Mitochondrial bioenergetics boost macrophage activation, promoting liver regeneration in metabolically compromised animals.

BACKGROUND AND AIMS: Hepatic ischemia-reperfusion injury (IRI) is the leading cause of early posttransplantation organ failure as mitochondrial respiration and ATP production are affected. A shortage of donors has extended liver donor criteria, including aged or steatotic livers, which are more susceptible to IRI. Given the lack of an effective treatment and the extensive transplantation waitlist, we aimed at characterizing the effects of an accelerated mitochondrial activity by silencing methylation-controlled J protein (MCJ) in three preclinical models of IRI and liver regeneration, focusing on metabolically compromised animal models. APPROACH AND RESULTS: Wild-type (WT), MCJ knockout (KO), and Mcj silenced WT mice were subjected to 70% partial hepatectomy (Phx), prolonged IRI, and 70% Phx with IRI. Old and young mice with metabolic syndrome were also subjected to these procedures. Expression of MCJ, an endogenous negative regulator of mitochondrial respiration, increases in preclinical models of Phx with or without vascular occlusion and in donor livers. Mice lacking MCJ initiate liver regeneration 12 h faster than WT and show reduced ischemic injury and increased survival. MCJ knockdown enables a mitochondrial adaptation that restores the bioenergetic supply for enhanced regeneration and prevents cell death after IRI. Mechanistically, increased ATP secretion facilitates the early activation of Kupffer cells and production of TNF, IL-6, and heparin-binding EGF, accelerating the priming phase and the progression through G1 /S transition during liver regeneration. Therapeutic silencing of MCJ in 15-month-old mice and in mice fed a high-fat/high-fructose diet for 12 weeks improves mitochondrial respiration, reduces steatosis, and overcomes regenerative limitations. CONCLUSIONS: Boosting mitochondrial activity by silencing MCJ could pave the way for a protective approach after major liver resection or IRI, especially in metabolically compromised, IRI-susceptible organs.

Medical Devices with Embedded Sensor Systems: Design and Development Methodology for Start-Ups.

Embedded systems have become a key technology for the evolution of medical devices. However, the regulatory requirements that must be met make designing and developing these devices challenging. As a result, many start-ups attempting to develop medical devices fail. Therefore, this article presents a methodology to design and develop embedded medical devices while minimising the economic investment during the technical risk stages and encouraging customer feedback. The proposed methodology is based on the execution of three stages: Development Feasibility, Incremental and Iterative Prototyping, and Medical Product Consolidation. All this is completed in compliance with the applicable regulations. The methodology mentioned above is validated through practical use cases in which the development of a wearable device for monitoring vital signs is the most relevant. The presented use cases sustain the proposed methodology, for the devices were successfully CE marked. Moreover, ISO 13485 certification is obtained by following the proposed procedures.

Next-Generation Pedal: Integration of Sensors in a Braking Pedal for a Full Brake-by-Wire System.

This article presents a novel approach to designing and validating a fully electronic braking pedal, addressing the growing integration of electronics in vehicles. With the imminent rise of brake-by-wire (BBW) technology, the brake pedal requires electronification to keep pace with industry advancements. This research explores technologies and features for the next-generation pedal, including low-power consumption electronics, cost-effective sensors, active adjustable pedals, and a retractable pedal for autonomous vehicles. Furthermore, this research brings the benefits of the water injection technique (WIT) as the base for manufacturing plastic pedal brakes towards reducing cost and weight while enhancing torsional stiffness. Communication with original equipment manufacturers (OEMs) has provided valuable insights and feedback, facilitating a productive exchange of ideas. The findings include two sensor prototypes utilizing inductive technology and printed-ink gauges. Significantly, reduced power consumption was achieved in a Hall-effect sensor already in production. Additionally, a functional BBW prototype was developed and validated. This research presents an innovative approach to pedal design that aligns with current electrification trends and autonomous vehicles. It positions the braking pedal as an advanced component that has the potential to redefine industry standards. In summary, this research significantly contributes to the electronic braking pedal technology presenting the critical industry needs that have driven technical studies and progress in the field of sensors, electronics, and materials, highlighting the challenges that component manufacturers will inevitably face in the forthcoming years.

Embedded Sensor Systems in Medical Devices: Requisites and Challenges Ahead.

The evolution of technology enables the design of smarter medical devices. Embedded Sensor Systems play an important role, both in monitoring and diagnostic devices for healthcare. The design and development of Embedded Sensor Systems for medical devices are subjected to standards and regulations that will depend on the intended use of the device as well as the used technology. This article summarizes the challenges to be faced when designing Embedded Sensor Systems for the medical sector. With this aim, it presents the innovation context of the sector, the stages of new medical device development, the technological components that make up an Embedded Sensor System and the regulatory framework that applies to it. Finally, this article highlights the need to define new medical product design and development methodologies that help companies to successfully introduce new technologies in medical devices.

A Method for Dynamically Selecting the Best Frequency Hopping Technique in Industrial Wireless Sensor Network Applications.

