Publications

Alzheimer's disease (AD) is a progressive neurodegenerative disease, and it is currently the seventh leading cause of death worldwide. It is characterized by the extracellular aggregation of the amyloid beta-peptide (A beta) into oligomers and fibrils that cause synaptotoxicity and neuronal death. A beta exhibits a dual role in promoting oxidative stress and inflammation. This review aims to unravel the intricate connection between these processes and their contribution to AD progression. The review delves into oxidative stress in AD, focusing on the involvement of metals, mitochondrial dysfunction, and biomolecule oxidation. The distinct yet overlapping concept of nitro-oxidative stress is also discussed, detailing the roles of nitric oxide, mitochondrial perturbations, and their cumulative impact on A beta production and neurotoxicity. Inflammation is examined through astroglia and microglia function, elucidating their response to A beta and their contribution to oxidative stress within the AD brain. The blood-brain barrier and oligodendrocytes are also considered in the context of AD pathophysiology. We also review current diagnostic methodologies and emerging therapeutic strategies aimed at mitigating oxidative stress and inflammation, thereby offering potential treatments for halting or slowing AD progression. This comprehensive synthesis underscores the pivotal role of A beta in bridging oxidative stress and inflammation, advancing our understanding of AD and informing future research and treatment paradigms.

JTD Keywords: A-beta, Alzheimer's disease, Amyloid beta-peptide, Bace, Blood-brain-barrier, Central-nervous-system, Genome-wide association, Mitochondrial dysfunctio, Mouse model, Neurodegeneration, Nitric-oxide, Nitro-oxidative stress, Precursor protein, Reactive oxygen, Receptor-related protein-1

Gap junction channels (GJCs) mediate intercellular communication by connecting two neighbouring cells and enabling direct exchange of ions and small molecules. Cell coupling via connexin-43 (Cx43) GJCs is important in a wide range of cellular processes in health and disease (Churko and Laird, 2013; Liang et al., 2020; Poelzing and Rosenbaum, 2004), yet the structural basis of Cx43 function and regulation has not been determined until now. Here, we describe the structure of a human Cx43 GJC solved by cryo-EM and single particle analysis at 2.26 Å resolution. The pore region of Cx43 GJC features several lipid-like densities per Cx43 monomer, located close to a putative lateral access site at the monomer boundary. We found a previously undescribed conformation on the cytosolic side of the pore, formed by the N-terminal domain and the transmembrane helix 2 of Cx43 and stabilized by a small molecule. Structures of the Cx43 GJC and hemichannels (HCs) in nanodiscs reveal a similar gate arrangement. The features of the Cx43 GJC and HC cryo-EM maps and the channel properties revealed by molecular dynamics simulations suggest that the captured states of Cx43 are consistent with a closed state.© 2023, Qi, Acosta Gutierrez et al.

JTD Keywords: cryo-em, dehydroepiandrosterone dhea, expression, gap junction channel, gene, gja1 mutations, hemichannel, membrane protein, phenotype, protein, structure, system, visualization, Biochemistry, Chemical biology, Connexin-43, Cryo-em, Gap junction channel, Hemichannel, Human, Membrane protein, Molecular biophysics, Oculodentodigital dysplasia, Structural biology, Structure

In clinical practice, when a patient is undergoing mechanical ventilation, it is important to identify the optimal moment for extubation, minimizing the risk of failure. However, this prediction remains a challenge in the clinical process. In this work, we propose a new protocol to study the extubation process, including the electromyographic diaphragm signal (diaEMG) recorded through 5-channels with surface electrodes around the diaphragm muscle. First channel corresponds to the electrode on the right. A total of 40 patients in process of withdrawal of mechanical ventilation, undergoing spontaneous breathing tests (SBT), were studied. According to the outcome of the SBT, the patients were classified into two groups: successful (SG: 19 patients) and failure (FG: 21 patients) groups. Parameters extracted from the envelope of each channel of diaEMG in time and frequency domain were studied. After analyzing all channels, the second presented maximum differences when comparing the two groups of patients, with parameters related to root mean square (p = 0.005), moving average (p = 0.001), and upward slope (p = 0.017). The third channel also presented maximum differences in parameters as the time between maximum peak (p = 0.004), and the skewness (p = 0.027). These results suggest that diaphragm EMG signal could contribute to increase the knowledge of the behaviour of respiratory system in these patients and improve the extubation process.Clinical Relevance - This establishes the characterization of success and failure patients in the extubation process. © 2021 IEEE.

