Reducing acetylated tau is neuroprotective in brain injury.

Traumatic brain injury (TBI) is the largest non-genetic, non-aging related risk factor for Alzheimer's disease (AD). We report here that TBI induces tau acetylation (ac-tau) at sites acetylated also in human AD brain. This is mediated by S-nitrosylated-GAPDH, which simultaneously inactivates Sirtuin1 deacetylase and activates p300/CBP acetyltransferase, increasing neuronal ac-tau. Subsequent tau mislocalization causes neurodegeneration and neurobehavioral impairment, and ac-tau accumulates in the blood. Blocking GAPDH S-nitrosylation, inhibiting p300/CBP, or stimulating Sirtuin1 all protect mice from neurodegeneration, neurobehavioral impairment, and blood and brain accumulation of ac-tau after TBI. Ac-tau is thus a therapeutic target and potential blood biomarker of TBI that may represent pathologic convergence between TBI and AD. Increased ac-tau in human AD brain is further augmented in AD patients with history of TBI, and patients receiving the p300/CBP inhibitors salsalate or diflunisal exhibit decreased incidence of AD and clinically diagnosed TBI.

Development of Smart Irrigation Equipment for Soilless Crops Based on the Current Most Representative Water-Demand Sensors.

Due to the edaphoclimatic conditions in southeast Spain, which are expected to worsen due to climate change, more efficient ways of using water must be found to maintain sustainable agriculture. Due to the current high price of irrigation control systems in southern Europe, 60-80% of soilless crops are still irrigated, based on the experience of the grower or advisor. The hypothesis of this work is that the development of a low-cost, high-performance control system will allow small farmers to improve the efficiency of water use by obtaining better control of soilless crops. The objective of the present study was to design and develop a cost-effective control system for the optimization of soilless crop irrigation after evaluating the three most commonly used irrigation control systems to determine the most efficient. Based on the agronomic results comparing these methods, a prototype of a commercial smart gravimetric tray was developed. The device records the irrigation and drainage volumes and drainage pH and EC. It also offers the possibility of determining the temperature, EC, and humidity of the substrate. This new design is scalable thanks to the use of an implemented data acquisition system called SDB and the development of software in the Codesys programming environment based on function blocks and variable structures. The reduced wiring achieved by the Modbus-RTU communication protocols means the system is cost-effective even with multiple control zones. It is also compatible with any type of fertigation controller through external activation. Its design and features solve the problems in similar systems available on the market at an affordable cost. The idea is to allow farmers to increase their productivity without having to make a large outlay. The impact of this work will make it possible for small-scale farmers to have access to affordable, state-of-the-art technology for soilless irrigation management leading to a considerable improvement in productivity.

A Multirobot System in an Assisted Home Environment to Support the Elderly in Their Daily Lives.

The increasing isolation of the elderly both in their own homes and in care homes has made the problem of caring for elderly people who live alone an urgent priority. This article presents a proposed design for a heterogeneous multirobot system consisting of (i) a small mobile robot to monitor the well-being of elderly people who live alone and suggest activities to keep them positive and active and (ii) a domestic mobile manipulating robot that helps to perform household tasks. The entire system is integrated in an automated home environment (AAL), which also includes a set of low-cost automation sensors, a medical monitoring bracelet and an Android application to propose emotional coaching activities to the person who lives alone. The heterogeneous system uses ROS, IoT technologies, such as Node-RED, and the Home Assistant Platform. Both platforms with the home automation system have been tested over a long period of time and integrated in a real test environment, with good results. The semantic segmentation of the navigation and planning environment in the mobile manipulator for navigation and movement in the manipulation area facilitated the tasks of the later planners. Results about the interactions of users with the applications are presented and the use of artificial intelligence to predict mood is discussed. The experiments support the conclusion that the assistance robot correctly proposes activities, such as calling a relative, exercising, etc., during the day, according to the user's detected emotional state, making this is an innovative proposal aimed at empowering the elderly so that they can be autonomous in their homes and have a good quality of life.