Industrial wireless applications often share the communication channel with other wireless technologies and communication protocols. This coexistence produces interferences and transmission errors which require appropriate mechanisms to manage retransmissions. Nevertheless, these mechanisms increase the network latency and overhead due to the retransmissions. Thus, the loss of data packets and the measures to handle them produce an undesirable drop in the QoS and hinder the overall robustness and energy efficiency of the network. Interference avoidance mechanisms, such as frequency hopping techniques, reduce the need for retransmissions due to interferences but they are often tailored to specific scenarios and are not easily adapted to other use cases. On the other hand, the total absence of interference avoidance mechanisms introduces a security risk because the communication channel may be intentionally attacked and interfered with to hinder or totally block it. In this paper we propose a method for supporting the design of communication solutions under dynamic channel interference conditions and we implement dynamic management policies for frequency hopping technique and channel selection at runtime. The method considers several standard frequency hopping techniques and quality metrics, and the quality and status of the available frequency channels to propose the best combined solution to minimize the side effects of interferences. A simulation tool has been developed and used in this work to validate the method.

Low Cost Photonic Sensor for in-Line Oil Quality Monitoring: Methodological Development Process towards Uncertainty Mitigation.

Lubricant and hydraulic fluid ageing impacts the performance of the machines, gears, transmissions or automatisms where they are being used. This manuscript describes the work accomplished for bringing an innovative measurement concept for analysing the physical- chemical properties of these fluids, to a real industrial product ready to be integrated into different industrial equipment. The steps taken to deal with uncertainties and evolving requirements while progressing in the sensor development are described, covering the stages of theoretical formulation of the problem, optical and fluidic simulations, sensor prototype development and tests. The sensor working principle is based on a combination of transmittance and diffuse reflectance photonic inspection of the fluid sample that is collected in a microcavity through a standard hydraulic fitting. Photonics, electronics, micro-mechanics, fluidics, data processing and analysis has been merged with a deep knowledge in the lubricant degradation process to develop a sensor solution that is able to measure the Oil Degradation Index, Oil Oxidation, Acid Number, Ruler and Membrane Patch Colorimetry data from an inservice lubricating oil sample. The photonic micro sensor presented here offers a powerful tool that operates directly immersed in the fluid, at an economic cost and compacted size for inline oil degradation monitoring.

Photonic Low Cost Micro-Sensor for in-Line Wear Particle Detection in Flowing Lube Oils.

The presence of microscopic particles in suspension in industrial fluids is often an early warning of latent or imminent failures in the equipment or processes where they are being used. This manuscript describes work undertaken to integrate different photonic principles with a micro- mechanical fluidic structure and an embedded processor to develop a fully autonomous wear debris sensor for in-line monitoring of industrial fluids. Lens-less microscopy, stroboscopic illumination, a CMOS imager and embedded machine vision technologies have been merged to develop a sensor solution that is able to detect and quantify the number and size of micrometric particles suspended in a continuous flow of a fluid. A laboratory test-bench has been arranged for setting up the configuration of the optical components targeting a static oil sample and then a sensor prototype has been developed for migrating the measurement principles to real conditions in terms of operating pressure and flow rate of the oil. Imaging performance is quantified using micro calibrated samples, as well as by measuring real used lubricated oils. Sampling a large fluid volume with a decent 2D spatial resolution, this photonic micro sensor offers a powerful tool at very low cost and compacted size for in-line wear debris monitoring.

Anti-miR-873-5p improves alcohol-related liver disease by enhancing hepatic deacetylation via SIRT1.

Background & Aims: Current therapies for the treatment of alcohol-related liver disease (ALD) have proven largely ineffective. Patients relapse and the disease progresses even after liver transplantation. Altered epigenetic mechanisms are characteristic of alcohol metabolism given excessive acetate and NAD depletion and play an important role in liver injury. In this regard, novel therapeutic approaches based on epigenetic modulators are increasingly proposed. MicroRNAs, epigenetic modulators acting at the post-transcriptional level, appear to be promising new targets for the treatment of ALD. Methods: MiR-873-5p levels were measured in 23 liver tissue from Patients with ALD, and GNMT levels during ALD were confirmed using expression databases (transcriptome n = 62, proteome n = 68). High-resolution proteomics and metabolomics in mice following the Gao-binge model were used to investigate miR-873-5p expression in ALD. Hepatocytes exposed to 50 mM alcohol for 12 h were used to study toxicity. The effect of anti-miR-873-5p in the treatment outcomes of ALD was investigated. Results: The analysis of human and preclinical ALD samples revealed increased expression of miR-873-5p in the liver. Interestingly, there was an inverse correlation with NNMT, suggesting a novel mechanism for NAD depletion and aberrant acetylation during ALD progression. High-resolution proteomics and metabolomics identified miR-873-5p as a key regulator of NAD metabolism and SIRT1 deacetylase activity. Anti-miR-873-5p reduced NNMT activity, fuelled the NAD salvage pathway, restored the acetylome, and modulated the levels of NF-κB and FXR, two known SIRT1 substrates, thereby protecting the liver from apoptotic and inflammatory processes, and improving bile acid homeostasis. Conclusions: These data indicate that targeting miR-873-5p, a repressor of GNMT previously associated with NAFLD and acetaminophen-induced liver failure. is a novel and attractive approach to treating alcohol-induced hepatoxicity. Impact and implications: The role of miR-873-5p has not been explicitly examined in the progression of ALD, a pathology with no therapeutic options. In this study, inhibiting miR-873-5p exerted hepatoprotective effects against ALD through rescued SIRT1 activity and consequently restored bile acid homeostasis and attenuated the inflammatory response. Targeting hepatic miR-873-5p may represent a novel therapeutic approach for the treatment of ALD.

