Discovery and Functional Characterization of a Potent, Selective, and Metabolically Stable PROTAC of the Protein Kinases DYRK1A and DYRK1B.

Small-molecule-induced protein degradation has emerged as a promising pharmacological modality for inactivating disease-relevant protein kinases. DYRK1A and DYRK1B are closely related protein kinases that are involved in pathological processes such as neurodegeneration, cancer development, and adaptive immune homeostasis. Herein, we report the development of the first DYRK1 proteolysis targeting chimeras (PROTACs) that combine a new ATP-competitive DYRK1 inhibitor with ligands for the E3 ubiquitin ligase component cereblon (CRBN) to induce ubiquitination and subsequent proteasomal degradation of DYRK1A and DYRK1B.

The NRF2-p97-NRF2 negative feedback loop.

p97 is a ubiquitin-targeted ATP-dependent segregase that regulates proteostasis, in addition to a variety of other cellular functions. Previously, we demonstrated that p97 negatively regulates NRF2 by extracting ubiquitylated NRF2 from the KEAP1-CUL3-RBX1 E3 ubiquitin ligase complex, facilitating proteasomal destruction. In the current study, we identified p97 as an NRF2-target gene that contains a functional ARE, indicating the presence of an NRF2-p97-NRF2 negative feedback loop that maintains redox homeostasis.

Stapled Peptides as Direct Inhibitors of Nrf2-sMAF Transcription Factors.

Nuclear factor erythroid-related 2-factor 2 (Nrf2) is a transcription factor traditionally thought of as a cellular protector. However, in many cancers, Nrf2 is constitutively activated and correlated with therapeutic resistance. Nrf2 heterodimerizes with small musculoaponeurotic fibrosarcoma Maf (sMAF) transcription factors, allowing binding to the antioxidant responsive element (ARE) and induction of transcription of Nrf2 target genes.

Anti-Ferroptotic Effects of Nrf2: Beyond the Antioxidant Response.

The transcription factor Nrf2 was originally identified as a master regulator of redox homeostasis, as it governs the expression of a battery of genes involved in mitigating oxidative and electrophilic stress. However, the central role of Nrf2 in dictating multiple facets of the cellular stress response has defined the Nrf2 pathway as a general mediator of cell survival. Recent studies have indicated that Nrf2 regulates the expression of genes controlling ferroptosis, an ironand lipid peroxidation-dependent form of cell death.

Evaluation of packing single and multiple atoms and molecules in the porous organic cage CC3-.

The absorption of multiple atoms and molecules, including Kr, Xe, CH, CO, CH, HO, and SF, within CC3, a Porous Organic Cage (POC), was calculated and analyzed. The CC3 molecule has one central cavity and four window sites. Most adsorbents were modeled with either one unit in the central cavity, four units in the window sites, or with five units in both sites.

Muscle architecture of vastus medialis obliquus and longus and its functional implications: A three-dimensional investigation.

Vastus medialis (VM) has two partitions, longus (VML), and obliquus (VMO), which have been implicated in knee pathologies. However, muscle architecture of VMO and VML has not been documented volumetrically. The aims of this study were to determine and compare the muscle architecture of VMO and VML in three-dimensional (3D) space, and to elucidate their relative functional capabilities.

Mild cognitive impairment in long-term brain tumor survivors following brain irradiation.

Introduction: There is no accepted classification of cognitive impairment in cancer survivors. We assess the extent of mild cognitive impairment (MCI) syndrome in brain tumor survivors using criteria adapted from the National Institute on Aging and the Alzheimer's Association (NIA-AA).

Methods: We retrospectively reviewed the cognitive data of brain tumor survivors post-radiation therapy (RT) enrolled from 2008 to 2011 in a randomized trial of donepezil versus placebo for cognitive impairment.

Diagnosing and treating severe aplastic anemia.

Severe aplastic anemia is a disorder of stem cell failure, leading to pancytopenia. The condition is characterized by an impairment of the function of hematopoietic stem cells. Patients typically have fatigue, infections, and increased or unusual bleeding.

Saturn Systems.

Several ring systems (Saturn systems) have been studied using DFT methods that include dispersion effects. Comparison with X-ray structures are made with three systems, and the agreement is quite good. Binding enthalpies and binding free energies in dichloromethane and toluene have been computed.

Participatory health research: celebrating smoke-free homes.

For community engagement to be successful, the interests of the community must be taken into account and researchers must become facilitators. Patience is required. Meaningful and sustainable relationships that have been developed over time promote mutual learning and capacity building among the partners (Elders, community members, health care providers, and researchers).