Robotic-Based Well-Being Monitoring and Coaching System for the Elderly in Their Daily Activities.

The increasingly ageing population and the tendency to live alone have led science and engineering researchers to search for health care solutions. In the COVID 19 pandemic, the elderly have been seriously affected in addition to suffering from isolation and its associated and psychological consequences. This paper provides an overview of the RobWell (Robotic-based Well-Being Monitoring and Coaching System for the Elderly in their Daily Activities) system. It is a system focused on the field of artificial intelligence for mood prediction and coaching. This paper presents a general overview of the initially proposed system as well as the preliminary results related to the home automation subsystem, autonomous robot navigation and mood estimation through machine learning prior to the final system integration, which will be discussed in future works. The main goal is to improve their mental well-being during their daily household activities. The system is composed of ambient intelligence with intelligent sensors, actuators and a robotic platform that interacts with the user. A test smart home system was set up in which the sensors, actuators and robotic platform were integrated and tested. For artificial intelligence applied to mood prediction, we used machine learning to classify several physiological signals into different moods. In robotics, it was concluded that the ROS autonomous navigation stack and its autodocking algorithm were not reliable enough for this task, while the robot's autonomy was sufficient. Semantic navigation, artificial intelligence and computer vision alternatives are being sought.

ECCO2R therapy in the ICU: consensus of a European round table meeting.

BACKGROUND: With recent advances in technology, patients with acute respiratory distress syndrome (ARDS) and severe acute exacerbations of chronic obstructive pulmonary disease (ae-COPD) could benefit from extracorporeal CO2 removal (ECCO2R). However, current evidence in these indications is limited. A European ECCO2R Expert Round Table Meeting was convened to further explore the potential for this treatment approach. METHODS: A modified Delphi-based method was used to collate European experts' views to better understand how ECCO2R therapy is applied, identify how patients are selected and how treatment decisions are made, as well as to identify any points of consensus. RESULTS: Fourteen participants were selected based on known clinical expertise in critical care and in providing respiratory support with ECCO2R or extracorporeal membrane oxygenation. ARDS was considered the primary indication for ECCO2R therapy (n = 7), while 3 participants considered ae-COPD the primary indication. The group agreed that the primary treatment goal of ECCO2R therapy in patients with ARDS was to apply ultra-protective lung ventilation via managing CO2 levels. Driving pressure (≥ 14 cmH2O) followed by plateau pressure (Pplat; ≥ 25 cmH2O) was considered the most important criteria for ECCO2R initiation. Key treatment targets for patients with ARDS undergoing ECCO2R included pH (> 7.30), respiratory rate (< 25 or < 20 breaths/min), driving pressure (< 14 cmH2O) and Pplat (< 25 cmH2O). In ae-COPD, there was consensus that, in patients at risk of non-invasive ventilation (NIV) failure, no decrease in PaCO2 and no decrease in respiratory rate were key criteria for initiating ECCO2R therapy. Key treatment targets in ae-COPD were patient comfort, pH (> 7.30-7.35), respiratory rate (< 20-25 breaths/min), decrease of PaCO2 (by 10-20%), weaning from NIV, decrease in HCO3- and maintaining haemodynamic stability. Consensus was reached on weaning protocols for both indications. Anticoagulation with intravenous unfractionated heparin was the strategy preferred by the group. CONCLUSIONS: Insights from this group of experienced physicians suggest that ECCO2R therapy may be an effective supportive treatment for adults with ARDS or ae-COPD. Further evidence from randomised clinical trials and/or high-quality prospective studies is needed to better guide decision making.

Screening for Family Psychosocial Risk in Pediatric Hematopoietic Stem Cell Transplantation with the Psychosocial Assessment Tool.

