Generating and validating renewable affimer protein binding reagents targeting SH2 domains.

Despite SH2 domains, being pivotal in protein interactions linked to various diseases like cancer, we lack specific research tools for intracellular assays. Understanding SH2-mediated interactions and creating effective inhibitors requires tools which target individual protein domains. Affimer reagents exhibit promise, yet their potential against the extensive SH2 domain family remains largely unexplored.

Affimer reagents enable targeted delivery of therapeutic agents and RNA via virus-like particles.

Monoclonal antibodies have revolutionized therapies, but non-immunoglobulin scaffolds are becoming compelling alternatives owing to their adaptability. Their ability to be labeled with imaging or cytotoxic compounds and to create multimeric proteins is an attractive strategy for therapeutics. Focusing on HER2, a frequently overexpressed receptor in breast cancer, this study addresses some limitations of conventional targeting moieties by harnessing the potential of these scaffolds.

Stem cell-derived CAR T cells show greater persistence, trafficking, and viral control compared to ex vivo transduced CAR T cells.

Adoptive cell therapy (ACT) using T cells expressing chimeric antigen receptors (CARs) is an area of intense investigation in the treatment of malignancies and chronic viral infections. One of the limitations of ACT-based CAR therapy is the lack of in vivo persistence and maintenance of optimal cell function. Therefore, alternative strategies that increase the function and maintenance of CAR-expressing T cells are needed.

Prior experience with behavioral control over stress facilitates social dominance.

Dominance status has extensive effects on physical and mental health, and an individual's relative position can be shaped by experiential factors. A variety of considerations suggest that the experience of behavioral control over stressors should produce winning in dominance tests and that winning should blunt the impact of later stressors, as does prior control. To investigate the interplay between competitive success and stressor control, we first examined the impact of stressor controllability on subsequent performance in a warm spot competition test modified for rats.

A Multisite Electronic Health Record Integrated Remote Monitoring Intervention for Hypertension Improvement: Protocol for a Randomized Pragmatic Comparative Effectiveness Trial.

Background: Hypertension is a major contributor to various adverse health outcomes. Although previous studies have shown the benefits of home blood pressure (BP) monitoring over office-based measurements, there is limited evidence comparing the effectiveness of whether a BP monitor integrated into the electronic health record is superior to a nonintegrated BP monitor.

Objective: In this paper, we describe the protocol for a pragmatic multisite implementation of a quality improvement initiative directly comparing integrated to nonintegrated BP monitors for hypertension improvement.

Affimer-mediated locking of p21-activated kinase 5 in an intermediate activation state results in kinase inhibition.

Kinases are important therapeutic targets, and their inhibitors are classified according to their mechanism of action, which range from blocking ATP binding to covalent inhibition. Here, a mechanism of inhibition is highlighted by capturing p21-activated kinase 5 (PAK5) in an intermediate state of activation using an Affimer reagent that binds in the P+1 pocket. PAK5 was identified from a non-hypothesis-driven high-content imaging RNAi screen in urothelial cancer cells.

Prior experience with behavioral control over stress facilitates social dominance.

Dominance status has extensive effects on physical and mental health, and an individual's relative position can be shaped by experiential factors. A variety of considerations suggest that the experience of behavioral control over stressors should produce winning in dominance tests and that winning should blunt the impact of later stressors, as does prior control. To investigate the interplay between competitive success and stressor control, we first examined the impact of stressor controllability on subsequent performance in a warm spot competition test modified for rats.

Identification of Safe and Effective Intravenous Dose of AAVrh.10hFXN to Treat the Cardiac Manifestations of Friedreich's Ataxia.

Friedreich's ataxia (FA) is a life-threatening autosomal recessive disorder characterized by neurological and cardiac dysfunction. Arrhythmias and heart failure are the main cause of premature death. From prior studies in murine models of FA, adeno-associated virus encoding the normal human frataxin gene (AAVrh.

