Fragment-Based Discovery of Novel MUS81 Inhibitors.

MUS81 is a structure-selective endonuclease that cleaves various branched DNA structures arising from natural physiological processes such as homologous recombination and mitosis. Due to this, MUS81 is able to relieve replication stress, and its function has been reported to be critical to the survival of many cancers, particularly those with dysfunctional DNA-repair machinery. There is therefore interest in MUS81 as a cancer drug target, yet there are currently few small molecule inhibitors of this enzyme reported, and no liganded crystal structures are available to guide hit optimization.

Discovery of a Potent and Orally Bioavailable Zwitterionic Series of Selective Estrogen Receptor Degrader-Antagonists.

Herein, we report the optimization of a meta-substituted series of selective estrogen receptor degrader (SERD) antagonists for the treatment of ER+ breast cancer. Structure-based design together with the use of modeling and NMR to favor the bioactive conformation led to a highly potent series of basic SERDs with promising physicochemical properties. Issues with hERG activity resulted in a strategy of zwitterion formation and ultimately in the identification of .

A method to extract slip system dependent information for crystal plasticity models.

A tool to implement a length scale dependency to classical crystal plasticity simulations is presented. Classical crystal plasticity models do not include a size effect; therefore, the size of the grain does not influence the simulated deformation. Classical crystal plasticity advancements have been through the inclusion of stress or strain gradient based constitutive models to improve the simulation of length scale dependent deformation.

Body Condition Score Change throughout Lactation Utilizing an Automated BCS System: A Descriptive Study.

Body condition scoring (BCS) is a traditional visual technique often using a five-point scale to non-invasively assess fat reserves in cattle. However, recent studies have highlighted the potential in automating body condition scoring using imaging technology. Therefore, the objective was to implement a commercially available automated body condition scoring (ABCS) camera system to collect data for developing a predictive equation of body condition dynamics throughout the lactation period.