Family psychosocial risk screening is an important initial step in delivering evidence-based care in hematopoietic stem cell transplantation (HCT). Establishing an evidence-based screening approach that is acceptable, reliable, and valid is an essential step in psychosocial care delivery. This is a 3-institution multimethod study. In part 1, caregivers of children about to undergo HCT (n = 140) completed the Psychosocial Assessment Tool-Hematopoietic Cell Transplantation (PAT-HCT), a brief parent report screener adapted for HCT, and validating questionnaires. Families received feedback on their risks identified on the PAT-HCT. In part 2, 12 caregivers completed a semistructured interview about their perceptions of the PAT and the feedback process. The reliability and validity of the PAT-HCT total and subscale scores were tested using Kuder-Richardson-20 (KR-20) and Pearson correlations. Thematic content analysis was used to analyze the qualitative interview data. Internal consistency for the total score (KR-20 = .88) and the Child Problems, Sibling Problems, Family Problems, and Stress Reactions subscales were strong (KR-20 >.70). Family Structure, Social Support, and Family Beliefs subscales were adequate (KR-20 = .55 to .63). Moderate to strong correlations with the criteria measures provided validation for the total and subscale scores. Feedback was provided to 97.14% of the families who completed the PAT-HCT, and the mean rating of acceptability was >4.00 (on a 5-point scale). The qualitative data indicate that families appreciate the effort to provide screening and feedback. The PAT-HCT is a psychometrically sound screener for use in HCT. Feedback can be given to families. Both the screener and the feedback process are acceptable to caregivers.

Smart Industrial IoT Monitoring and Control System Based on UAV and Cloud Computing Applied to a Concrete Plant.

Unmanned aerial vehicles (UAVs) are now considered one of the best remote sensing techniques for gathering data over large areas. They are now being used in the industry sector as sensing tools for proactively solving or preventing many issues, besides quantifying production and helping to make decisions. UAVs are a highly consistent technological platform for efficient and cost-effective data collection and event monitoring. The industrial Internet of things (IIoT) sends data from systems that monitor and control the physical world to data processing systems that cloud computing has shown to be important tools for meeting processing requirements. In fog computing, the IoT gateway links different objects to the internet. It can operate as a joint interface for different networks and support different communication protocols. A great deal of effort has been put into developing UAVs and multi-UAV systems. This paper introduces a smart IIoT monitoring and control system based on an unmanned aerial vehicle that uses cloud computing services and exploits fog computing as the bridge between IIoT layers. Its novelty lies in the fact that the UAV is automatically integrated into an industrial control system through an IoT gateway platform, while UAV photos are systematically and instantly computed and analyzed in the cloud. Visual supervision of the plant by drones and cloud services is integrated in real-time into the control loop of the industrial control system. As a proof of concept, the platform was used in a case study in an industrial concrete plant. The results obtained clearly illustrate the feasibility of the proposed platform in providing a reliable and efficient system for UAV remote control to improve product quality and reduce waste. For this, we studied the communication latency between the different IIoT layers in different IoT gateways.

Screening for Family Psychosocial Risk in Pediatric Cancer: Validation of the Psychosocial Assessment Tool (PAT) Version 3.

Objective: Family psychosocial risk screening is an important initial step in delivering evidence-based care. The Psychosocial Assessment Tool (PAT) is a brief parent report screener based on the trilevel Pediatric Psychosocial Preventative Health Model (PPPHM; Universal, Targeted, Clinical). The current article validates a revised PAT (version 3.0) in pediatric oncology that includes new items (for families of younger patients; clinically relevant risk items) and applicable to broad health literacy levels (a 4th grade reading level). Methods: Primary caregivers of 394 children newly diagnosed with cancer participated in this multisite investigation, completing the PAT and validation measures using REDCap. Results: The original structure of the PAT, with seven subscales (Family Structure, Social Support, Child Problems, Sibling Problems, Family Problems, Stress Reactions, and Family Beliefs) was supported using a confirmatory factor analysis. Internal consistency for the total score (Kuder-Richardson 20 coefficient [KR20] = 0.81) and the subscales (KR20 = 0.59-0.85) was moderate to strong. Moderate to strong correlations with the criteria measures provided validation for the total and subscale scores. The validation measures varied significantly, as expected, across the three levels of the PPPHM. Receiver operating characteristic (ROC) analyses showed that the PAT total and subscale scores can discriminate families above and below clinical thresholds. Conclusions: Results reinforce the psychometric properties of this approach for screening of family psychosocial risk. The PAT provides an evidence-based screener that identifies families at three levels of risk and can provide the basis for further evaluation and treatment of children with cancer and their families.

