Biology subjects

Minguillon, J.

Publications and source records attributed to Minguillon, J..

8 recordsLinked to original sources

bioRxiv2026

Fanconi Anaemia E3 Ligase complex activity is regulated by a druggable metabolite binding site in FANCX

The Fanconi anaemia (FA) DNA repair pathway is an emerging target for precision cancer therapy. Using a high-throughput FANCD2-monoubiquitination assay, we identified a class of small molecules, including MSG010, that inhibit the FA E3 ligase complex in vitro. Because these molecules, and the metabolite, palmitoyl-CoA, are known to engage allosteric drug and metabolite (ADaM) binding site in AMP-activated kinase (AMPK), we hypothesised that a similar pocket exists within the FA complex. Supporting this, long-chain, but not short-chain, fatty acyl-CoA molecules inhibited the FA E3 ligase complex activity, and sequence analysis revealed similarity between the AMPK ADaM site and a WD40 repeat in the FA subunit FANCX. Targeted mutagenesis of this FANCX region disrupted E3 ligase activity or abolished inhibition by MSG010, suggesting the presence of an ADaM-like site in FANCX. Moreover, MSG010 preferentially killed BRCA1-deficient cells in vitro. These findings identify a putative small-molecule binding site in the FA pathway that may be developed further to test for exploitation as anticancer therapeutics.

cancer biology↗

bioRxiv2023

Cardiorespiratory fitness is associated with neuroelectric activity complexity in children with overweight or obesity

Cardiorespiratory fitness is one of the most important markers of health. Several studies have demonstrated the relationship between cardiorespiratory fitness and brain functioning in healthy children. Some of these works suggested that cardiorespiratory fitness may have a protective role on the executive function, which represents a set of cognitive mechanisms used to control and coordinate other cognitive abilities. This is particularly relevant in children with overweight or obesity. In these studies, neuroelectric activity is recorded using medical imaging techniques or electroencephalography (EEG). Among the EEG studies, analyses based on the P3 event related potential stand out. However, complementary analyses are necessary to understand the neural mechanisms underlying the associations between cardiorespiratory fitness and brain functioning. EEG complexity, a useful feature that measures the regularity of neuroelectric activity, has been previously associated with cardiorespiratory fitness in adolescents. In this work, we evaluate this association in a group of 87 Caucasian children with overweight/obesity. Our results reveal that the children with higher cardiorespiratory fitness present less EEG complexity while performing a cognitive task that challenges the executive function. In addition, they suggest that the line length, the metric that we used to estimate EEG complexity, performs equally well as those metrics based on the P3 and better than other complexity metrics like sample entropy, as an indicator of cardiorespiratory fitness. Finally, the line length has advantages over the P3: more consistency across EEG regions and cognitive loads, lower experimental complexity, lower computational cost, and higher automatization capability.

neuroscience↗

bioRxiv2023

First-in-human demonstration of floating EMG sensors and stimulators wirelessly powered and operated by volume conduction

BackgroundRecently we reported the design and evaluation of floating semi-implantable devices that receive power from and bidirectionally communicate with an external system using coupling by volume conduction. The approach, of which the semi-implantable devices are proof-of-concept prototypes, may overcome some limitations presented by existing neuroprostheses, especially those related to implant size and deployment, as the implants avoid bulky components and can be developed as threadlike devices. Here, it is reported the first-in-human acute demonstration of these devices for electromyography (EMG) sensing and electrical stimulation. MethodsA proof-of-concept device, consisting of implantable thin-film electrodes and a non-implantable miniature electronic circuit connected to them, was deployed in the upper or lower limb of six healthy participants. Two external electrodes were strapped around the limb and were connected to the external system which delivered high frequency current bursts. Within these bursts, 13 commands were modulated to communicate with the implant. ResultsFour devices were deployed in the biceps brachii and the gastrocnemius medialis muscles, and the external system was able to power and communicate with them. Limitations regarding insertion and communication speed are reported. Sensing and stimulation parameters were configured from the external system. In one participant, electrical stimulation and EMG acquisition assays were performed, demonstrating the feasibility of the approach to power and communicate with the floating device. ConclusionsThis is the first-in-human demonstration of EMG sensors and electrical stimulators powered and operated by volume conduction. These proof-of-concept devices can be miniaturized using current microelectronic technologies, enabling fully implantable networked neuroprosthetics.