JTD Keywords: classification, recognition, Airway extubation, Artificial ventilation, Clinical practices, Clinical process, Diaphragm, Diaphragm muscle, Diaphragms, Electrodes, Electromyographic, Extubation, Frequency domain analysis, Human, Humans, Maximum differences, Mechanical ventilation, New protocol, Respiration, artificial, Respiratory system, Risk of failure, Spontaneous breathing, Surface electrode, Surface emg signals, Thorax, Ventilation, Ventilator weaning

The ability to control neural activity is essential for research not only in basic neuroscience, as spatiotemporal control of activity is a fundamental experimental tool, but also in clinical neurology for therapeutic brain interventions. Transcranial-magnetic, ultrasound, and alternating/direct current (AC/DC) stimulation are some available means of spatiotemporal controlled neuromodulation. There is also light-mediated control, such as optogenetics, which has revolutionized neuroscience research, yet its clinical translation is hampered by the need for gene manipulation. As a drug-based light-mediated control, the effect of a photoswitchable muscarinic agonist (Phthalimide-Azo-Iper (PAI)) on a brain network is evaluated in this study. First, the conditions to manipulate M2 muscarinic receptors with light in the experimental setup are determined. Next, physiological synchronous emergent cortical activity consisting of slow oscillations-as in slow wave sleep-is transformed into a higher frequency pattern in the cerebral cortex, both in vitro and in vivo, as a consequence of PAI activation with light. These results open the way to study cholinergic neuromodulation and to control spatiotemporal patterns of activity in different brain states, their transitions, and their links to cognition and behavior. The approach can be applied to different organisms and does not require genetic manipulation, which would make it translational to humans.

JTD Keywords: brain states, light-mediated control, muscarinic acetylcholine receptors, neuromodulation, Activation, Alternating/direct currents, Basal forebrain, Brain, Brain states, Clinical research, Clinical translation, Controlled drug delivery, Cortex, Forebrain cholinergic system, Genetic manipulations, Higher frequencies, Hz oscillation, Light‐, Light-mediated control, Mediated control, Muscarinic acetylcholine receptors, Muscarinic agonists, Muscarinic receptor, Neurology, Neuromodulation, Neurons, Noradrenergic modulation, Parvalbumin-positive interneurons, Photopharmacology, Receptor-binding, Slow, Spatiotemporal control, Spatiotemporal patterns

© 2020 Wiley-VCH GmbH In recent years, magnetism has gained an enormous amount of interest among researchers for actuating different sizes and types of bio/soft robots, which can be via an electromagnetic-coil system, or a system of moving permanent magnets. Different actuation strategies are used in robots with magnetic actuation having a number of advantages in possible realization of microscale robots such as bioinspired microrobots, tetherless microrobots, cellular microrobots, or even normal size soft robots such as electromagnetic soft robots and medical robots. This review provides a summary of recent research in magnetically actuated bio/soft robots, discussing fabrication processes and actuation methods together with relevant applications in biomedical area and discusses future prospects of this way of actuation for possible improvements in performance of different types of bio/soft robots.

JTD Keywords: capsule endoscope, controlled propulsion, conventional gastroscopy, digital microfluidics, guided capsule, liquid-metal, magnetic drug delivery, magnetic microrobots, magnetically guided capsule endoscopy, magnetotactic bacteria, nanoscribe ip-dip, navigation system, Gallium-indium egain, Magnetic bioinspired micromanipulation, Magnetic drug delivery, Magnetic microrobots, Magnetically guided capsule endoscopy, Magnetotactic bacteria

Diaphragm neuromechanical coupling (NMC), which reflects the efficiency of conversion of neural activation to transdiaphragmatic pressure (Pdi), is increasingly recognized to be a useful clinical index of diaphragm function and respiratory mechanics in neuromuscular weakness and cardiorespiratory disease. However, the current gold standard assessment of diaphragm NMC requires invasive measurements of Pdi and crural diaphragm electromyography (oesEMGdi), which complicates the measurement of diaphragm NMC in clinical practice. This is the first study to compare invasive measurements of diaphragm NMC (iNMC) using the relationship between Pdi and oesEMGdi, with noninvasive assessment of NMC (nNMC) using surface mechanomyography (sMMGlic) and electromyography (sEMGlic) of lower chest wall inspiratory muscles. Both invasive and noninvasive measurements were recorded in twelve healthy adult subjects during an inspiratory threshold loading protocol. A linear relationship between noninvasive sMMGlic and sEMGlic measurements was found, resulting in little change in nNMC with increasing inspiratory load. By contrast, a curvilinear relationship between invasive Pdi and oesEMGdi measurements was observed, such that there was a progressive increase in iNMC with increasing inspiratory threshold load. Progressive recruitment of lower ribcage muscles, serving to enhance the mechanical advantage of the diaphragm, may explain the more linear relationship between sMMGlic and sEMGlic (both representing lower intercostal plus costal diaphragm activity) than between Pdi and crural oesEMGdi. Noninvasive indices of NMC derived from sEMGlic and sMMGlic may prove to be useful indices of lower chest wall inspiratory muscle NMC, particularly in settings that do not have access to invasive measures of diaphragm function.

