Characterization and Validation of Flexible Dry Electrodes for Wearable Integration.

When long-term biosignal monitoring is required via surface electrodes, the use of conventional silver/silver chloride (Ag/AgCl) gelled electrodes may not be the best solution, as the gel in the electrodes tends to dry out over time. In this work, the electrical behaviour and performance of dry electrodes for biopotential monitoring was assessed. Three materials were investigated and compared against the gold-standard Ag/AgCl gelled electrodes. To characterize their electrical behaviour, the impedance response over the frequency was evaluated, as well as its signal to noise ratio. The electrodes' performance was evaluated by integrating them in a proven electrocardiogram (ECG) acquisition setup where an ECG signal was acquired simultaneously with a set of dry electrodes and a set of standard Ag/AgCl gelled electrodes as reference. The obtained results were morphologically compared using the Normalised Root Mean Squared Error (nRMSE) and the Cosine Similarity (CS). The findings of this work suggest that the use of dry electrodes for biopotential monitoring is a suitable replacement for the conventional Ag/AgCl gelled electrodes. The signal obtained with dry electrodes is comparable to the one obtained with the gold standard, with the advantage that these do not require the use of gel and can be easily integrated into fabric to facilitate their use in long-term monitoring scenarios.

Developmental Toxicity Studies: The Path towards Humanized 3D Stem Cell-Based Models.

Today, it is recognized that medicines will eventually be needed during pregnancy to help prevent to, ameliorate or treat an illness, either due to gestation-related medical conditions or pre-existing diseases. Adding to that, the rate of drug prescription to pregnant women has increased over the past few years, in accordance with the increasing trend to postpone childbirth to a later age. However, in spite of these trends, information regarding teratogenic risk in humans is often missing for most of the purchased drugs. So far, animal models have been the gold standard to obtain teratogenic data, but inter-species differences have limited the suitability of those models to predict human-specific outcomes, contributing to misidentified human teratogenicity. Therefore, the development of physiologically relevant in vitro humanized models can be the key to surpassing this limitation. In this context, this review describes the pathway towards the introduction of human pluripotent stem cell-derived models in developmental toxicity studies. Moreover, as an illustration of their relevance, a particular emphasis will be placed on those models that recapitulate two very important early developmental stages, namely gastrulation and cardiac specification.

Temporomandibular trauma and reflections on personal evaluation.

The International Consortium Network/Orofacial Pain Special Interest Group focuses on temporomandibular disease diagnosis procedure guidelines as a reference iQAn this scope. Concerning this reference, the aim of this study was to comprehensively analyze injury and sequela frames within European and American approaches to personal damage. A quasiexperimental pilot study of Portuguese orofacial trauma cases in a medico-legal evaluation database was performed with an interrupted time series design. The clinical data were recorded following five criteria of TMJ diagnosis (jaw opening, pain, anatomical deficit, functional deficit, clinical sounds, and occlusal deficit) under three degrees of severity. The injury frame evaluation was recorded in the first-degree stage in all criteria. Pain, as a sequela, was the criterion present in 45% of the sample as spontaneous (20%) or stimulated (25%). Temporomandibular trauma damage evaluation emphasizes the accurate injury diagnosis and sequela framework. Orofacial trauma analysis should focus on the inclusion or exclusion of a TMD diagnosis. This study suggests revising the reference tables on personal damage, considering the inclusion of TMD and its categorization and impact.

Orofacial trauma injuries and disability assessment in adolescents: A Portuguese study.

BACKGROUND/AIMS: Orofacial injuries are a significant public health issue. The evidence-based knowledge associated with adolescent violence and trauma is highlighted by the World Health Organization with regard to its specific needs related to disability, violence, and unintentional injuries. The main aim of this study was to present evidence-based information about orofacial traumatic injuries of an adolescent population using Portuguese epidemiological data. The second aim was to report follow-up data of injuries for disability assessment in a trauma prevention approach. METHODS: An observational cohort study was performed using the clinical database of the national-specialist-healthcare-centre-of-trauma (2014-2018). Information was collected regarding gender, school age range, etiology, injury type, injury time, and severity. Mann-Whitney (p < .05), Kruskal-Wallis (p < .001), and Cox regression (p < .001) analyses were performed. RESULTS: Orofacial trauma injuries were present in 23.3% of Portuguese adolescents (age range 10-18 years). The majority were male (72.6%), and no age range stood out in frequency. School accidents (90.6%) were the major etiology for all groups of injuries. The diagnosis of superficial intraoral injuries was the most frequent (50.8%), followed by similar injuries to the face (22.5%). A Cox regression model with an adequate fit was yielded (χ2 [6] = 54.893, p < .001), suggesting that variable injury type was a predictor of disability, considering injury time. Tooth and alveolar loss, complicated tooth fracture, complicated face injury, and temporomandibular injuries were more predictive (1

Form, development and function of grass stomata.