Validation of the Spanish Version of the Psychosocial Assessment Tool (PAT) in Pediatric Cancer.

Objective: Family psychosocial risk screening is an important initial step in delivering evidence-based care and in addressing health disparities. There is currently no validated measure of family psychosocial risk in Spanish. The Psychosocial Assessment Tool (PAT) is a brief parent report screener based on the trilevel Pediatric Preventative Psychosocial Risk Model (PPPHM; Universal, Targeted, and Clinical). The current article validates a Spanish version of the PAT (Version 3.0) in pediatric oncology. Method: Spanish-speaking Hispanic primary caregivers of 79 children newly diagnosed with cancer participated in this 4-institution multisite investigation, completing Spanish versions of the PAT and validation measures using REDCap. Results: Over 60% of the sample had a high school or lower level of education and they primarily identified as Hispanic in terms of acculturation. Internal consistency for the total score (KR20 = 0.76) and the Social Support, Child Problems, Sibling Problems, and Family Problems subscales was strong (KR20 = 0.69-0.79). Stress Reactions, Family Structure, and Family Beliefs subscales were lower (KR20 = 0.43-0.55). Moderate to strong correlations with the criteria measures provided validation for the total and subscale scores. Nearly two-thirds of the sample scored in the Targeted or Clinical range of the PPPHM. The PAT was successful in identifying clinical cases. Conclusions: The Spanish version of the PAT can be used with families of children newly diagnosed with cancer. Elevated psychosocial risks were found and warrant particular attention in providing psychosocial care attentive to the needs of Spanish-speaking families.

Single Fusion Events at Polarized Liquid-Liquid Interfaces.

A new electrochemical framework for tracking individual soft particles in solution and monitoring their fusion with polarized liquid-liquid interfaces is reported. The physicochemical principle lies in the interfacial transfer of an ionic probe confined in the particles dispersed in solution and that is released upon their collision and fusion with the fluid interface. As a proof-of-concept, spike-like transients of a stochastic nature are reported in the current-time response of 1,2-dichloroethane(DCE)|water(W) submilli-interfaces after injection of DCE-in-W emulsions. The sign and potential dependence of the spikes reflect the charge and lipophilicity of the ionic load of the droplets. A comparison with dynamic light scattering measurements indicates that each spike is associated with the collision of a single sub-picoliter droplet. This opens a new framework for the study of single fusion events at the micro- and nanoscale and of ion transport across biomimetic soft interfaces.

Ubiquinol-10 ameliorates mitochondrial encephalopathy associated with CoQ deficiency.

Coenzyme Q10 (CoQ10) deficiency (MIM 607426) causes a mitochondrial syndrome with variability in the clinical presentations. Patients with CoQ10 deficiency show inconsistent responses to oral ubiquinone-10 supplementation, with the highest percentage of unsuccessful results in patients with neurological symptoms (encephalopathy, cerebellar ataxia or multisystemic disease). Failure in the ubiquinone-10 treatment may be the result of its poor absorption and bioavailability, which may be improved by using different pharmacological formulations. In a mouse model (Coq9(X/X)) of mitochondrial encephalopathy due to CoQ deficiency, we have evaluated oral supplementation with water-soluble formulations of reduced (ubiquinol-10) and oxidized (ubiquinone-10) forms of CoQ10. Our results show that CoQ10 was increased in all tissues after supplementation with ubiquinone-10 or ubiquinol-10, with the tissue levels of CoQ10 with ubiquinol-10 being higher than with ubiquinone-10. Moreover, only ubiquinol-10 was able to increase the levels of CoQ10 in mitochondria from cerebrum of Coq9(X/X) mice. Consequently, ubiquinol-10 was more efficient than ubiquinone-10 in increasing the animal body weight and CoQ-dependent respiratory chain complex activities, and reducing the vacuolization, astrogliosis and oxidative damage in diencephalon, septum-striatum and, to a lesser extent, in brainstem. These results suggest that water-soluble formulations of ubiquinol-10 may improve the efficacy of CoQ10 therapy in primary and secondary CoQ10 deficiencies, other mitochondrial diseases and neurodegenerative diseases.