bioengineering↗

bioRxiv2022

Combining Aperiodic 1/f Slopes and Brain Simulation: An EEG/MEG Proxy Marker of Excitation/Inhibition Imbalance in Alzheimer's Disease

Accumulation and interaction of amyloid-beta (A{beta}) and tau proteins during progression of Alzheimers disease (AD) are shown to tilt neuronal circuits away from balanced excitation/inhibition (E/I). Current available techniques for noninvasive interrogation of E/I in the intact human brain, e.g., magnetic resonance spectroscopy (MRS), are highly restrictive (i.e., limited spatial extent), have low temporal and spatial resolution and suffer from the limited ability to distinguish accurately between different neurotransmitters complicating its interpretation. As such, these methods alone offer an incomplete explanation of E/I. Recently, the aperiodic component of neural power spectrum, often referred to in the literature as the 1/f slope, has been described as a promising and scalable biomarker that can track disruptions in E/I potentially underlying a spectrum of clinical conditions, such as autism, schizophrenia, or epilepsy, as well as developmental E/I changes as seen in aging. Using 1/f slopes from resting-state spectral data and computational modelling we developed a new method for inferring E/I alterations in AD. We tested our method on recent freely and publicly available electroencephalography (EEG) and magnetoencephalography (MEG) datasets of patients with AD or prodromal disease and demonstrated the methods potential for uncovering regional patterns of abnormal excitatory and inhibitory parameters. Our results provide a general framework for investigating circuit-level disorders in AD and developing therapeutic interventions that aim to restore the balance between excitation and inhibition.

neuroscience↗

bioRxiv2022

Fanca and p53 genes cooperate to suppress oral SCC in transgenic mice

Fanconi anemia (FA) patients frequently develop oral squamous cell carcinoma (OSCC). This cancer in FA patients is diagnosed within the first 3-4 decades of life, very often preceded by lesions that suffer a malignant transformation. In addition, they respond poorly to current treatments due to toxicity or multiple recurrences. Translational research of new chemopreventive agents and therapeutic strategies has been unsuccessful partly due to scarcity of disease models or failure to fully reproduce the disease. Here we report that Fanca gene knockout mice (Fanca-/-) frequently display pre-malignant lesions in the oral cavity. Moreover, when these animals were crossed with animals having conditional deletion of Trp53 gene in oral mucosa (K14cre;Trp53F2-10/F2-10), they spontaneously developed OSCC with a high penetrance and a median latency of less than ten months. Tumors were well differentiated and expressed markers of squamous differentiation, such as keratins K5 and K10. In conclusion, Fanca and Trp53 genes cooperate to suppress oral cancer in mice, and Fanca-/-;K14cre;Trp53F2-10/F2-10 mice constitute the first animal model of spontaneous OSCC in FA.

cancer biology↗

bioRxiv2022

Wireless networks of injectable microelectronic stimulators based on rectification of volume conducted high frequency currents

ObjectiveTo develop and in vivo demonstrate threadlike wireless implantable neuromuscular microstimulators that are digitally addressable. ApproachThese devices perform, through its two electrodes, electronic rectification of innocuous high frequency current bursts delivered by volume conduction via epidermal textile electrodes. By avoiding the need of large components to obtain electrical energy, this approach allows the development of thin devices that can be intramuscularly implanted by minimally invasive procedures such as injection. For compliance with electrical safety standards, this approach requires a minimum distance, in the order of millimeters or a very few centimeters, between the implant electrodes. Additionally, the devices must cause minimal mechanical damage to tissues, avoid dislocation and be adequate for long-term implantation. Considering these requirements, the implants were conceived as tubular and flexible devices with two electrodes at opposite ends and, at the middle section, a hermetic metallic capsule housing the electronics. Main resultsThe developed implants have a submillimetric diameter (0.97 mm diameter, 35 mm length) and consist of a microcircuit, which contains a single custom-developed integrated circuit, housed within a titanium capsule (0.7 mm diameter, 6.5 mm length), and two platinum-iridium coils that form two electrodes (3 mm length) located at opposite ends of a silicone body. These neuromuscular stimulators are addressable, allowing to establish a network of microstimulators that can be controlled independently. Their operation was demonstrated by injecting a few of them in the hind limb of anesthetized rabbits and inducing controlled and independent contractions. SignificanceThese results show the feasibility of manufacturing threadlike wireless addressable neuromuscular stimulators by using fabrication techniques and materials well established for chronic electronic implants. This paves the way to the clinical development of advanced motor neuroprostheses formed by dense networks of such wireless devices.

