC) subtype of diffuse large B cell lymphoma (DLBCL) cell lines OCI-LY3 and OCI-LY10, which are Bruton tyrosine kinase (BTK) inhibitor ibrutinib-resistant and -responsive respectively. Our compounds are potent inhibitors of IL10 secretion in both OCI-LY3 and OCI-LY10 cells, which is consistent with the inhibition of NF-κB signaling. We also examined the effect of our MALT1 inhibitors on ABC-DLBCL cell proliferation. Our inhibitors demonstrated potent anti-proliferative effects in both OCI-LY3 and OCI-LY10 cell lines, as well as synergistic effects with ibrutinib in a BTKi sensitive ABC-DLBCL cell panel. Examinations of a protease panel and off-target safety screening panel, as well as in vivo high dose tolerability study showed our compound had excellent selectivity and significant safety margin. Plasma IL10 and tumor BCL10 have been identified as robust PD markers in PK/PD studies in both OCI-LY3 and OCI-LY10 tumor bearing mice. Dose-dependent tumor growth inhibition was observed after 3 weeks of treatment in OCI-LY3 xenograft model, with efficacy also observed in combination with venetoclax. Ongoing work: We are continuing to explore the synergistic effects of our compounds with BTK inhibitors in B-cell lymphoma mouse models. Preliminary data showed potent inhibition of IL-2 secretion in Jurkat cells from our compound treatment. Additional studies are ongoing to elucidate the role of MALT1 inhibition in Treg as well as Teffector cells in vitro and in vivo. Refinement of the current inhibitor series, using co-crystal structures, is in progress in preparation for further development of optimized molecules. Conclusion and Future Plans: We have identified novel potent MALT1 protease small molecule inhibitors that are efficacious in the in vitro B-cell lymphoma cell proliferation assays and in the in vivo B-cell lymphoma xenograft model. Our data suggest that targeting MALT1 may expand therapy options for patients with selected B-cell lymphomas, such as ABC-DLBCL. Our work provided insight into the anti-tumor efficacy of our inhibitors in B-cell lymphomas as single agent, and ongoing work will continue to assess the potential combination with BTKi to overcome drug-induced resistance in patients with relapsed/refractory B-cell lymphoma. Disclosures Yin: Schrodinger: Current Employment, Current equity holder in publicly-traded company. Zhe:Schrodinger: Current Employment, Current equity holder in publicly-traded company. Placzek:Schrodinger: Current Employment, Current equity holder in publicly-traded company. Trzoss:Schrodinger: Current Employment, Current equity holder in publicly-traded company. Krilov:Schrodinger: Current Employment, Current equity holder in publicly-traded company. Feng:Schrodinger: Current Employment, Current equity holder in publicly-traded company. Lawrenz:Schrodinger: Current Employment, Current equity holder in publicly-traded company. Pelletier:Schrodinger: Current Employment, Current equity holder in publicly-traded company. Lai:Triplet Therapeutics: Current Employment, Current equity holder in private company. Bell:Schrodinger: Current Employment, Current equity holder in publicly-traded company. Calkins:Schrodinger: Current Employment, Current equity holder in publicly-traded company. Grimes:Schrodinger: Current Employment, Current equity holder in publicly-traded company. Tang:Schrodinger: Current Employment, Current equity holder in publicly-traded company. McRobb:Schrodinger: Current Employment, Current equity holder in publicly-traded company. Gerasyuto:Schrodinger: Current Employment, Current equity holder in publicly-traded company. Feher:Schrodinger: Current Employment, Current equity holder in publicly-traded company. Mondal:Schrodinger: Current Employment, Current equity holder in publicly-traded company. Jensen:Schrodinger: Current Employment, Current equity holder in publicly-traded company. Wright:Schrodinger: Current Employment, Current equity holder in publicly-traded company. Akinsanya:Schrodinger: Current Employment, Current equity holder in publicly-traded company.

PURPOSE Best practice guidelines for cardiac rehabilitation (CR) suggest routine screening for anxiety and depression, yet many patients are not screened nor do they receive mental health treatment. Protocols are required to identify those in need of care and to ensure that appropriate assistance is provided. METHODS Consecutive patients entering CR in our setting from May 4, 2012, to May 3, 2013, completed the Hospital Anxiety and Depression Scale (HADS). As per our Screening and Triage protocol for Anxiety and Depression (STAD), patients with high scores (≥16) were referred to a clinical psychologist; those with low scores (

Les regimes epistemiques qui gouvernent les cadres nosographiques diagnostiques de la psychiatrie et de la psychologie, tels le dsm et la cim, laissent entendre que le reel dont traitent ces disciplines est descriptible sous forme d’entites psychopathologiques naturelles ou, au mieux, construites operationnellement. Or, la caracteristique principale de ces regimes epistemiques appliques au champ de la souffrance psychique est l’abolition du au mieuxsymptome en tant que marque meme du reel, dans sa rencontre avec le langage. En resulte donc une clinique sourde au reel que traite la psychanalyse, un reel sans loi, sans logique, sans histoire ni narration, un reel dont le sujet en tant qu’il « ex-siste » au langage n’est pas sans rien dire. Les sciences objectivantes ne peuvent eviter de se mettre au risque de la psychanalyse.