Problem-based learning for inter-professional education: evidence from an inter-professional PBL module on palliative care.

Introduction: The objective of this article was to analyze the theory and pedagogical basis of the use of problem-based learning (PBL) for inter-professional education (IPE) in undergraduate health science education and present evidence from a palliative care iPBL (inter-professional PBL) module that confirms the importance of the two methodologies being used together.

Methods: More than 1000 student surveys collected over 4 years were analyzed for components of usefulness, enjoyment and facilitator effectiveness. A retrospective self-assessment of learning was used for both content knowledge of palliative care and knowledge of the other professions participating in the module.

Effective management of lower respiratory tract infections in childhood.

This article summarises the five most common lower respiratory tract infections seen in acute care, guiding the nurse in assessment and early recognition of signs of deterioration. A discussion on each condition is provided along with guidance on prevention, advice for parents and on managing patients. This article is intended for students or newly qualified children's nurses, however, it can also serve as a refresher for all professionals working with children.

Neuromuscular partitioning in the extensor carpi radialis longus and brevis based on intramuscular nerve distribution patterns: A three-dimensional modeling study.

Differential activation of specific regions within a skeletal muscle has been linked to the presence of neuromuscular compartments. However, few studies have investigated the extra- or intramuscular innervation throughout the muscle volume of extensor carpi radialis longus (ECRL) and brevis (ECRB). The aim of this study was to determine the presence of neuromuscular partitions in ECRL and ECRB based on the extra- and intramuscular innervation using three-dimensional modeling.

Dissecting the accessory soleus muscle: a literature review, cadaveric study, and imaging study.

The accessory soleus muscle (ASM) has been an unusual anatomical variant since its first recordings in Guy's Hospital Reports of the early nineteenth century. Individuals with an ASM may present with symptoms of pain and/or swelling and were often misdiagnosed as soft-tissue tumors such as hemangioma, sarcoma, or lipoma. The aim of our study was threefold: (1) to review the cadaveric and clinical literature to determine the reported prevalence of ASM; (2) to conduct a cadaveric study investigating the prevalence and attachment sites of the ASM; (3) to conduct a retrospective analysis of magnetic resonance imaging (MRI) of patients presenting with ankle symptoms to determine prevalence and attachment sites of the ASM.

Fibre bundle element method of determining physiological cross-sectional area from three-dimensional computer muscle models created from digitised fibre bundle data.

Physiological cross-sectional area (PCSA) is used to compare force-producing capabilities of muscles. A limitation of PCSA is that it cannot be measured directly from a specimen, as there is usually no area within the muscle traversed by all fibres. Traditionally, a formula requiring averaged architectural parameters has been used.

Investigation of the static and dynamic musculotendinous architecture of supraspinatus.

To date, the architecture of supraspinatus (SP) and its relation to joint position has not been investigated. The purpose of this study was to quantify the dynamic architecture of the distinct regions of SP using ultrasound (US). Seventeen subjects (8 M/9 F), mean age 36.

Determining physiological cross-sectional area of extensor carpi radialis longus and brevis as a whole and by regions using 3D computer muscle models created from digitized fiber bundle data.

Architectural parameters and physiological cross-sectional area (PCSA) are important determinants of muscle function. Extensor carpi radialis longus (ECRL) and brevis (ECRB) are used in muscle transfers; however, their regional architectural differences have not been investigated. The aim of this study is to develop computational algorithms to quantify and compare architectural parameters (fiber bundle length, pennation angle, and volume) and PCSA of ECRL and ECRB.

Computational representation of the aponeuroses as NURBS surfaces in 3D musculoskeletal models.

Computational musculoskeletal (MSK) models - 3D graphics-based models that accurately simulate the anatomical architecture and/or the biomechanical behaviour of organ systems consisting of skeletal muscles, tendons, ligaments, cartilage and bones - are valued biomedical tools, with applications ranging from pathological diagnosis to surgical planning. However, current MSK models are often limited by their oversimplifications in anatomical geometries, sometimes lacking discrete representations of connective tissue components entirely, which ultimately affect their accuracy in biomechanical simulation. In particular, the aponeuroses - the flattened fibrous connective sheets connecting muscle fibres to tendons - have never been geometrically modeled.

Cultivating interest in family medicine: family medicine interest group reaches undergraduate medical students.

Problem Addressed: Fewer medical students are choosing careers in family medicine across Canada. One way to cultivate student interest is through creation of family medicine interest groups. Students, residents, community-based family physicians, and academic faculty can all contribute to the success of such groups.