Publications by authors named "David House"

Identifying pharmacological probes for human proteins represents a key opportunity to accelerate the discovery of new therapeutics. High-content screening approaches to expand the ligandable proteome offer the potential to expedite the discovery of novel chemical probes to study protein function. Screening libraries of reactive fragments by chemoproteomics offers a compelling approach to ligand discovery, however, optimising sample throughput, proteomic depth, and data reproducibility remains a key challenge.

View Article and Find Full Text PDF

Reactive fragment (RF) screening has emerged as an efficient method for ligand discovery across the proteome, irrespective of a target's perceived tractability. To date, however, the efficiency of subsequent optimisation campaigns has largely been low-throughput, constrained by the need for synthesis and purification of target compounds. We report an efficient platform for 'direct-to-biology' (D2B) screening of cysteine-targeting chloroacetamide RFs, wherein synthesis is performed in 384-well plates allowing direct assessment in downstream biological assays without purification.

View Article and Find Full Text PDF

Microsatellite-unstable (MSI) cancers require WRN helicase to resolve replication stress due to expanded DNA (TA)n dinucleotide repeats. WRN is a promising synthetic lethal target for MSI tumors, and WRN inhibitors are in development. In this study, we used CRISPR-Cas9 base editing to map WRN residues critical for MSI cells, validating the helicase domain as the primary drug target.

View Article and Find Full Text PDF

As multidisciplinary emergency care becomes increasingly complex, all team members must be aware of their respective roles and responsibilities. In the emergency department, nurse practitioners are integral members of the team. They possess a wide range of clinical and leadership competencies that allow them to perform specific and differentiated tasks within the emergency department.

View Article and Find Full Text PDF

The development and optimisation of a photoaffinity labelling (PAL) displacement assay is presented, where a highly efficient PAL probe was used to report on the relative binding affinities of compounds to specific binding sites in multiple recombinant protein domains in tandem. The N- and C-terminal bromodomains of BRD4 were used as example target proteins. A test set of 264 compounds annotated with activity against the bromodomain and extra-terminal domain (BET) family in ChEMBL were used to benchmark the assay.

View Article and Find Full Text PDF

The screening of covalent or 'reactive' fragment libraries against proteins is becoming an integral approach in hit identification, enabling the development of targeted covalent inhibitors and tools. To date, reactive fragment screening has been limited to targeting cysteine residues, thus restricting applicability across the proteome. Carboxylate residues present a unique opportunity to expand the accessible residues due to high proteome occurrence (∼12%).

View Article and Find Full Text PDF

Sulfur(VI) fluorides (SFs) have emerged as valuable electrophiles for the design of "beyond-cysteine" covalent inhibitors and offer potential for expansion of the liganded proteome. Since SFs target a broad range of nucleophilic amino acids, they deliver an approach for the covalent modification of proteins without requirement for a proximal cysteine residue. Further to this, libraries of reactive fragments present an innovative approach for the discovery of ligands and tools for proteins of interest by leveraging a breadth of mass spectrometry analytical approaches.

View Article and Find Full Text PDF

Purpose/aims: The aim of this study was to investigate the current practice of clinical nurse specialists working in US emergency care settings to (1) explicate the application of the Emergency Nurses Association core competencies and define the specialized clinical nurse specialist role in emergency care and (2) align current clinical nurse specialist practice in emergency settings with the National Association of Clinical Nurse Specialists core competencies and the identified substantive areas of clinical nurse specialist practice.

Design: This study used a quantitative exploratory descriptive approach using survey data.

Methods: A purposive convenience sample was recruited from the Emergency Nurses Association and the National Association of Clinical Nurse Specialists.

View Article and Find Full Text PDF

Background: Building capacity for teamwork, communication, role clarification and recognition of shared values is essential for interprofessional healthcare workforce development. Requirements to demonstrate interprofessional practice competencies have coincided with pivots to online delivery. Comparison of in-person and online delivery models for interprofessional education is important for future curriculum design.

View Article and Find Full Text PDF
Article Synopsis
  • This study explores sulfur(VI) fluorides (S-Fs) as reactive chemical groups that can modify important amino acids like lysine, tyrosine, histidine, and serine in proteins.
  • Different types of S-Fs were tested for their stability and how effectively they react with specific amino acid sidechains.
  • The research shows that S-Fs can be used in living cells to identify new protein targets, demonstrating their potential to enhance our understanding of the proteome.
View Article and Find Full Text PDF

α-ketoglutarate (αKG) is a central metabolic node with a broad influence on cellular physiology. The αKG analogue N-oxalylglycine (NOG) and its membrane-permeable pro-drug derivative dimethyl-oxalylglycine (DMOG) have been extensively used as tools to study prolyl hydroxylases (PHDs) and other αKG-dependent processes. In cell culture media, DMOG is rapidly converted to MOG, which enters cells through monocarboxylate transporter MCT2, leading to intracellular NOG concentrations that are sufficiently high to inhibit glutaminolysis enzymes and cause cytotoxicity.

View Article and Find Full Text PDF

Methods for rapid identification of chemical tools are essential for the validation of emerging targets and to provide medicinal chemistry starting points for the development of new medicines. Here, we report a screening platform that combines 'direct-to-biology' high-throughput chemistry (D2B-HTC) with photoreactive fragments. The platform enabled the rapid synthesis of >1000 PhotoAffinity Bits (HTC-PhABits) in 384-well plates in 24 h and their subsequent screening as crude reaction products with a protein target without purification.

View Article and Find Full Text PDF

Management of traumatic extremity injuries in the emergency department is typically time consuming, often requiring multiple resources including pain control and procedural sedation. A hematoma block is a safe and effective alternative treatment of pain and may eliminate the need for procedural sedation. The hematoma block requires fewer emergency department resources and may decrease time and costs that are associated with procedural sedation and analgesia.

View Article and Find Full Text PDF

Meningitis is a significant viral, bacterial, or fungal infection of the meninges that cover and protect the brain and the spinal cord. Symptoms of meningitis may present rapidly or develop gradually over a period of days, manifesting with common prodromal flu-like symptoms of headache, photophobia, fever, nuchal rigidity, myalgias, and fatigue. Character and significance of symptoms vary by patient age.

View Article and Find Full Text PDF

Advances in genomic analyses enable the identification of new proteins that are associated with disease. To validate these targets, tool molecules are required to demonstrate that a ligand can have a disease-modifying effect. Currently, as tools are reported for only a fraction of the proteome, platforms for ligand discovery are essential to leverage insights from genomic analyses.

View Article and Find Full Text PDF

Angioedema from angiotensin-converting enzyme inhibitors (ACEIs) is a potential, emergent, and frightening problem that presents to the emergency department. This article focuses on angioedema caused by using ACEIs. The presentation, pathology, diagnostic testing, treatment, and patient education of angioedema are explored.

View Article and Find Full Text PDF

Protein ubiquitination plays a key role in the regulation of cellular processes, and misregulation of the ubiquitin system is linked to many diseases. So far, development of tool compounds that target enzymes of the ubiquitin system has been slow and only a few specific inhibitors are available. Here, we report the selection of single-domain antibodies (single-dAbs) based on a human scaffold that recognize the catalytic domain of HOIP, a subunit of the multi-component E3 LUBAC and member of the RBR family of E3 ligases.

View Article and Find Full Text PDF