Most recent primary aluminium smelting technologies requires a lot of energy (from 12.8 to 14,5 kWh/t Al). Despite the progress made over the past decades, Alouette has always operated in an energy constrain mode ever since its start-up in 1992. Considering the limited amount of energy available and its vision of sustainability, Alouette has been exploring uncharted territories to make the cell technology (Aluminium Pechiney) more ‘efficient’ by increasing cell productivity while reducing energy consumption. As a result, the smelter has been able to produce more aluminium with its power limitation. Now facing the lower limit of the Anode-Cathode Distance (ACD) of the technology, this has brought additional operational challenges. To overcome this challenging situation, Alouette has developed an assisted anode gauging system on Pot Tending Machines (PTM) coupled with an improved anode setting precision method. This results in an improved cell performance by having a positive impact on Key Performances Indicators (KPI).

Fourteen strawberry genotypes (Fragaria x ananassa Duch.) were evaluated in the field for yield and fruit size. 'Honeoye' was found to be the highest yielding cultivar, followed by 'Kent,' Chambly,' 'Glooscap,' and 'Oka.' The fourteen genotypes were inoculated with individual North American (NA) eastern races (A-1 to A-6) and NA west coast races (A-7 to A-10) of Phyfophthora fragariae or a mixture of them which are the cause of red stele. A disease severity index (DSI), based on the number of oospores in the root stele and the percent root length with stela reddening, was used to quantify genotype susceptibility. 'Jewel,' 'Elvira,' 'Veestar,' 'Annapolis,' and Midway' were found to be more resistant than the other genotypes to the mixture of the ten races (Al-AlO) of P.fragariae. Inoculation of the fourteen genotypes with individual races of American red stele showed that 'Annapolis' and 'Sparkle' were resistant to most races of P.fragariae, whereas 'Honeoye' and 'Bounty' were the most susceptible.

How to re-establish confidence between society and finance ? How can we do away with fear in the face of the « tyranny » of financial markets, of changes in the banking system, and of the growing separation between finance and real economy ? In order to answer to these questions, the « Association d'Économie Financière » has organized a round table, on the occasion of the third edition of their « Moral Report on Money in the World ». Based on questions raised by this annual collection of analysis and contributions by specialists from different fields, some financial market players have started to reflect upon matters related to money dealing and dysfunctioning. Debating about a general subject « Finance and Society », participants have raised sensitive questions : corporate governance, the shift to « Euro », the war against money laundering, markets transparency, the assumption of an ethical chart for financial institutions world-wide. Frequently reminded of their duties and responsibilities, financial players have recommended a better reciprocal knowledge and understanding between finance and society. A.L., Comment rétablir la confiance entre la société et la finance ? Comment exorciser les craintes face à la « tyrannie » des marchés financiers, aux mutations du système bancaire, à la déconnexion croissante entre finance et économie réelle ? Pour répondre à ces questions, l'Association d'économie financière a organisé une Table ronde, à l'occasion de la publication de la troisième édition du Rapport moral sur l'argent dans le monde. A partir des questions soulevées par ce recueil annuel d'analyses et contributions de spécialistes de diverses disciplines, quelques acteurs de la place financière ont entamé une réflexion sur les pratiques et les dysfonctionnements dans l'utilisation de l'argent. Réunis autour du thème général « Finance et société », les participants ont abordé des questions sensibles : le gouvernement d'entreprise, le passage à l'Euro, la lutte contre le blanchiment de l'argent sale, la transparence sur les marchés, l'hypothèse d'une charte éthique des institutions financières du monde entier. Rappelés souvent à leurs devoirs et à leurs responsabilités, les acteurs financiers ont prôné une meilleure connaissance et compréhension réciproque entre finance et société., Lagayette Philippe, Ploix Hélène, Charkham Jonathan P., Pelletier Robert, Roma Giuseppe, Izraelewicz Erik. Finance et Société. Table ronde à l'occasion de la présentation du « Rapport moral sur l'argent dans le monde 1996 ». In: Revue d'économie financière, n°38, 1996. Finance et Europe : Questions de confiance ? pp. 167-188.