Neurons as Immunomodulators: From Rapid Neural Activity to Prolonged Regulation of Cytokines and Microglia.

Regulation of the brain's neuroimmune system is central to development, normal function, and disease. Neuronal communication to microglia, the primary immune cells of the brain, is well known to involve purinergic signaling mediated via ATP secretion and the cytokine fractalkine. Recent evidence shows that neurons release multiple cytokines beyond fractalkine, yet these are less studied and poorly understood.

Microengineered in vitro CAR T cell screens and assays.

Established and emergent microengineered in vitro systems enable the evaluation of chimeric antigen receptor (CAR) T cell product purity, avidity, and functionality. Here, we describe such systems and how they have been used to optimize CAR T cell products by selecting highly viable cells, eliminating off-target cells, and tailoring avidity to balance efficacy and safety. The future of CAR T cell therapy development and manufacturing is expected to be anchored in a cyclical process that integrates multiple high-throughput and patient-centered techniques for identifying, enriching, and evaluating T cell subtypes.

Elucidation of the Active Agents in a West African Ground Herbal Medicine Formulation That Elicit Antimalarial Activities in In Vitro and In Vivo Models.

Agunmu (ground herbal medicine) is a form of West African traditional medicine consisting of a cocktail of herbs. The goal of this study is to evaluate a formulation of Agunmu made from , , , , and , sold in the open market and commonly used for the treatment of malaria by the locals, for its antimalarial effects and to determine the active principles that may contribute to the antimalarial effect. The ethanolic extract obtained from this formulation (Ag-Iba) was analyzed, using TLC, LC-MS, and Tandem-MS techniques, to determine its phytochemical properties.

IONIC NANOMEDICINE STRATEGY TO DEVELOP EFFECTIVE CHEMO-PTT COMBINATION CANCER THERAPEUTICS.

Herein, a detailed investigation of nanodrugs derived by combining a chemotherapy (chemo) and photothermal therapy (PTT) approaches to enhance chemo drug efficacy is presented. Tamoxifen and its metabolite; N-desmethyltamoxifen are the selected chemo drugs that were electrostatically attached with a PTT agent, NaIR820, via a metathesis approach to develop two different ionic material (IM)-based chemo-PTT drugs. Ionic nanomaterials (INMs) were synthesized using reprecipitation method, and these carrier- free nanoparticles were characterized in detail.

Microbial Metagenomes Across a Complete Phytoplankton Bloom Cycle: High-Resolution Sampling Every 4 Hours Over 22 Days.

In May and June of 2021, marine microbial samples were collected for DNA sequencing in East Sound, WA, USA every 4 hours for 22 days. This high temporal resolution sampling effort captured the last 3 days of a Rhizosolenia sp. bloom, the initiation and complete bloom cycle of Chaetoceros socialis (8 days), and the following bacterial bloom (2 days).

Super Resolved Single-Cell Spatial Metabolomics from Multimodal Mass Spectrometry Imaging guided by Imaging Mass Cytometry.

Mass spectrometry imaging (MSI) is a powerful technique for spatially resolved analysis of metabolites and other biomolecules within biological titissues. However, the inherent low spatial resolution of MSI often limits its ability to provide detailed cellular-level information. To address this limitation, we propose a guided super-resolution (GSR) approach that leverages high-resolution Imaging Mass Cytometry (IMC) images to enhance the spatial resolution of low-resolution MSI data.

Therapeutic Immunomodulation of Tumor-Lymphatic Crosstalk via Intratumoral Immunotherapy.

Intra- and peritumoral lymphatics and tumor-draining lymph nodes play major roles in mediating the adaptive immune response to cancer immunotherapy. Despite this, current paradigms of clinical cancer management seldom seek to therapeutically modulate tumor-lymphatic immune crosstalk. This review explores recent developments that set the stage for how this regulatory axis can be therapeutically manipulated, with a particular emphasis on tumor-localized immunomodulation.

Spatially resolved subcellular protein-protein interactomics in drug-perturbed lung-cancer cultures and tissues.

Protein-protein interactions (PPIs) regulate signalling pathways and cell phenotypes, and the visualization of spatially resolved dynamics of PPIs would thus shed light on the activation and crosstalk of signalling networks. Here we report a method that leverages a sequential proximity ligation assay for the multiplexed profiling of PPIs with up to 47 proteins involved in multisignalling crosstalk pathways. We applied the method, followed by conventional immunofluorescence, to cell cultures and tissues of non-small-cell lung cancers with a mutated epidermal growth-factor receptor to determine the co-localization of PPIs in subcellular volumes and to reconstruct changes in the subcellular distributions of PPIs in response to perturbations by the tyrosine kinase inhibitor osimertinib.

Generation of nanobodies with conformational specificity for tau oligomers that recognize tau aggregates from human Alzheimer's disease samples.

Tauopathies are neurodegenerative diseases that involve tau misfolding and aggregation in the brain. These diseases, including Alzheimer's disease (AD), are some of the least understood and most difficult to treat neurodegenerative disorders. Antibodies and antibody fragments that target tau oligomers, which are especially toxic forms of tau, are promising options for immunotherapies and diagnostic tools for tauopathies.

Microglia morphological response to mesenchymal stromal cell extracellular vesicles demonstrates EV therapeutic potential for modulating neuroinflammation.