Melatonin blunts the mitochondrial/NLRP3 connection and protects against radiation-induced oral mucositis.

Mucositis is a common and distressing side effect of chemotherapy or radiotherapy that has potentially severe consequences, and no treatment is available. The purpose of this study was to analyze the molecular pathways involved in the development of oral mucositis and to evaluate whether melatonin can prevent this pathology. The tongue of male Wistar rats was subjected to irradiation (X-ray YXLON Y.Tu 320-D03 irradiator; the animals received a dose of 7.5 Gy/day for 5 days). Rats were treated with 45 mg/day melatonin or vehicle for 21 days postirradiation, either by local application into their mouths (melatonin gel) or by subcutaneous injection. A connection between reactive oxygen species, generating mitochondria and the NLRP3 (NLR-related protein 3 nucleotide-binding domain leucine-rich repeat containing receptor-related protein 3) inflammasome, has been reported in mucositis. Here, we show that mitochondrial oxidative stress, bioenergetic impairment and subsequent NLRP3 inflammasome activation are involved in the development of oral mucositis after irradiation and that melatonin synthesized in the rat tongue is depleted after irradiation. The application of melatonin gel restores physiological melatonin levels in the tongue and prevents mucosal disruption and ulcer formation. Melatonin gel protects the mitochondria from radiation damage and blunts the NF-κB/NLRP3 inflammasome signaling activation in the tongue. Our results suggest new molecular pathways involved in radiotherapy-induced mucositis that are inhibited by topical melatonin application, suggesting a potential preventive therapy for mucositis in patients with cancer.

The beneficial effects of melatonin against heart mitochondrial impairment during sepsis: inhibition of iNOS and preservation of nNOS.

While it is accepted that the high production of nitric oxide (NO˙) by the inducible nitric oxide synthase (iNOS) impairs cardiac mitochondrial function during sepsis, the role of neuronal nitric oxide synthase (nNOS) may be protective. During sepsis, there is a significantly increase in the expression and activity of mitochondrial iNOS (i-mtNOS), which parallels the changes in cytosolic iNOS. The existence of a constitutive NOS form (c-mtNOS) in heart mitochondria has been also described, but its role in the heart failure during sepsis remains unclear. Herein, we analyzed the changes in mitochondrial oxidative stress and bioenergetics in wild-type and nNOS-deficient mice during sepsis, and the role of melatonin, a known antioxidant, in these changes. Sepsis was induced by cecal ligation and puncture, and heart mitochondria were analyzed for NOS expression and activity, nitrites, lipid peroxidation, glutathione and glutathione redox enzymes, oxidized proteins, and respiratory chain activity in vehicle- and melatonin-treated mice. Our data show that sepsis produced a similar induction of iNOS/i-mtNOS and comparable inhibition of the respiratory chain activity in wild-type and in nNOS-deficient mice. Sepsis also increased mitochondrial oxidative/nitrosative stress to a similar extent in both mice strains. Melatonin administration inhibited iNOS/i-mtNOS induction, restored mitochondrial homeostasis in septic mice, and preserved the activity of nNOS/c-mtNOS. The effects of melatonin were unrelated to the presence or the absence of nNOS. Our observations show a lack of effect of nNOS on heart bioenergetic impairment during sepsis and further support the beneficial actions of melatonin in sepsis.

Tyrosinase-catalyzed hydroxylation of hydroquinone, a depigmenting agent, to hydroxyhydroquinone: A kinetic study.