JTD Keywords: Cardiovascular system, Diaphragms, Diseases, Electromyography, Medical signal processing, Neurophysiology, Patient monitoring, Pneumodynamics, Inspiratory muscle neuromechanical coupling, Diaphragm neuromechanical coupling, Neural activation, Transdiaphragmatic pressure, Diaphragm function, Respiratory mechanics, Diaphragm NMC, Invasive measurements, Crural diaphragm electromyography, iNMC, Noninvasive assessment, nNMC, Lower chest wall inspiratory muscles, Inspiratory threshold loading protocol, Noninvasive sMMGlic measurements, sEMGlic measurements, oesEMGdi measurements, Inspiratory threshold load, Lower ribcage muscles, Lower intercostal plus costal diaphragm activity, Crural oesEMGdi, Noninvasive indices, sEMGlic sMMGlic, Lower chest wall inspiratory muscle NMC, Surface mechanomyography, Electromyography, Inspiratory threshold loading, Mechanomyography, Neuromechanical coupling, Respiratory muscles

This study evaluates the onset and offset of neural inspiratory time estimated from surface diaphragm electromyographic (EMGdi) recordings. EMGdi and airflow signals were recorded in ten healthy subjects according to two respiratory protocols based on respiratory rate (RR) increments, from 15 to 40 breaths per minute (bpm), and fractional inspiratory time (Ti/Ttot) decrements, from 0.54 to 0.18. The analysis of diaphragm electromyographic (EMGdi) signal amplitude is an alternative approach for the quantification of neural respiratory drive (NRD). The EMGdi amplitude was estimated using the fixed sample entropy computed over a 250 ms moving window of the EMGdi signal (EMGdifse). The neural onset was detected through a dynamic threshold over the EMGdifse using the kernel density estimation method, while neural offset was detected by finding when the EMGdifse had decreased to 70 % of the peak value reached during inspiration. The Bland-Altman analysis between airflow and neural onsets showed a global bias of 46 ms in the RR protocol and 22 ms in the Ti/Ttot protocol. The Bland-Altman analysis between airflow and neural offsets reveals a global bias of 11 ms in the RR protocol and -2 ms in the Ti/Ttot protocol. The relationship between pairs of RR values (Pearson’s correlation coefficient of 0.99, Bland- Altman limits of -2.39 to 2.41 bpm, and mean bias of 0.01 bpm) and between pairs of Ti/Ttot values (Pearson’s correlation coefficient of 0.86, Bland-Altman limits of -0.11 to 0.10, and mean bias of -0.01) showed a good agreement. In conclusion, we propose a method for determining neural onset and neural offset based on non-invasive recordings of the electrical activity of the diaphragm that requires no filtering of cardiac muscle interference.

JTD Keywords: Kernel density estimation (KDE),, Surface diaphragm electromyographic,, (EMGdi) signal,, Inspiratory time,, Neural respiratory drive (NRD),, Neural inspiratory time,, Fixed sample entropy (fSampEn)

The inclusion compound (IC) of cyclodextrin (CD) containing the antitumor drug Methotrexate (MTX) as a guest molecule was obtained to increase the solubility of MTX and decrease its inherent toxic effects in nonspecific cells. The IC was conjugated with gold nanoparticles (AuNPs), obtained by a chemical method, creating a ternary intelligent delivery system for MTX molecules, based on the plasmonic properties of the AuNPs. Irradiation of the ternary system, with a laser wavelength tunable with the corresponding surface plasmon of AuNPs, causes local energy dissipation, producing the controlled release of the guest from CD cavities. Finally, cell viability was evaluated using MTS assays for β-CD/MTX and AuNPs + β-CD/MTX samples, with and without irradiation, against HeLa tumor cells. The irradiated sample of the ternary system AuNPs + β-CD/MTX produced a diminution in cell viability attributed to the photothermal release of MTX.

