A Focused Review of Neural Recording and Stimulation Techniques With Immune-Modulatory Targets

The complex interactions established between the nervous and immune systems have been investigated for a long time. With the advent of small and portable devices to record and stimulate nerve activity, researchers from many fields began to be interested in how nervous activity can elicit immune responses and whether this activity can be manipulated to trigger specific immune responses. Pioneering works demonstrated the existence of a cholinergic inflammatory reflex, capable of controlling the systemic inflammatory response through a vagus nerve-mediated modulation of the spleen. This work inspired many different areas of technological and conceptual advancement, which are here reviewed to provide a concise reference for the main works expanding the knowledge on vagus nerve immune-modulatory capabilities. In these works the enabling technologies of peripheral nervous activity recordings were implemented and embody the current efforts aimed at controlling neural activity with modulating functions in immune response, both in experimental and clinical contexts.

Modulating Functions Based Fast and Robust Estimation for a Class of Fractional Order Vibration Systems

This paper aims to fast and robustly estimate the fractional integrals and derivatives of positions from noisy accelerations for a class of fractional order vibration systems defined by the Caputo fractional derivative. The main idea is to convert the original issue into the estimation of the fractional integrals of accelerations and the ones of the unknown initial conditions, on the basis of the additive index law. Being proper integrals, the fractional integrals of accelerations can be estimated via a numerical method. Consequently, solving the original problem boils down to estimating the unknown initial values. To this end, the modulating functions method is adopted. By constructing appropriate modulating functions, the unknown initial values are exactly given in terms of algebraic integral formulas in different situations. Finally, two illustrations are presented to verify the correctness and robustness of the proposed estimators.

Allosteric Receptor Modulation uncovers an FFAR2 antagonist as a positive orthosteric modulator/agonist in disguise

Two earlier described Free Fatty Acid Receptor 2 (FFAR2)-specific antagonists (CATPB and GLPG0974) have different receptor-interaction characteristics at the molecular/functional level. The inhibitory effect of the two antagonists, on the novel receptor-cross-talk activation signals generated by the ATP-receptor, show that both antagonists inhibit the effect of the positive allosteric FFAR2 modulators (PAMs) AZ1729 and Cmp58. No neutrophil activation was induced by AZ1729 or Cmp58 alone, but together they were co-agonistic PAMs and activated the superoxide generating NADPH-oxidase in neutrophils. This response was inhibited by CATPB but not by GLPG0974; in contrast, GLPG0974 acted as a positive modulator that increased the potency but not the efficacy of the response. At the signaling level, GLPG0974 changed the biased signaling induced by the co-agonistic PAMs, to include a rise in the cytosolic concentration of free calcium ions (Ca2+). This effect was reciprocal, i.e., GLPG0974 triggers a rise in intracellular Ca2+, demonstrating that GLPG0974 may act as an FFAR2 agonist. In summary, by studying the effects of the FFAR2 ligand GLPG0974 on neutrophils activation induced by the co-agonists AZ1729 and Cmp58, we reveal that GLPG0974 in addition to be an antagonist, displays also agonistic and positive FFAR2 modulating functions that affects the NADPH-oxidase activity and the receptor down-stream signaling induced by the two co-agonistic PAMs.

Focus on Osteosclerotic Progression in Primary Myelofibrosis

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by hematopoietic stem-cell-derived clonal proliferation, leading to bone marrow (BM) fibrosis. Hematopoiesis alterations are closely associated with modifications of the BM microenvironment, characterized by defective interactions between vascular and endosteal niches. As such, neoangiogenesis, megakaryocytes hyperplasia and extensive bone marrow fibrosis, followed by osteosclerosis and bone damage, are the most relevant consequences of PMF. Moreover, bone tissue deposition, together with progressive fibrosis, represents crucial mechanisms of disabilities in patients. Although the underlying mechanisms of bone damage observed in PMF are still unclear, the involvement of cytokines, growth factors and bone marrow microenvironment resident cells have been linked to disease progression. Herein, we focused on the role of megakaryocytes and their alterations, associated with cytokines and chemokines release, in modulating functions of most of the bone marrow cell populations and in creating a complex network where impaired signaling strongly contributes to progression and disabilities.

Exosomal MiRNA Transfer between Retinal Microglia and RPE

The retinal pigment epithelium (RPE), the outermost layer of the retina, provides essential support to both the neural retina and choroid. Additionally, the RPE is highly active in modulating functions of immune cells such as microglia, which migrate to the subretinal compartment during aging and age-related degeneration. Recently, studies have highlighted the important roles of microRNA (miRNA) in the coordination of general tissue maintenance as well as in chronic inflammatory conditions. In this study, we analyzed the miRNA profiles in extracellular vesicles (EVs) released by the RPE, and identified and validated miRNA species whose expression levels showed age-dependent changes in the EVs. Using co-culture of RPE and retinal microglia, we further demonstrated that miR-21 was transferred between the two types of cells, and the increased miR-21 in microglia influenced the expression of genes downstream of the p53 pathway. These findings suggest that exosome-mediated miRNA transfer is a signaling mechanism that contributes to the regulation of microglia function in the aging retina.