Hydroquinone (HQ) is used as a depigmenting agent. In this work we demonstrate that tyrosinase hydroxylates HQ to 2-hydroxyhydroquinone (HHQ). Oxy-tyrosinase hydroxylates HQ to HHQ forming the complex met-tyrosinase-HHQ, which can evolve in two different ways, forming deoxy-tyrosinase and p-hydroxy-o-quinone, which rapidly isomerizes to 2-hydroxy-p-benzoquinone or on the other way generating met-tyrosinase and HHQ. In the latter case, HHQ is rapidly oxidized by oxygen to generate 2-hydroxy-p-benzoquinone, and therefore, it cannot close the enzyme catalytic cycle for the lack of reductant (HHQ). However, in the presence of hydrogen peroxide, met-tyrosinase (inactive on hydroquinone) is transformed into oxy-tyrosinase, which is active on HQ. Similarly, in the presence of ascorbic acid, HQ is transformed into 2-hydroxy-p-benzoquinone by the action of tyrosinase; however, in this case, ascorbic acid reduces met-tyrosinase to deoxy-tyrosinase, which after binding to oxygen, originates oxy-tyrosinase. This enzymatic form is now capable of reacting with HQ to generate p-hydroxy-o-quinone, which rapidly isomerizes to 2-hydroxy-p-benzoquinone. The formation of HHQ during the action of tyrosinase on HQ is demonstrated by means of high performance liquid chromatography mass spectrometry (HPLC-MS) by using hydrogen peroxide and high ascorbic acid concentrations. We propose a kinetic mechanism for the tyrosinase oxidation of HQ which allows us the kinetic characterization of the process. A possible explanation of the cytotoxic effect of HQ is discussed.

Eco-Innovation in the Food Industry: Exploring Consumer Motivations in an Emerging Market.

The utilization of eco-innovative products has witnessed a surge in adoption, driven by their inherent capacity to address pressing environmental concerns. To comprehensively fathom the underlying motivations propelling consumers to embrace these products, we conducted an in-depth investigation employing "The Not Company" (Chile) as a compelling case study. We conducted qualitative interviews with a cohort of 20 Chilean consumers, guided by the Theory of Planned Behavior theoretical framework. The research methodology harnessed the principles of thematic analysis, yielding insights that underscore the significance of key determinants in shaping consumers' choices towards eco-innovative products. Specifically, our findings highlighted that consumer choices in this domain are profoundly influenced by their attitudes, subjective norms, and perceived behavioral control. Moreover, within these overarching categories, we unearthed sub-themes illuminating the intricate influences guiding consumer choices. These sub-themes encompassed beliefs about food manufacturing and packaging, the persuasive impact of social media and advertising, and the indelible impressions left by prior encounters with eco-innovative products. This study highlights consumers' fundamental role in the broader eco-innovation landscape, particularly within the food industry context.

An Uncommon Case of Myocarditis Secondary to Durvalumab Plus Tremelimumab.

Tumor immunotherapy is an important clinical strategy for the treatment of various solid and hematological malignancies, and its use is on the rise. Immune checkpoint inhibitors (ICIs) are immunotherapies that boost anticancer immune responses by targeting receptors on the surface of T-lymphocytes. Two important ICIs are anti-programmed death ligand-1 (anti-PD-L1) monoclonal antibodies and anti-cytotoxic T-lymphocyte-associated antigen-4 (anti-CTLA-4) monoclonal antibodies. Tremelimumab (anti-CTLA-4) and durvalumab (anti-PD-L1) have been shown to be effective monotherapies. However, their combination has demonstrated effective and encouraging antitumor activity with manageable safety in patients with unresectable hepatocellular carcinoma. We present the case of an 80-year-old male with hepatocellular carcinoma who had undergone drug-eluting bead transarterial chemoembolization (DEB-TACE) on three occasions and had been started on a combination of ICIs, durvalumab, and tremelimumab. He subsequently developed various immune-related adverse effects in different organ systems, including hepatic and cardiovascular complications. Appropriate treatment was administered, but ultimately, he passed away. We aim to discuss the initial evaluation for suspected immune-related adverse events, specifically those related to myocarditis and its various manifestations, prognosis, and treatment.

