Mobilization in Neurocritical Care: Challenges and Opportunities.

Purpose Of Review: Mobilization in the Neurological Intensive Care Unit (NICU) significantly improves outcomes and functional recovery while preventing immobility-related complications. The heterogeneity of neurologic conditions necessitates tailored, interdisciplinary mobilization strategies. This article reviews recent research on enhancing the feasibility and effectiveness of mobilization interventions in NICU settings.

A Randomized Clinical Trial of Mindfulness-Based Stress Reduction Program Among Breast Cancer Survivors Post-Treatment: Evaluating Mediators of Cognitive Improvement.

Unlabelled: The Mindfulness-Based Stress Reduction program for breast cancer survivors (MBSR [BCs]) is a stress-reducing program designed to increase cognitive functioning through four meditational practices. This randomized clinical trial aimed to determine if improvements in cognitive functioning and perceived cognitive abilities achieved from the MBSR(BC) were mediated through increased mindfulness, decreased rumination, and decreased perceived stress. Breast cancer survivors (BCSs) who met inclusion criteria of stage I, II, or III BC and received either chemotherapy (CT) or both CT and radiation were randomized to either the 6-week MBSR(BC), or Breast Cancer Education Support (BCES) program, or to a usual care (UC) regimen.

SMAC mimetics induce human macrophages to phagocytose live cancer cells.

Macrophages engulf apoptotic bodies and cellular debris as part of homeostasis, but they can also phagocytose live cells such as aged red blood cells. Pharmacologic reprogramming with the SMAC mimetic LCL161 in combination with T cell-derived cytokines can induce macrophages to phagocytose live cancer cells in mouse models. Here we extend these findings to encompass a wide range of monovalent and bivalent SMAC mimetic compounds, demonstrating that live cell phagocytosis is a class effect of these agents.

A Kinetic Scout Approach Accelerates Targeted Protein Degrader Development.

Bifunctional molecules such as targeted protein degraders induce proximity to promote gain-of-function pharmacology. These powerful approaches have gained broad traction across academia and the pharmaceutical industry, leading to an intensive focus on strategies that can accelerate their identification and optimization. We and others have previously used chemical proteomics to map degradable target space, and these datasets have been used to develop and train multiparameter models to extend degradability predictions across the proteome.

Discovery of CRBN-Dependent WEE1 Molecular Glue Degraders from a Multicomponent Combinatorial Library.

Small molecules promoting protein-protein interactions produce a range of therapeutic outcomes. Molecular glue degraders exemplify this concept due to their compact drug-like structures and ability to engage targets without reliance on existing cognate ligands. While cereblon molecular glue degraders containing glutarimide scaffolds have been approved for treatment of multiple myeloma and acute myeloid leukemia, the design of new therapeutically relevant monovalent degraders remains challenging.

Discovery of electrophilic degraders that exploit SAr chemistry.

Targeted covalent inhibition (TCI) and targeted protein degradation (TPD) have proven effective in pharmacologically addressing formerly 'undruggable' targets. Integration of both methodologies has resulted in the development of electrophilic degraders where recruitment of a suitable E3 ubiquitin ligase is achieved through formation of a covalent bond with a cysteine nucleophile. Expanding the scope of electrophilic degraders requires the development of electrophiles with tempered reactivity that enable selective ligase recruitment and reduce cross-reactivity with other cellular nucleophiles.

Unveiling the hidden interactome of CRBN molecular glues with chemoproteomics.

Targeted protein degradation and induced proximity refer to strategies that leverage the recruitment of proteins to facilitate their modification, regulation or degradation. As prospective design of glues remains challenging, unbiased discovery methods are needed to unveil hidden chemical targets. Here we establish a high throughput affinity purification mass spectrometry workflow in cell lysates for the unbiased identification of molecular glue targets.

The United Nations' General Assembly High-Level Meeting on antimicrobial resistance: a joint statement from the Heads of Government and Chief Medical Officers of the United Kingdom's Overseas Territories.

The UK Overseas Territories (UKOTs) are small, often remote territories with historical and territorial links to the UK. They range from densely populated areas (Cayman, Bermuda, Gibraltar) to land with no permanent inhabitants (British Antarctic Territory, South Georgia). However, they are linked by ecosystem instability (the permacrisis) including antimicrobial resistance (AMR), climate change and biodiversity disruption.