bioengineering↗

bioRxiv2022

Floating EMG Sensors and Stimulators Wirelessly Powered and Operated by Volume Conduction for Networked Neuroprosthetics

BackgroundImplantable neuroprostheses consisting of a central electronic unit wired to electrodes benefit thousands of patients worldwide. However, they present limitations that restrict their use. Those limitations, which are more adverse in motor neuroprostheses, mostly arise from their bulkiness and the need to perform complex surgical implantation procedures. Alternatively, it has been proposed the development of distributed networks of intramuscular wireless microsensors and microstimulators that communicate with external systems for analyzing neuromuscular activity and performing stimulation or controlling external devices. This paradigm requires the development of miniaturized implants that can be wirelessly powered and operated by an external system. To accomplish this, we propose a wireless power transfer (WPT) and communications approach based on volume conduction of innocuous high frequency (HF) current bursts. The currents are applied through external textile electrodes and are collected by the wireless devices through two electrodes for powering and bidirectional digital communications. As these devices do not require bulky components for obtaining power, they may have a flexible threadlike conformation, facilitating deep implantation by injection. MethodsWe report the design and evaluation of advanced prototypes based on the above approach. The system consists of an external unit, floating semi-implantable devices for sensing and stimulation, and a bidirectional communications protocol. The devices are intended for their future use in acute human trials to demonstrate the distributed paradigm. The technology is assayed in vitro using an agar phantom, and in vivo in hindlimbs of anesthetized rabbits. ResultsThe semi-implantable devices were able to power and bidirectionally communicate with the external unit. Using 13 commands modulated in innocuous 3 MHz HF current bursts, the external unit configured the sensing and stimulation parameters, and controlled their execution. Raw EMG was successfully acquired by the wireless devices at 1 ksps. ConclusionsThe demonstrated approach overcomes key limitations of existing neuroprostheses, paving the way to the development of distributed flexible threadlike sensors and stimulators. To the best of our knowledge, these devices are the first based on WPT by volume conduction that can work as EMG sensors and as electrical stimulators in a network of wireless devices.

bioengineering↗

bioRxiv2021

Powering electronic implants by high frequency volume conduction: in human validation

Wireless power transfer (WPT) is frequently used as an alternative to batteries to accomplish miniaturization in electronic medical implants (eMIs). However, established WPT methods require bulky parts within the implant or cumbersome external systems, hindering minimally invasive deployments and the development of networks of eMIs. As an alternative, we propose a WPT approach based on volume conduction of high frequency (HF) current bursts. These currents are applied through external textile electrodes and are collected by the eMIs through two electrodes at their opposite ends. This approach avoids bulky components to obtain power, making it possible to develop implants with a flexible threadlike conformation. In here we study in humans if HF (6.78 MHz) current bursts complying with safety standards and applied through two textile electrodes strapped around a limb can provide substantial powers from pairs of implanted electrodes. Time averaged electric powers obtained from needle electrodes (diameter = 0.4 mm, length = 3 mm, separation = 30 mm) inserted into arms and lower legs of five healthy participants were 5.9 {+/-} 0.7 mW and 2.4 {+/-} 0.3 mW respectively. We also report a procedure to characterize the coupling between the external system and the implants using two-port impedance models generated from medical images. The results demonstrate for the first time in humans that innocuous and imperceptible HF current bursts that flow through the tissues by volume conduction can be used to wirelessly power threadlike eMIs, overcoming the limitations of existing WPT methods in terms of minimal invasiveness and usability.

bioengineering↗