Immune Response After Cochlear Implantation

A cochlear implant (CI) is an electronic device that enables hearing recovery in patients with severe to profound hearing loss. Although CIs are a successful treatment for profound hearing impairment, their effectivity may be improved by reducing damages associated with insertion of electrodes in the cochlea, thus preserving residual hearing ability. Inner ear trauma leads to inflammatory reactions altering cochlear homeostasis and reducing post-operative audiological performances and electroacoustic stimulation. Strategies to preserve residual hearing ability led to the development of medicated devices to minimize CI-induced cochlear injury. Dexamethasone-eluting electrodes recently showed positive outcomes. In previous studies by our research group, intratympanic release of dexamethasone for 14 days was able to preserve residual hearing from CI insertion trauma in a Guinea pig model. Long-term effects of dexamethasone-eluting electrodes were therefore evaluated in the same animal model. Seven Guinea pigs were bilaterally implanted with medicated rods and four were implanted with non-eluting ones. Hearing threshold audiograms were acquired prior to implantation and up to 60 days by recording compound action potentials. For each sample, we examined the amount of bone and fibrous connective tissue grown within the scala tympani in the basal turn of the cochlea, the cochleostomy healing, the neuronal density, and the correlation between electrophysiological parameters and histological results. Detection of tumor necrosis factor alpha, interleukin-6, and foreign body giant cells showed that long-term electrode implantation was not associated with an ongoing inflammation. Growth of bone and fibrous connective tissue around rods induced by CI was reduced in the scala tympani by dexamethasone release. For cochleostomy sealing, dexamethasone-treated animals showed less bone tissue growth than negative. Dexamethasone did not affect cell density in the spiral ganglion. Overall, these results support the use of dexamethasone as anti-inflammatory additive for eluting electrodes able to protect the cochlea from CI insertion trauma

Customized bioreactor enables the production of 3D diaphragmatic constructs influencing matrix remodeling and fibroblast overgrowth

The production of skeletal muscle constructs useful for replacing large defects in vivo, such as in congenital diaphragmatic hernia (CDH), is still considered a challenge. The standard application of prosthetic material presents major limitations, such as hernia recurrences in a remarkable number of CDH patients. With this work, we developed a tissue engineering approach based on decellularized diaphragmatic muscle and human cells for the in vitro generation of diaphragmatic-like tissues as a proof-of-concept of a new option for the surgical treatment of large diaphragm defects. A customized bioreactor for diaphragmatic muscle was designed to control mechanical stimulation and promote radial stretching during the construct engineering. In vitro tests demonstrated that both ECM remodeling and fibroblast overgrowth were positively influenced by the bioreactor culture. Mechanically stimulated constructs also increased tissue maturation, with the formation of new oriented and aligned muscle fibers. Moreover, after in vivo orthotopic implantation in a surgical CDH mouse model, mechanically stimulated muscles maintained the presence of human cells within myofibers and hernia recurrence did not occur, suggesting the value of this approach for treating diaphragm defects

Characterization of the nonequilibrium steady state of a heterogeneous nonlinear q-voter model with zealotry

We introduce an heterogeneous nonlinear q-voter model with zealots and two types of susceptible voters, and study its non-equilibrium properties when the population is finite and well mixed. In this two-opinion model, each individual supports one of two parties and is either a zealot or a susceptible voter of type q1 or q2. While here zealots never change their opinion, a qi-susceptible voter (i = 1, 2) consults a group of qi neighbors at each time step, and adopts their opinion if all group members agree. We show that this model violates the detailed balance whenever q1 ≠ q2 and has surprisingly rich properties. Here, we focus on the characterization of the model’s non-equilibrium stationary state (NESS) in terms of its probability distribution and currents in the distinct regimes of low and high density of zealotry. We unveil the NESS properties in each of these phases by computing the opinion distribution and the circulation of probability currents, as well as the two-point correlation functions at unequal times (formally related to a “probability angular momentum”). Our analytical calculations obtained in the realm of a linear Gaussian approximation are compared with numerical results

Copernicus Marine Service ocean state report, issue 4

This is the final version. Available from Taylor & Francis via the DOI in this record. FCT/MCTE

A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease

Label-free, real-time on-chip sensing of living cells via grating-coupled surface plasmon resonance

The application of nanotechnologies to address biomedical questions is a key strategy for innovation in biomedical research. Among others, a key point consists in the availability of nanotechnologies for monitoring cellular processes in a real-time and label-free approach. Here, we focused on a grating-coupled Surface Plasmon Resonance (GC-SPR) sensor exploiting phase interrogation. This sensor can be integrated in a microfluidic chamber that ensures cell viability and avoids cell stress. We report the calibration of the sensor response as a function of cell number and its application to monitor cell adhesion kinetics as well as cell response to an external stimulus. Our results show that GC-SPR sensors can offer a valuable alternative to prism-coupled or imaging SPR devices, amenable for microfluidic implementation

CD73+ extracellular vesicles inhibit angiogenesis through adenosine A2B receptor signalling

Pathological angiogenesis is a hallmark of several conditions including eye diseases, inflammatory diseases, and cancer. Stromal cells play a crucial role in regulating angiogenesis through the release of soluble factors or direct contact with endothelial cells. Here, we analysed the properties of the extracellular vesicles (EVs) released by bone marrow mesenchymal stromal cells (MSCs) and explored the possibility of using them to therapeutically target angiogenesis. We demonstrated that in response to pro-inflammatory cytokines, MSCs produce EVs that are enriched in TIMP-1, CD39 and CD73 and inhibit angiogenesis targeting both extracellular matrix remodelling and endothelial cell migration. We identified a novel anti-angiogenic mechanism based on adenosine production, triggering of A2B adenosine receptors, and induction of NOX2-dependent oxidative stress within endothelial cells. Finally, in pilot experiments, we exploited the anti-angiogenic EVs to inhibit tumour progression in vivo. Our results identify novel pathways involved in the crosstalk between endothelial and stromal cell and suggest new therapeutic strategies to target pathological angiogenesis

Customized bioreactor enables the production of 3D diaphragmatic constructs influencing matrix remodeling and fibroblast overgrowth

The production of skeletal muscle constructs useful for replacing large defects in vivo, such as in congenital diaphragmatic hernia (CDH), is still considered a challenge. The standard application of prosthetic material presents major limitations, such as hernia recurrences in a remarkable number of CDH patients. With this work, we developed a tissue engineering approach based on decellularized diaphragmatic muscle and human cells for the in vitro generation of diaphragmatic-like tissues as a proof-of-concept of a new option for the surgical treatment of large diaphragm defects. A customized bioreactor for diaphragmatic muscle was designed to control mechanical stimulation and promote radial stretching during the construct engineering. In vitro tests demonstrated that both ECM remodeling and fibroblast overgrowth were positively influenced by the bioreactor culture. Mechanically stimulated constructs also increased tissue maturation, with the formation of new oriented and aligned muscle fibers. Moreover, after in vivo orthotopic implantation in a surgical CDH mouse model, mechanically stimulated muscles maintained the presence of human cells within myofibers and hernia recurrence did not occur, suggesting the value of this approach for treating diaphragm defects