Selective and brain-penetrant lanosterol synthase inhibitors target glioma stem-like cells by inducing 24(S),25-epoxycholesterol production.

Glioblastoma (GBM) is an aggressive adult brain cancer with few treatment options due in part to the challenges of identifying brain-penetrant drugs. Here, we investigated the mechanism of MM0299, a tetracyclic dicarboximide with anti-glioblastoma activity. MM0299 inhibits lanosterol synthase (LSS) and diverts sterol flux away from cholesterol into a "shunt" pathway that culminates in 24(S),25-epoxycholesterol (EPC). EPC synthesis following MM0299 treatment is both necessary and sufficient to block the growth of mouse and human glioma stem-like cells by depleting cellular cholesterol. MM0299 exhibits superior selectivity for LSS over other sterol biosynthetic enzymes. Critical for its application in the brain, we report an MM0299 derivative that is orally bioavailable, brain-penetrant, and induces the production of EPC in orthotopic GBM tumors but not normal mouse brain. These studies have implications for the development of an LSS inhibitor to treat GBM or other neurologic indications.

FDA approved drugs with antiviral activity against SARS-CoV-2: From structure-based repurposing to host-specific mechanisms.

The continuing heavy toll of the COVID-19 pandemic necessitates development of therapeutic options. We adopted structure-based drug repurposing to screen FDA-approved drugs for inhibitory effects against main protease enzyme (Mpro) substrate-binding pocket of SARS-CoV-2 for non-covalent and covalent binding. Top candidates were screened against infectious SARS-CoV-2 in a cell-based viral replication assay. Promising candidates included atovaquone, mebendazole, ouabain, dronedarone, and entacapone, although atovaquone and mebendazole were the only two candidates with IC50s that fall within their therapeutic plasma concentration. Additionally, we performed Mpro assays on the top hits, which demonstrated inhibition of Mpro by dronedarone (IC50 18 µM), mebendazole (IC50 19 µM) and entacapone (IC50 9 µM). Atovaquone showed only modest Mpro inhibition, and thus we explored other potential mechanisms. Although atovaquone is Dihydroorotate dehydrogenase (DHODH) inhibitor, we did not observe inhibition of DHODH at the respective SARS-CoV-2 IC50. Metabolomic profiling of atovaquone treated cells showed dysregulation of purine metabolism pathway metabolite, where ecto-5'-nucleotidase (NT5E) was downregulated by atovaquone at concentrations equivalent to its antiviral IC50. Atovaquone and mebendazole are promising candidates with SARS-CoV-2 antiviral activity. While mebendazole does appear to target Mpro, atovaquone may inhibit SARS-CoV-2 viral replication by targeting host purine metabolism.

Mitochondrial DNA and inflammatory diseases.

Increasing experimental evidence supports a connection between inflammation and mitochondrial dysfunction. Both acute and chronic inflammatory diseases course with elevated free radicals production that may affect mitochondrial proteins, lipids, and mtDNA. The subsequent mitochondrial impairment produces more reactive oxygen species that further reduce the ATP generation, increasing the probability of cell death. Mitochondrial impairment in now considered a key factor in inflammation because (1) there are specific pathologies directly derived from mtDNA mutations, causing chronic inflammatory diseases such as neuromuscular and neurodegenerative disorders, (2) there are neurodegenerative, metabolic, and other inflammatory diseases in which their progression is accompanied by mitochondrial dysfunction, which is directly involved in the cell death. Recently, a direct implication of mitochondrial reactive oxygen species and, particularly, mtDNA in the innate immune response has been reported. Thus, the mitochondria should be considered targets for new therapies related to the treatment of acute and chronic inflammatory diseases, including the auto-inflammatory ones.

A technical improvement in retropharyngeal carotid reconstruction.

The carotid-carotid bypass via a retropharyngeal tunnel enables treating proximal occlusions. With reference to two clinical cases, we present a technique that consists of transposition of one of the carotid arteries to contralateral position, avoiding simultaneous clamping of both carotids.