Brain exposure of osimertinib in patients with epidermal growth factor receptor mutation non-small cell lung cancer and brain metastases: A positron emission tomography and magnetic resonance imaging study.

Brain metastases (BMs) are associated with poor prognosis in epidermal growth factor receptor mutation-positive (EGFRm) non-small cell lung cancer (NSCLC). Osimertinib is a third-generation, irreversible, EGFR-tyrosine kinase inhibitor that potently and selectively inhibits EGFR-sensitizing and T790M resistance mutations with efficacy in EGFRm NSCLC including central nervous system (CNS) metastases. The open-label phase I positron emission tomography (PET) and magnetic resonance imaging (MRI) study (ODIN-BM) assessed [ C]osimertinib brain exposure and distribution in patients with EGFRm NSCLC and BMs.

Targeting autophagy to treat HIV immune dysfunction.

Chronic immune activation and inflammation are hallmarks of Human Immunodeficiency Virus-1 (HIV-1) pathogenesis. Therefore, approaches to safely reduce systematic inflammation are essential to improve immune responses and thus slow or prevent HIV progression. Autophagy is a cellular mechanism for the disposal of damaged organelles and elimination of intracellular pathogens.

Content Analysis for a Statewide Substance Use Disorder and Pain Management Curriculum for Health Professional Students (ALAHOPE).

Objectives: Alabama's health professions schools have many common goals when it comes to educating their students about substance use disorder (SUD) and pain, but a statewide consistent SUD and pain management curriculum does not exist in Alabama. The ALAbama Health professionals' Opioid and Pain management Education (ALAHOPE) project set out to create an interprofessional curriculum around SUD and pain management that all Alabama health professions schools can use to promote consistent evidence-based teaching and a patient-centered approach around these two topics. An adapted form of the Kern model of curriculum development was used to guide the project.

A Tet-Inducible CRISPR Platform for High-Fidelity Editing of Human Pluripotent Stem Cells.

Pluripotent stem cells (PSCs) offer an exciting resource for probing human biology; however, gene-editing efficiency remains relatively low in many cell types, including stem cells. Gene-editing using the CRISPR-Cas9 system offers an attractive solution that improves upon previous gene-editing approaches; however, like other technologies, off-target mutagenesis remains a concern. High-fidelity Cas9 variants greatly reduce off-target mutagenesis and offer a solution to this problem.

Influence of High School Socioeconomic Status on Athlete Injuries during the COVID-19 Pandemic: An Ecological Study.

Background: It is presently unclear how the cessation of high school sport has affected injury incidence at different socioeconomic levels. The COVID-19 pandemic may have disproportionately affected athletes of lower socioeconomic status, potentially increasing injury risk in this population.

Purpose: To 1) Describe athlete injury incidence prior to and during the 2019-2020 and 2020-2021 school years in high school athletes by socioeconomic status; 2) Investigate the association between socioeconomic status and injury incidence in high school athletes.

Autophagy inducer rapamycin treatment reduces IFN-I-mediated Inflammation and improves anti-HIV-1 T cell response in vivo.

A hallmark of HIV-1 infection is chronic inflammation, even in patients treated with antiretroviral therapy (ART). Chronic inflammation drives HIV-1 pathogenesis, leading to loss of CD4+ T cells and exhaustion of antiviral immunity. Therefore, strategies to safely reduce systematic inflammation are needed to halt disease progression and restore defective immune responses.

Oral Combinational Antiretroviral Treatment in HIV-1 Infected Humanized Mice.

The human immunodeficiency virus (HIV-1) pandemic continues to spread unabated worldwide, and currently, there is no vaccine available against HIV. Although combinational antiretroviral therapy (cART) has been successful in suppressing viral replication, it cannot completely eradicate the reservoir from HIV-infected individuals. A safe and effective cure strategy for HIV infection will require multipronged methods, and therefore the advancements of animal models for HIV-1 infection are pivotal for the development of HIV cure research.

