Lipid-siRNA Organization Modulates the Intracellular Dynamics of Lipid Nanoparticles.

Lipid nanoparticles (LNPs) are widely used for delivering therapeutic nucleic acids, yet the relationship between their internal structure and intracellular behavior, particularly before RNA release, remains unclear. Here, we elucidate how lipid-siRNA organization within LNPs can modulate their intracellular delivery dynamics. We use cryo-electron microscopy and photochemical assays to reveal that increased siRNA loading can reduce helper lipids' distribution to the LNP surface, while siRNA consistently localizes near the surface.

The interpretation-use argument- the essential ingredient for high quality assessment design and validation.

There is increasing interest in health professions education (HPE) in applying argument-based validity approaches, such as Kane's, to assessment design. The critical first step in employing Kane's approach is to specify the interpretation-use argument (IUA). However, in the HPE literature, this step is often poorly articulated.

Imaging-Assisted Antisense Oligonucleotide Delivery for Tumor-Targeted Gene Therapy.

Antisense oligonucleotide (ASO) represents a class of practical tools for targeting undruggable oncogenes with several candidates currently undergoing clinical investigation. The advancement of antisense therapeutics necessitates comprehensive approaches for evaluating their efficacy and improving their accuracy. Molecular imaging techniques offer a qualitative and quantitative means to assess therapeutics at the molecular, cellular, and levels, as well as to elucidate biodistribution and pharmacokinetics.

Strong-Coupling Phases of Trions and Excitons in Electron-Hole Bilayers at Commensurate Densities.

We introduce density imbalanced electron-hole bilayers at a commensurate 2:1 density ratio as a platform for realizing novel phases of electrons, excitons, and trions. Through the independently tunable carrier densities and interlayer spacing, competition between kinetic energy, intralayer repulsion, and interlayer attraction yields a rich phase diagram. By a combination of theoretical analysis and numerical calculation, we find a variety of strong-coupling phases in different parameter regions, including quantum crystals of electrons, excitons, and trions.

ZnMo-MOF as anti-CO hydrogen electrocatalyst enhance microbial electrosynthesis for CO/CO conversion.

Microbial electrosynthesis (MES) is an electrically driven technology that can be used for converting CO/CO into chemicals. The unique electronic and substrate properties of CO make it an important research target for MES. However, CO can poison the cathode and increase the overpotential of hydrogen evolution reaction (HER), thus reducing the electron transfer rate via H.

Assessing Trends in Cytokine-CYP Drug Interactions and Relevance to Drug Dosing.

The regulation of drug-metabolizing enzymes and transporters by cytokines has been extensively studied in vitro and in clinic. Cytokine-mediated suppression of cytochrome P450 (CYP) or drug transporters may increase or decrease the systemic clearance of drug substrates that are primarily cleared via these pathways; neutralization of cytokines by therapeutic proteins may thereby alter systemic exposures of such drug substrates. The Food and Drug Administration recommends evaluating such clinical drug interactions during clinical development and has provided labeling recommendations for therapeutic proteins.

Direct structural analysis of a single acyl carrier protein domain in fatty acid synthase from the fungus Saccharomyces cerevisiae.

Acyl carrier protein (ACP) is the work horse of polyketide (PKS) and fatty acid synthases (FAS) and acts as a substrate shuttling domain in these mega enzymes. In fungi, FAS forms a 2.6 MDa symmetric assembly with six identical copies of FAS1 and FAS2 polypeptides.

Human Alzheimer's disease reactive astrocytes exhibit a loss of homeostastic gene expression.

Astrocytes are one of the brain's major cell types and are responsible for maintaining neuronal homeostasis via regulating the extracellular environment, providing metabolic support, and modulating synaptic activity. In neurodegenerative diseases, such as Alzheimer's disease, astrocytes can take on a hypertrophic appearance. These reactive astrocytes are canonically associated with increases in cytoskeletal proteins, such as glial fibrillary acidic protein and vimentin.

Leveraging spatial transcriptomics data to recover cell locations in single-cell RNA-seq with CeLEry.

Single-cell RNA sequencing (scRNA-seq) has revolutionized our understanding of cellular heterogeneity in health and disease. However, the lack of physical relationships among dissociated cells has limited its applications. To address this issue, we present CeLEry (Cell Location recovEry), a supervised deep learning algorithm that leverages gene expression and spatial location relationships learned from spatial transcriptomics to recover the spatial origins of cells in scRNA-seq.

Atomic model for core modifying region of human fatty acid synthase in complex with Denifanstat.

Fatty acid synthase (FASN) catalyzes the de novo synthesis of palmitate, a 16-carbon chain fatty acid that is the primary precursor of lipid metabolism and an important intracellular signaling molecule. FASN is an attractive drug target in diabetes, cancer, fatty liver diseases, and viral infections. Here, we develop an engineered full-length human FASN (hFASN) that enables isolation of the condensing and modifying regions of the protein post-translation.

Convergent Approaches to Delineate the Metabolic Regulation of Tumor Invasion by Hyaluronic Acid Biosynthesis.

Metastasis is the leading cause of breast cancer-related deaths and is often driven by invasion and cancer-stem like cells (CSCs). Both the CSC phenotype and invasion are associated with increased hyaluronic acid (HA) production. How these independent observations are connected, and which role metabolism plays in this process, remains unclear due to the lack of convergent approaches integrating engineered model systems, computational tools, and cancer biology.

An integrated virtual pathology education platform developed using Microsoft Power Apps and Microsoft Teams.

The transition towards digital pathology and an extensive selection of video conferencing platforms have helped provide continuity to education even during the COVID-19 pandemic. Innovative approaches for pathology education, will likely persist beyond the pandemic, as they have powerful didactic potential. While there is a wide selection of software for use as educational tools, an environment to access all resources with ease is clearly lacking.

