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).

Validation of Saliva as the Clinical Specimen Type for a University-Wide COVID-19 Surveillance Program.

At the beginning of the COVID-19 pandemic, the Georgia Institute of Technology made the decision to keep the university doors open for on-campus attendance. To manage COVID-19 infection rates, internal resources were applied to develop and implement a mass asymptomatic surveillance program. The objective was to identify infections early for proper follow-on verification testing, contact tracing, and quarantine/isolation as needed.

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.

Harnessing cellular therapeutics for type 1 diabetes mellitus: progress, challenges, and the road ahead.

Type 1 diabetes mellitus (T1DM) is a growing global health concern that affects approximately 8.5 million individuals worldwide. T1DM is characterized by an autoimmune destruction of pancreatic β cells, leading to a disruption in glucose homeostasis.

Discovery and Folding Dynamics of a Fused Bicyclic Cysteine Knot Undecapeptide from the Marine Sponge .

We describe the discovery and structure of an undecapeptide natural product from a marine sponge, termed halichondamide A, that is morphed into a fused bicyclic ring topology via two disulfide bonds. Molecular dynamics simulations allow us to posit that the installation of one disulfide bond biases the intermediate peptide conformation and predisposes the formation of the second disulfide bond. The natural product was found to be mildly cytotoxic against liver and breast cancer cell lines.

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.

Mini-colons predict drug toxicity in vitro.

Mitrofanova et al. engineer a human colonic in vitro model capable of producing an intestinal mucus barrier, with potential applications for predicting drug-induced gastrointestinal toxicity. This improved system paves the way for more accurate and efficient drug development processes.

Selective removal of copper from complex biological media with an agarose-immobilized high-affinity PSP ligand.

The elucidation of metal-dependent biological processes requires selective reagents for manipulating metal ion levels within biological solutions such as growth media or cell lysates. To this end, we immobilized a phosphine sulfide-stabilized phosphine (PSP) ligand on agarose to create a resin for the selective removal of copper from chemically complex biological media through simple filtration or centrifugation. Comprised of a conformationally preorganized phenylene-bridged backbone, the PSP-ligand binds Cu(I) with a 1:1 stoichiometry and exhibits a pH-independent Cu(I) dissociation constant in the low zeptomolar range.

The evolution and ongoing challenge of unproven cell-based interventions.

Unproven cell-based interventions (CBIs) emerged early in the 2000s as a particularly problematic form of unproven therapy and remain a vexing policy problem to this day. These unproven interventions can harm patients both physically and financially and can complicate the process of developing a rigorous evidence base to support the translation of novel stem cell or other cell therapies. In this concise review, we examine the emergence of unproven CBIs and the various policy approaches that have been pursued or proposed to address this problem.

Fluorescence-Based Proteoliposome Methods to Monitor Redox-Active Transition Metal Transmembrane Translocation by Metal Transporters.

Transmembrane transition metal transporter proteins are central gatekeepers in selectively controlling vectorial metal cargo uptake and extrusion across cellular membranes in all living organisms, thus playing key roles in essential and toxic metal homeostasis. Biochemical characterization of transporter-mediated translocation events and transport kinetics of redox-active metals, such as iron and copper, is challenged by the complexity in generating reconstituted systems in which vectorial metal transport can be studied in real time. We present fluorescence-based proteoliposome methods to monitor redox-active metal transmembrane translocation upon reconstitution of purified metal transporters in artificial lipid bilayers.

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.

Proximity Labeling Proteomics Reveals Kv1.3 Potassium Channel Immune Interactors in Microglia.

Microglia are resident immune cells of the brain and regulate its inflammatory state. In neurodegenerative diseases, microglia transition from a homeostatic state to a state referred to as disease-associated microglia (DAM). DAM express higher levels of proinflammatory signaling molecules, like STAT1 and TLR2, and show transitions in mitochondrial activity toward a more glycolytic response.

Comparing the lower limb joint biomechanics of the Power Knee, C-Leg and Rheo Knee during ramp and stair ambulation.

One of the most significant developments in prosthetic knee technology has been the introduction of the Microprocessor-Controlled Prosthetic Knee (MPK). However, there is a lack of consensus over how different types of MPKs affect performance in different ambulation modes. In this study, we investigated the biomechanical differences in ramp and stair maneuvers when an individual with transfemoral amputation wears three commercial MPKs: the Össur Power Knee, the Össur Rheo Knee and the Ottobock C-Leg 4.

Reconstitution of human tissue barrier function for precision and personalized medicine.

Tissue barriers in a body, well known as tissue-to-tissue interfaces represented by endothelium of the blood vessels or epithelium of organs, are essential for maintaining physiological homeostasis by regulating molecular and cellular transports. It is crucial for predicting drug response to understand physiology of tissue barriers through which drugs are absorbed, distributed, metabolized and excreted. Since the FDA Modernization Act 2.

Spatial lipidomics maps brain alterations associated with mild traumatic brain injury.

Traumatic brain injury (TBI) is a global public health problem with 50-60 million incidents per year, most of which are considered mild (mTBI) and many of these repetitive (rmTBI). Despite their massive implications, the pathologies of mTBI and rmTBI are not fully understood, with a paucity of information on brain lipid dysregulation following mild injury event(s). To gain more insight on mTBI and rmTBI pathology, a non-targeted spatial lipidomics workflow utilizing high resolution mass spectrometry imaging was developed to map brain region-specific lipid alterations in rats following injury.

Profiling the neuroimmune cascade in 3xTg-AD mice exposed to successive mild traumatic brain injuries.

Repetitive mild traumatic brain injuries (rmTBI) sustained within a window of vulnerability can result in long term cognitive deficits, depression, and eventual neurodegeneration associated with tau pathology, amyloid beta (Aβ) plaques, gliosis, and neuronal and functional loss. However, a comprehensive study relating acute changes in immune signaling and glial reactivity to neuronal changes and pathological markers after single and repetitive mTBIs is currently lacking. In the current study, we addressed the question of how repeated injuries affect the brain neuroimmune response in the acute phase of injury (< 24 h) by exposing the 3xTg-AD mouse model of tau and Aβ pathology to successive (1x-5x) once-daily weight drop closed-head injuries and quantifying immune markers, pathological markers, and transcriptional profiles at 30 min, 4 h, and 24 h after each injury.