Background: Mesenchymal stromal cell derived extracellular vesicles (MSC-EVs) are a promising therapeutic for neuroinflammation. MSC-EVs can interact with microglia, the resident immune cells of the brain, to exert their immunomodulatory effects. In response to inflammatory cues, such as cytokines, microglia undergo phenotypic changes indicative of their function e.

A Novel Liver Cancer-Selective Histone Deacetylase Inhibitor Is Effective against Hepatocellular Carcinoma and Induces Durable Responses with Immunotherapy.

Hepatocellular carcinoma (HCC) progression is facilitated by gene-silencing chromatin histone hypoacetylation due to histone deacetylase (HDAC) activation. However, inhibiting HDACs-an effective treatment for lymphomas-has shown limited success in solid tumors. We report the discovery of a class of HDAC inhibitors (HDACi) that demonstrates exquisite selective cytotoxicity against human HCC cells.

Microbial Metagenomes Across a Complete Phytoplankton Bloom Cycle: High-Resolution Sampling Every 4 Hours Over 22 Days.

In May and June of 2021, marine microbial samples were collected for DNA sequencing in East Sound, WA, USA every 4 hours for 22 days. This high temporal resolution sampling effort captured the last 3 days of a sp. bloom, the initiation and complete bloom cycle of (8 days), and the following bacterial bloom (2 days).

Different leukocyte subsets are targeted by systemic and locoregional administration despite conserved nanomaterial characteristics optimal for lymph node delivery.

Lymph nodes (LNs) house a large proportion of the body's leukocytes. Accordingly, engineered nanomaterials are increasingly developed to direct therapeutics to LNs to enhance their efficacy. Yet while lymphatic delivery of nanomaterials to LNs upon locoregional injection has been extensively evaluated, nanomaterial delivery to LN-localized leukocytes after intravenous administration has not been systematically explored nor benchmarked.

Electronic detection of apoptotic cells on a microchip.

Robust and rapid detection of apoptosis in cells is crucially needed for diagnostics, drug discovery, studying pathogenic mechanisms and tracking patient response to medical interventions and treatments. Traditionally, the methods employed to detect apoptosis rely on complex instrumentation like flow cytometers and fluorescence microscopes, which are both expensive and complex-to-operate except in centralized laboratories with trained labor. In this work, we introduce a microfluidic device that can screen cells in a suspension for apoptosis markers and report the assays results as electronic data.

Forced air oscillations - pneumatic capacitance in microfluidic oscillators produces non-linear responses and emergent behaviors.

Pneumatic control mechanisms have long been integral to microfluidic systems, primarily using solenoid valves, pressurized gases, and vacuums to direct liquid flow. Despite advancements in liquid-driven self-regulated microfluidic circuits, gas-driven systems leveraging fluid compressibility remain underexplored. This study presents a mathematical and experimental investigation of gas-driven microfluidic circuits, focusing on forced-air oscillators.

Lymphatic endothelial cell-targeting lipid nanoparticles delivering VEGFC mRNA improve lymphatic function after injury.

Dysfunction of the lymphatic system following injury, disease, or cancer treatment can lead to lymphedema, a debilitating condition with no cure. Advances in targeted therapy have shown promise for treating diseases where conventional therapies have been ineffective and lymphatic vessels have recently emerged as a new therapeutic target. Lipid nanoparticles (LNPs) have emerged as a promising strategy for tissue specific delivery of nucleic acids.

Spatial immunophenotyping using multiplexed imaging of immune follicles in secondary lymphoid tissues.

Secondary lymphoid organs (SLOs), including tonsils (TS), lymph nodes (LN), and Peyer's Patches, exhibit complementary immune functions. However, little is known about the spatial organization of immune cells and extracellular matrix (ECM) in the SLOs. Traditional imaging is limited to a few markers, confining our understanding of the differences between the SLOs.

Desorption Electrospray Ionization Cyclic Ion Mobility-Mass Spectrometry Imaging for Traumatic Brain Injury Spatial Metabolomics.

Lipidomics focuses on investigating alterations in a wide variety of lipids that harness important information on metabolic processes and disease pathology. However, the vast structural diversity of lipids and the presence of isobaric and isomeric species creates serious challenges in feature identification, particularly in mass spectrometry imaging experiments that lack front-end separations. Ion mobility has emerged as a potential solution to address some of these challenges and is increasingly being utilized as part of mass spectrometry imaging platforms.

Interrogating the Role of Endocytosis Pathway and Organelle Trafficking for Doxorubicin-Based Combination Ionic Nanomedicines.

We have studied the endocytic mechanisms that determine subcellular localization for three carrier-free chemotherapeutic-photothermal (chemo-PTT) combination ionic nanomedicines (INMs) composed of doxorubicin (DOX) and an near-infrared (NIR) dye (ICG, IR820, or IR783). This study aims to understand the cellular basis for previously published enhanced toxicity results of these combination nanomedicines toward MCF-7 breast cancer cells. The active transport mechanism of INMs, unlike free DOX, which is known to employ passive transport, was validated by conducting temperature-dependent cellular uptake of the drug in MCF-7 cells using confocal microscopy.

Microglia Morphological Response to Mesenchymal Stromal Cell Extracellular Vesicles Demonstrates EV Therapeutic Potential for Modulating Neuroinflammation.

Background: Mesenchymal stromal cell derived extracellular vesicles (MSC-EVs) are a promising therapeutic for neuroinflammation. MSC-EVs can interact with microglia, the resident immune cells of the brain, to exert their immunomodulatory effects. In response to inflammatory cues, such as cytokines, microglia undergo phenotypic changes indicative of their function e.