Discovery of Potent Degraders of the Dengue Virus Envelope Protein.

Targeted protein degradation has been widely adopted as a new approach to eliminate both established and previously recalcitrant therapeutic targets. Here, it is reported that the development of small molecule degraders of the envelope (E) protein of dengue virus. Two classes of bivalent E-degraders are developed by linking two previously reported E-binding small molecules, GNF-2, and CVM-2-12-2, to a glutarimide-based recruiter of the CRL4 ligase to effect proteosome-mediated degradation of the E protein.

Protocol of a Multisite Randomized Controlled Trial of Bright IDEAS-Young Adults: Problem-Solving Skills Training to Reduce Distress among Young Adults with Cancer.

Background: Young adults with cancer diagnosed between the ages of 18 to 39 are recognized as a vulnerable group with unique emotional, social, and practical needs that put them at risk of poor psychosocial outcomes and impaired health-related quality of life (HRQOL). This study describes the protocol of a randomized controlled trial to evaluate the efficacy of Bright IDEAS-Young Adults (Bright IDEAS-YA), a problem-solving skills training intervention, on psychosocial outcomes of young adults newly diagnosed with cancer.

Methods: Bright IDEAS-YA is a two-arm, parallel, randomized controlled trial.

Template-assisted covalent modification underlies activity of covalent molecular glues.

Molecular glues are proximity-inducing small molecules that have emerged as an attractive therapeutic approach. However, developing molecular glues remains challenging, requiring innovative mechanistic strategies to stabilize neoprotein interfaces and expedite discovery. Here we unveil a trans-labeling covalent molecular glue mechanism, termed 'template-assisted covalent modification'.

Bone Fragility in High Fat Diet-induced Obesity is Partially Independent of Type 2 Diabetes in Mice.

Obesity and type 2 diabetes (T2D) are risk factors for fragility fractures. It is unknown whether this elevated risk is due to a diet favoring obesity or the diabetes that often occurs with obesity. Therefore, we hypothesized that the fracture resistance of bone is lower in mice fed with a high fat diet (45% kcal; HFD) than in mice that fed on a similar, control diet (10% kcal; LFD), regardless of whether the mice developed overt T2D.

Polymerization of ZBTB transcription factors regulates chromatin occupancy.

BCL6, an oncogenic transcription factor (TF), forms polymers in the presence of a small-molecule molecular glue that stabilizes a complementary interface between homodimers of BCL6's broad-complex, tramtrack, and bric-à-brac (BTB) domain. The BTB domains of other proteins, including a large class of TFs, have similar architectures and symmetries, raising the possibility that additional BTB proteins self-assemble into higher-order structures. Here, we surveyed 189 human BTB proteins with a cellular fluorescent reporter assay and identified 18 ZBTB TFs that show evidence of polymerization.

Discovery of Potent Degraders of the Dengue Virus Envelope Protein.

Targeted protein degradation has been widely adopted as a new approach to eliminate both established and previously recalcitrant therapeutic targets. Here we report the development of small molecule degraders of the envelope (E) protein of dengue virus. We developed two classes of bivalent E-degraders, linking two previously reported E-binding small molecules, GNF-2 and CVM-2-12-2, to a glutarimide-based recruiter of the CRL4 ligase to effect proteosome-mediated degradation of the E protein.

Affective Responses to Acute Exercise: A Meta-Analysis of the Potential Beneficial Effects of a Single Bout of Exercise on General Mood, Anxiety, and Depressive Symptoms.

Objective: Acute exercise elicits various biobehavioral and psychological responses, but results are mixed with regard to the magnitude of exercise-induced affective reactions. This meta-analysis examines the magnitude of general mood state, anxiety, and depressive symptom responses to acute exercise while exploring exercise protocol characteristics and background health behaviors that may play a role in the affective response.

Methods: A total of 2770 articles were identified from a MEDLINE/PubMed search and an additional 133 articles from reviews of reference sections.

Pulmonary Embolism Triage: When to Do What.

Anticoagulation has been the standard therapy for treating pulmonary embolism. However, newly developed pharmacological and interventional treatment options have been shown to provide benefit for certain patient populations, depending on how they present. This column highlights the use of massive pulmonary embolism risk stratification in determining the presence of cor pulmonale and offers several key points to remember when caring for patients with a pulmonary embolism.