Methionine Cycle Rewiring by Targeting miR-873-5p Modulates Ammonia Metabolism to Protect the Liver from Acetaminophen.

Drug-induced liver injury (DILI) development is commonly associated with acetaminophen (APAP) overdose, where glutathione scavenging leads to mitochondrial dysfunction and hepatocyte death. DILI is a severe disorder without effective late-stage treatment, since N-acetyl cysteine must be administered 8 h after overdose to be efficient. Ammonia homeostasis is altered during liver diseases and, during DILI, it is accompanied by decreased glycine N-methyltransferase (GNMT) expression and S-adenosylmethionine (AdoMet) levels that suggest a reduced methionine cycle. Anti-miR-873-5p treatment prevents cell death in primary hepatocytes and the appearance of necrotic areas in liver from APAP-administered mice. In our study, we demonstrate a GNMT and methionine cycle activity restoration by the anti-miR-873-5p that reduces mitochondrial dysfunction and oxidative stress. The lack of hyperammoniemia caused by the therapy results in a decreased urea cycle, enhancing the synthesis of polyamines from ornithine and AdoMet and thus impacting the observed recovery of mitochondria and hepatocyte proliferation for regeneration. In summary, anti-miR-873-5p appears to be an effective therapy against APAP-induced liver injury, where the restoration of GNMT and the methionine cycle may prevent mitochondrial dysfunction while activating hepatocyte proliferative response.

Anti-miR-518d-5p overcomes liver tumor cell death resistance through mitochondrial activity.

Dysregulation of miRNAs is a hallmark of cancer, modulating oncogenes, tumor suppressors, and drug responsiveness. The multi-kinase inhibitor sorafenib is one of the first-line drugs for advanced hepatocellular carcinoma (HCC), although the outcome for treated patients is heterogeneous. The identification of predictive biomarkers and targets of sorafenib efficacy are sorely needed. Thus, selected top upregulated miRNAs from the C19MC cluster were analyzed in different hepatoma cell lines compared to immortalized liver human cells, THLE-2 as control. MiR-518d-5p showed the most consistent upregulation among them. Thus, miR-518d-5p was measured in liver tumor/non-tumor samples of two distinct cohorts of HCC patients (n = 16 and n = 20, respectively). Circulating miR-518d-5p was measured in an independent cohort of HCC patients receiving sorafenib treatment (n = 100), where miR-518d-5p was analyzed in relation to treatment duration and patient's overall survival. In vitro and in vivo studies were performed in human hepatoma BCLC3 and Huh7 cells to analyze the effect of miR-518d-5p inhibition/overexpression during the response to sorafenib. Compared with healthy individuals, miR-518d-5p levels were higher in hepatic and serum samples from HCC patients (n = 16) and in an additional cohort of tumor/non-tumor paired samples (n = 20). MiR-518d-5p, through the inhibition of c-Jun and its mitochondrial target PUMA, desensitized human hepatoma cells and mouse xenograft to sorafenib-induced apoptosis. Finally, serum miR-518d-5p was assessed in 100 patients with HCC of different etiologies and BCLC-stage treated with sorafenib. In BCLC-C patients, higher serum miR-518d-5p at diagnosis was associated with shorter sorafenib treatment duration and survival. Hence, hepatic miR-518d-5p modulates sorafenib resistance in HCC through inhibition of c-Jun/PUMA-induced apoptosis. Circulating miR-518d-5p emerges as a potential lack of response biomarker to sorafenib in BCLC-C HCC patients.

Cider fermentation process monitoring by Vis-NIR sensor system and chemometrics.

Optimization of a multivariate calibration process has been undertaken for a Visible-Near Infrared (400-1100nm) sensor system, applied in the monitoring of the fermentation process of the cider produced in the Basque Country (Spain). The main parameters that were monitored included alcoholic proof, l-lactic acid content, glucose+fructose and acetic acid content. The multivariate calibration was carried out using a combination of different variable selection techniques and the most suitable pre-processing strategies were selected based on the spectra characteristics obtained by the sensor system. The variable selection techniques studied in this work include Martens Uncertainty test, interval Partial Least Square Regression (iPLS) and Genetic Algorithm (GA). This procedure arises from the need to improve the calibration models prediction ability for cider monitoring.