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.

Generating Selective Leads for Mer Kinase Inhibitors-Example of a Comprehensive Lead-Generation Strategy.

Mer is a member of the TAM (Tyro3, Axl, Mer) kinase family that has been associated with cancer progression, metastasis, and drug resistance. Their essential function in immune homeostasis has prompted an interest in their role as modulators of antitumor immune response in the tumor microenvironment. Here we illustrate the outcomes of an extensive lead-generation campaign for identification of Mer inhibitors, focusing on the results from concurrent, orthogonal high-throughput screening approaches.

HIV Rev-isited.

The human immunodeficiency virus type 1 (HIV-1) proteome is expressed from alternatively spliced and unspliced genomic RNAs. However, HIV-1 RNAs that are not fully spliced are perceived by the host machinery as defective and are retained in the nucleus. During late infection, HIV-1 bypasses this regulatory mechanism by expression of the Rev protein from a fully spliced mRNA.

A-loop interactions in Mer tyrosine kinase give rise to inhibitors with two-step mechanism and long residence time of binding.

The activation loop (A-loop) plays a key role in regulating the catalytic activity of protein kinases. Phosphorylation in this region enhances the phosphoryl transfer rate of the kinase domain and increases its affinity for ATP. Furthermore, the A-loop possesses autoinhibitory functions in some kinases, where it collapses onto the protein surface and blocks substrate binding when unphosphorylated.

A review of the effectiveness of vegetated buffers to mitigate pesticide and nutrient transport into surface waters from agricultural areas.

A relatively large number of studies have investigated the effectiveness of vegetated buffer strips at reducing the movement of pesticides and nutrients from agriculture fields. This review outlines the observed influence of different factors (e.g.

Dalton's and Amagat's laws fail in gas mixtures with shock propagation.

A shock propagating through a gas mixture leads to pressure, temperature, and density increases across the shock front. Rankine-Hugoniot relations correlating pre- and post-shock quantities describe a calorically perfect gas but deliver a good approximation for real gases, provided the pre-shock conditions are well characterized with a thermodynamic mixing model. Two classic thermodynamic models of gas mixtures are Dalton's law of partial pressures and Amagat's law of partial volumes.

Structural insights into the critical DNA damage sensors DNA-PKcs, ATM and ATR.

ATM, ATR and DNA-PKCs are key effectors of DNA Damage response and have been extensively linked to tumourigenesis and survival of cancer cells after radio/chemotherapy. Despite numerous efforts, the structures of these proteins remained elusive until very recently. The resolution revolution in Cryo-EM allowed for molecular details of these proteins to be seen for the first time.

Validation of a Commercial Automated Body Condition Scoring System on a Commercial Dairy Farm.

Body condition scoring (BCS) is the management practice of assessing body reserves of individual animals by visual or tactile estimation of subcutaneous fat and muscle. Both high and low BCS can negatively impact milk production, disease, and reproduction. Visual or tactile estimation of subcutaneous fat reserves in dairy cattle relies on their body shape or thickness of fat layers and muscle on key areas of the body.

The role of vegetated buffers in agriculture and their regulation across Canada and the United States.

A vegetated buffer, barrier, or filter strip is a parcel of land that is designated to separate land used for agriculture from valued aquatic or terrestrial habitats. It exists partly with the intent to diffuse runoff and to impeded sediment, nutrients, pesticides, and other constituents from reaching off-site surface waters. Mandatory buffer implementation is regulated at various levels of government in North America - from the federal to the state and provincial levels, and by some municipalities and counties.

An in situ thermo-mechanical rig for lattice strain measurement during creep using neutron diffraction.

A long-term high-temperature testing stress rig has been designed and fabricated for performing in situ neutron diffraction tests at the ENGIN-X beamline, ISIS facility in the UK. It is capable of subjecting metals to high temperatures up to 800 °C and uniaxial loading under different boundary conditions including constant load, constant strain, and elastic follow-up, each with minimum of external control. Samples are held horizontally between grips and connected to a rigid rig frame, a soft aluminium bar, and a stepper motor with forces up to 20 kN.

Structures of closed and open conformations of dimeric human ATM.

ATM (ataxia-telangiectasia mutated) is a phosphatidylinositol 3-kinase-related protein kinase (PIKK) best known for its role in DNA damage response. ATM also functions in oxidative stress response, insulin signaling, and neurogenesis. Our electron cryomicroscopy (cryo-EM) suggests that human ATM is in a dynamic equilibrium between closed and open dimers.

Effect of boundary conditions on the evolution of lattice strains in a polycrystalline austenitic stainless steel.