Fenfluramine provides clinically meaningful reduction in frequency of drop seizures in patients with Lennox-Gastaut syndrome: Interim analysis of an open-label extension study.

Objective: This study was undertaken to evaluate the long-term safety and effectiveness of fenfluramine in patients with Lennox-Gastaut syndrome (LGS).

Methods: Eligible patients with LGS who completed a 14-week phase 3 randomized clinical trial enrolled in an open-label extension (OLE; NCT03355209). All patients were initially started on .

Targeting STAT5 Signaling Overcomes Resistance to IDH Inhibitors in Acute Myeloid Leukemia through Suppression of Stemness.

Unlabelled: Mutant isocitrate dehydrogenase 1 (IDH1) and IDH2 block the differentiation of acute myeloid leukemia (AML) cells through production of R-2-hydroxyglutarate (R-2-HG). IDH inhibitors can induce differentiation of AML cells by lowering R-2-HG but have limited clinical efficacy as single agents. Here, we performed a genome-wide CRISPR knockout screen in an Idh1-mutated hematopoietic progenitor cell line to identify genes that increased the differentiation response to ivosidenib, an IDH1 inhibitor.

SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation.

Viruses evade the innate immune response by suppressing the production or activity of cytokines such as type I interferons (IFNs). Here we report the discovery of a mechanism by which the SARS-CoV-2 virus coopts an intrinsic cellular machinery to suppress the production of the key immunostimulatory cytokine IFN-β. We reveal that the SARS-CoV-2 encoded nonstructural protein 2 (NSP2) directly interacts with the cellular GIGYF2 protein.

Astrocytic junctional adhesion molecule-A regulates T-cell entry past the glia limitans to promote central nervous system autoimmune attack.

Contact-mediated interactions between the astrocytic endfeet and infiltrating immune cells within the perivascular space are underexplored, yet represent potential regulatory check-points against CNS autoimmune disease and disability. Reactive astrocytes upregulate junctional adhesion molecule-A, an immunoglobulin-like cell surface receptor that binds to T cells via its ligand, the integrin, lymphocyte function-associated antigen-1. Here, we tested the role of astrocytic junctional adhesion molecule-A in regulating CNS autoinflammatory disease.

Assessment of Natural Language Processing Methods for Ascertaining the Expanded Disability Status Scale Score From the Electronic Health Records of Patients With Multiple Sclerosis: Algorithm Development and Validation Study.

Background: The Expanded Disability Status Scale (EDSS) score is a widely used measure to monitor disability progression in people with multiple sclerosis (MS). However, extracting and deriving the EDSS score from unstructured electronic health records can be time-consuming.

Objective: We aimed to compare rule-based and deep learning natural language processing algorithms for detecting and predicting the total EDSS score and EDSS functional system subscores from the electronic health records of patients with MS.

Fenfluramine significantly reduces day-to-day seizure burden by increasing number of seizure-free days and time between seizures in patients with Dravet syndrome: A time-to-event analysis.

Objective: The number, unpredictability, and severity of seizures experienced by patients with Dravet syndrome (DS) negatively impact quality of life (QOL) for patients, caregivers, and families. Metrics are needed to assess whether patients with residual seizures have moved meaningfully toward seizure freedom after treatment with new antiseizure medications.

Methods: We evaluated the time required postrandomization for each patient to experience the same number of seizures experienced during baseline (i.

Using machine learning to predict severe hypoglycaemia in hospital.

Aim: To predict the risk of hypoglycaemia using machine-learning techniques in hospitalized patients.

Methods: We conducted a retrospective cohort study of patients hospitalized under general internal medicine (GIM) and cardiovascular surgery (CV) at a tertiary care teaching hospital in Toronto, Ontario. Three models were generated using supervised machine learning: least absolute shrinkage and selection operator (LASSO) logistic regression; gradient-boosted trees; and a recurrent neural network.

Structural Characterization of Endogenous Tuberous Sclerosis Protein Complex Revealed Potential Polymeric Assembly.

Tuberous sclerosis protein complex (pTSC) nucleates a proteinaceous signaling hub that integrates information about the internal and external energy status of the cell in the regulation of growth and energy consumption. Biochemical and cryo-electron microscopy studies of recombinant pTSC have revealed its structure and stoichiometry and hinted at the possibility that the complex may form large oligomers. Here, we have partially purified endogenous pTSC from fasted mammalian brains of rat and pig by leveraging a recombinant antigen binding fragment (F) specific for the TSC2 subunit of pTSC.

Curriculum Innovation in Times of the COVID-19 Pandemic: The Thinking-Based Instruction Theory and Its Application.

At the beginning of 2020, to stop the spread of the coronavirus disease (COVID-19) to the campus, the Ministry of Education of China launched a policy "Suspension of classes without suspending schooling" for the spring semester of 2020. However, the drawbacks of online teaching (e.g.

Variation in Antithrombotic Therapy and Clinical Outcomes in Patients With Preexisting Atrial Fibrillation Undergoing Transcatheter Aortic Valve Replacement: Insights From the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry.

Background: Optimal antithrombotic management of patients with preexisting atrial fibrillation undergoing transcatheter aortic valve replacement is challenging given the need to balance the risk of bleeding and thromboembolism. We aimed to examine variation in care and association of antithrombotic therapies with 1-year outcomes of stroke, bleeding, and mortality in patients undergoing transcatheter aortic valve replacement with concomitant atrial fibrillation in the United States.

Methods: Patients who underwent transcatheter aortic valve replacement with preexisting atrial fibrillation from November 2011 through September 2015 in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy registry linked to the Medicare database were examined according to receipt of oral anticoagulants (OACs) or antiplatelet therapies (APTs) or a combination of these (OAC+APT) at discharge.