JTD Keywords: Cyclodextrin, Delivery system, Gold nanoparticles, Inclusion compound, Irradiation, Laser, Methotrexate, Photothermal release

The analysis of the electromyographic signal of the diaphragm muscle (EMGdi) can provide important information in order to evaluate the respiratory muscular function. However, EMGdi signals are usually contaminated by the electrocardiographic (ECG) signal. An adaptive noise cancellation (ANC) based on event-synchronous cancellation can be used to reduce the ECG interference in the recorded EMGdi activity. In this paper, it is proposed an ANC scheme for cancelling the ECG interference in EMGdi signals using only the EMGdi signal (without acquiring the ECG signal). In this case the detection of the QRS complex has been performed directly in the EMGdi signal, and the ANC algorithm must be robust to false or missing QRS detections. Furthermore, an automatic criterion to select the adaptive constant of the LMS algorithm has been proposed (μ). The μ constant is selected automatically so that the canceling signal energy equals the energy of the reference signal (which is an estimation of the ECG interference present in the EMGdi signal). This approach optimizes the tradeoff between cancellation of ECG interference and attenuation of EMG component. A number of weights equivalent of a time window that contains several QRS complexes is selected in order to make the algorithm robust to QRS detection errors.

JTD Keywords: Adaptive Canceller, EMG, Diaphragm muscle

Stroke is a major cause of disability, usually causing hemiplegic damage on the motor abilities of the patient. Stroke rehabilitation seeks restoring normal motion on the affected limb. However, normality’ of movements is usually assessed by clinical and functional tests, without considering how the motor system responds to therapy. We hypothesized that electromyographic (EMG) recordings could provide useful information for evaluating the outcome of rehabilitation from a neuromuscular perspective. Four healthy subjects were asked to perform 14 different functional movements simulating the action of reaching over a table. Each movement was defined according to the starting and target positions that the subject had to connect using linear trajectories. Bipolar recordings of EMG signals were taken from biceps and triceps muscles, and spectral and temporal characteristics were extracted for each movement. Using pattern recognition techniques we found that only two EMG channels were sufficient to accurately determine the spatial characteristics of motor activity: movement direction, length and execution zone. Our results suggest that muscles may fire in a patterned way depending on the specific characteristics of the movement and that EMG signals may codify such detailed information. These findings may be of great value to quantitatively assess post-stroke rehabilitation and to compare the neuromuscular activity of the affected and unaffected limbs, from a physiological perspective. Furthermore, disturbed movements could be characterized in terms of the muscle function to identify, which is the spatial characteristic that fails, e.g. movement direction, and guide personalized rehabilitation to enhance the training of such characteristic.

JTD Keywords: EMG, Movement spatial characteristics, Pattern recognition, Stroke rehabilitation, Upper-limb

In bone tissue engineering, the composition of the ionic extracellular environment (IEE) can determine both cellular fate and a biomaterial's development and performance. Therefore, precise control of the IEE and a perfect understanding of the dynamic changes that it can be subject to due to cellular activity is highly desired. To achieve this, we initially monitored how two standard osteoblast-like cell models that expressed either high or low alkaline phosphatase activity - SAOS-2 and MG63 cells, respectively - affected the extracellular concentrations of calcium and phosphate during long-term cultures. It was observed that cellular influence on the IEE varied greatly between the two models and could be linked to the capacity of cells to deposit calcium in the extracellular matrix. Miniaturized ion-selective electrodes that could allow for real-time monitoring of calcium in a minimally invasive way were then constructed. The electrodes were characterized in standard in vitro cell culture environments, prior to being successfully applied for periods of 24h, to record the dynamics of cell-induced deposition of calcium in the extracellular matrix, while using osteogenic media of either high or low concentrations of phosphate. As a result, this study provides the background and technological means for the non-destructive evaluation of the IEE in vitro and allows for the optimization and development of better models of bone tissue construction.

JTD Keywords: Extracellular ions, Ion-selective electrode, MG63, Mineralization, Osteoblasts, Saos-2, Sensor, Tissue engineering

We report the use of ion-selective field effect transistor devices (ISFETs) with an integrated pseudo-reference electrode for on-line monitoring of bacterial metabolism by monitoring of the pH variation. As a model we tested the ability of Lactobacillus strains to ferment sugars, producing lactic acid, which results in a decrease in pH in the suspension medium. We have tested and compared sugar uptake by L. sakei and a L. curvatus strains. The results obtained show that it is possible to distinguish between both types of Lactobacillus strains through their pattern of ribose uptake. The use of ISFETs represents a non-invasive methodology that can be used to monitor biological activity in a wide variety of systems.

JTD Keywords: Lactobacillus-sakei, Technology, Sensors, System, Growth, Cells, State, Meat