The effect of boundary conditions (constant load, constant strain and elastic follow-up) on lattice strain evolution during creep in a polycrystalline austenitic stainless steel was studied using in situ neutron diffraction at 550 °C. The lattice strains were found to remain constant under constant load control. However, under constant strain and elastic follow-up control, the lattice strains relaxed the most in the elastically softest lattice plane {200} and the least in the elastically stiffest lattice plane {111}.

Development of a toolkit for early identification of cauda equina syndrome.

Unlabelled: Aim To develop a simple cauda equina syndrome (CES) toolkit to facilitate the subjective examination of low back pain patients potentially at risk of CES. To undertake preliminary validation of the content of the toolkit.

Background: CES is a rare condition which can be very challenging to identify in a generalist medical setting.

A high-throughput screening-compatible homogeneous time-resolved fluorescence assay measuring the glycohydrolase activity of human poly(ADP-ribose) glycohydrolase.

Poly(ADP-ribose) (PAR) polymers are transient post-translational modifications, and their formation is catalyzed by poly(ADP-ribose) polymerase (PARP) enzymes. A number of PARP inhibitors are in advanced clinical development for BRCA-mutated breast cancer, and olaparib has recently been approved for BRCA-mutant ovarian cancer; however, there has already been evidence of developed resistance mechanisms. Poly(ADP-ribose) glycohydrolase (PARG) catalyzes the hydrolysis of the endo- and exo-glycosidic bonds within the PAR polymers.

Patterns of Adverse Drug Reaction in the Medical Wards of a Teaching Hospital: A Prospective Observational Cohort Study.

Introduction: According to the World Health Organization (WHO) definition, an Adverse Drug Reaction (ADR) is a response to a drug that is noxious and unintended and occurs at doses normally used in humans for the prophylaxis, diagnosis, and treatment of disease. The risk factors of ADR are multi-factorial and include poly-pharmacy, age, gender, race, genetics and inter-current disease.

Patients And Methods: This was a hospital based, prospective, observational cohort study undertaken in a tertiary care hospital in south India to assess the different patterns of adverse drug reaction in medical wards over 6 months.

Are chronically ill patients high users of homecare services in Canada?

Objectives: Chronically ill patients often need healthcare and supportive services, with formal homecare services an important source of community-based assistance. Although people diagnosed with 1 or more chronic diseases are thought to be the most common homecare clients, and perhaps the highest users of homecare services, few studies have analyzed homecare services utilization by specific clients. A study was done to determine if a relationship exists between chronic illness and homecare services utilization.

Completing the structural family portrait of the human EphB tyrosine kinase domains.

The EphB receptors have key roles in cell morphology, adhesion, migration and invasion, and their aberrant action has been linked with the development and progression of many different tumor types. Their conflicting expression patterns in cancer tissues, combined with their high sequence and structural identity, present interesting challenges to those seeking to develop selective therapeutic molecules targeting this large receptor family. Here, we present the first structure of the EphB1 tyrosine kinase domain determined by X-ray crystallography to 2.

Stability and solubility engineering of the EphB4 tyrosine kinase catalytic domain using a rationally designed synthetic library.

The inability to generate soluble, correctly folded recombinant protein is often a barrier to successful structural and functional studies. Access to affordable synthetic genes has, however, made it possible to design, make and test many more variants of a target protein to identify suitable constructs. We have used rational design and gene synthesis to create a controlled randomised library of the EphB4 receptor tyrosine kinase, with the aim of obtaining soluble, purifiable and active catalytic domain material at multi-milligram levels in Escherichia coli.

Biochemical and biophysical characterization of four EphB kinase domains reveals contrasting thermodynamic, kinetic and inhibition profiles.

The Eph (erythropoietin-producing hepatocellular carcinoma) B receptors are important in a variety of cellular processes through their roles in cell-to-cell contact and signalling; their up-regulation and down-regulation has been shown to have implications in a variety of cancers. A greater understanding of the similarities and differences within this small, highly conserved family of tyrosine kinases will be essential to the identification of effective therapeutic opportunities for disease intervention. In this study, we have developed a route to production of multi-milligram quantities of highly purified, homogeneous, recombinant protein for the kinase domain of these human receptors in Escherichia coli.

Structures of the human poly (ADP-ribose) glycohydrolase catalytic domain confirm catalytic mechanism and explain inhibition by ADP-HPD derivatives.

Poly(ADP-ribose) glycohydrolase (PARG) is the only enzyme known to catalyse hydrolysis of the O-glycosidic linkages of ADP-ribose polymers, thereby reversing the effects of poly(ADP-ribose) polymerases. PARG deficiency leads to cell death whilst PARG depletion causes sensitisation to certain DNA damaging agents, implicating PARG as a potential therapeutic target in several disease areas. Efforts to develop small molecule inhibitors of PARG activity have until recently been hampered by a lack of structural information on PARG.