Cannabidiol modulates expression of type I IFN response genes and HIV infection in macrophages.

Cannabis () is a widely used drug in the United States and the frequency of cannabis use is particularly high among people living with HIV (PLWH). One key component of cannabis, the non-psychotropic (-)-cannabidiol (CBD) exerts a wide variety of biological actions, including anticonvulsive, analgesic, and anti-inflammatory effects. However, the exact mechanism of action through which CBD affects the immune cell signaling remains poorly understood.

[Epilepsy surgery seems underutilized in Sweden].

Epilepsy surgery should be considered for individuals with drug-resistant focal epilepsy. The pre-surgical evaluation is highly multi-disciplinary and performed by a team consisting of neurologists, neurophysiologists, neurosurgeons, neuroradiologists, neuropsychologists, biomedical scientists, speech-language pathologists and nursing staff. The evaluation comprises of a meticulous medical history with focus on seizure semiology, a 3 Tesla MRI, ictal video-EEG, neuropsychological evaluation and sometimes also MEG, nTMS, fMRI, PET or SISCOM/ictal SPECT.

Strategies and Lessons Learned from a Home Delivery Food Prescription Program for Older Adults.

Food insecurity (FI) is a growing health problem, worsening during the COVID-19 pandemic. Fresh food prescription programs (FFRx) have been shown to increase healthy eating and decrease FI, but few FFRx are community-informed, or theory based. Our FFRx was a delivery program developed to alleviate FI for older adults.

11C-methionine PET/MRI in postoperative patients after craniotomy: zero echo time and head atlas versus CT-based attenuation correction.

Background: Attenuation correction (AC) is an important topic in PET/MRI and particularly challenging after brain tumor surgery, near metal implants, adjacent bone and burr holes. In this study, we evaluated the performance of two MR-driven AC methods, zero-echo-time AC (ZTE-AC) and atlas-AC, in comparison to reference standard CT-AC in patients with surgically treated brain tumors at C-methionine PET/MRI.

Methods: This retrospective study investigated seven postoperative patients with neuropathologically confirmed brain tumor at C-methionine PET/MRI.

Impact of a screen, triage and treat program for identifying chronic disease risk in Indigenous children.

Background: The First Nations Community Based Screening to Improve Kidney Health and Prevent Dialysis project was a point-of-care screening program in rural and remote First Nations communities in Manitoba that aimed to identify and treat hypertension, diabetes and chronic kidney disease. The program identified chronic disease in 20% of children screened. We aimed to characterize clinical screening practices before and after intervention in children aged 10-17 years old and compare outcomes with those who did not receive the intervention.

Correction: Robust CAR-T memory formation and function via hematopoietic stem cell delivery.

[This corrects the article DOI: 10.1371/journal.ppat.

Effect of Alteplase Use on Outcomes in Patients With Atrial Fibrillation: Analysis of the Initiation of Anticoagulation After Cardioembolic Stroke Study.

Background Intravenous alteplase improves outcome after acute ischemic stroke without a benefit in 90-day mortality. There are limited data on whether alteplase is associated with reduced mortality in patients with atrial fibrillation (AF)-related ischemic stroke whose mortality rate is relatively high. We sought to determine the association of alteplase with hemorrhagic transformation and mortality in patients with AF.

RAS-inhibiting biologics identify and probe druggable pockets including an SII-α3 allosteric site.

RAS mutations are the most common oncogenic drivers across human cancers, but there remains a paucity of clinically-validated pharmacological inhibitors of RAS, as druggable pockets have proven difficult to identify. Here, we identify two RAS-binding Affimer proteins, K3 and K6, that inhibit nucleotide exchange and downstream signaling pathways with distinct isoform and mutant profiles. Affimer K6 binds in the SI/SII pocket, whilst Affimer K3 is a non-covalent inhibitor of the SII region that reveals a conformer of wild-type RAS with a large, druggable SII/α3 pocket.