Stomata are cellular breathing pores on leaves that open and close to absorb photosynthetic carbon dioxide and to restrict water loss through transpiration, respectively. Grasses (Poaceae) form morphologically innovative stomata, which consist of two dumbbell-shaped guard cells flanked by two lateral subsidiary cells (SCs). This 'graminoid' morphology is associated with faster stomatal movements leading to more water-efficient gas exchange in changing environments. Here, we offer a genetic and mechanistic perspective on the unique graminoid form of grass stomata and the developmental innovations during stomatal cell lineage initiation, recruitment of SCs and stomatal morphogenesis. Furthermore, the functional consequences of the four-celled, graminoid stomatal morphology are summarized. We compile the identified players relevant for stomatal opening and closing in grasses, and discuss possible mechanisms leading to cell-type-specific regulation of osmotic potential and turgor. In conclusion, we propose that the investigation of functionally superior grass stomata might reveal routes to improve water-stress resilience of agriculturally relevant plants in a changing climate.

Rhizobium response to sole and combined exposure to cadmium and the phytocompounds alpha-pinene and quercetin.

Soils can be contaminated with substances arising from anthropogenic sources, but also with natural bioactive compounds produced by plants, such as terpenes and flavonoids. While terpenes and flavonoids have received much less attention from research studies than metals, the effects that phytocompounds can have on soil organisms such as beneficial microorganisms should not be neglected. Herein we report the sole and combined exposure of Rhizobium to cadmium, to the monoterpene alpha-pinene and to the flavanol quercetin. A range of environmentally relevant concentrations of the phytocompounds was tested. Physiological (growth, protein content and intracellular Cd concentration), oxidative damage (lipid peroxidation, protein carbonylation) and antioxidant mechanisms (superoxide dismutase, catalase, glutathione, glutathione-S-transferases, protein electrophoretic profiles) were assessed. Results suggest that exposure to both phytocompounds do not influence Rhizobium growth, but for combined exposure to phytocompounds and Cd, different responses are observed. At low concentrations, phytocompounds seem to relieve the stress imposed by Cd by increasing antioxidant responses, but at high concentrations this advantage is lost and membrane damage may even be exacerbated. Thus, the presence of bioactive phytocompounds in soil may influence the tolerance of microorganisms to persistent toxicants, and may change their impact on the environment.

Evaluation of the efficacy of dentin hypersensitivity treatments-A systematic review and follow-up analysis.

OBJECTIVES: To compare the treatments used to treat dentin hypersensitivity (DH), based on its efficacy and effect duration. METHODS: Medline/PubMed, Cochrane Library, EMBASE and ClinicalTrials were searched for articles published between 1 January 2008 and 14 November 2018, in English, Portuguese or Spanish, reporting clinical trials, completed and with results. This systematic review protocol was registered in PROSPERO, number CRD42019121986. RESULTS: Seventy-four randomised clinical trials were included in the systematic review, reporting patients from 16 to 65 years old, with a clinical diagnosis of DH, that evaluate the efficacy of a desensitising product, compared to pre-treatment, used the evaporative method stimulation and the visual analogue scale. These studies evaluated 5366 patients and at least 9167 teeth. Seven follow-up periods were considered corresponding to an immediate, medium or long-time effect. Sixty-six studies were included in the quantitative synthesis. Glutaraldehyde with HEMA, glass ionomer cements and Laser present significant immediate (until 7 days) DH reduction. Medium-term (until 1 month) reduction was observed in stannous fluoride, glutaraldehyde with HEMA, hydroxyapatite, glass ionomer cements and Laser groups. Finally, long-term significant reduction was seen at potassium nitrate, arginine, glutaraldehyde with HEMA, hydroxyapatite, adhesive systems, glass ionomer cements and LASER. CONCLUSIONS: All active ingredients show efficacy in DH reduction in different follow-up times. Only in-office treatments are effective in immediate DH reduction, maintaining its efficacy over time. For long-time effects, at-home treatments can also be used. More standardised evaluation protocols should be implemented to increase the robustly of the results.

Interaction studies between periplasmic cytochromes provide insights into extracellular electron transfer pathways of Geobacter sulfurreducens.

Geobacter bacteria usually prevail among other microorganisms in soils and sediments where Fe(III) reduction has a central role. This reduction is achieved by extracellular electron transfer (EET), where the electrons are exported from the interior of the cell to the surrounding environment. Periplasmic cytochromes play an important role in establishing an interface between inner and outer membrane electron transfer components. In addition, periplasmic cytochromes, in particular nanowire cytochromes that contain at least 12 haem groups, have been proposed to play a role in electron storage in conditions of an environmental lack of electron acceptors. Up to date, no redox partners have been identified in Geobacter sulfurreducens, and concomitantly, the EET and electron storage mechanisms remain unclear. In this work, NMR chemical shift perturbation measurements were used to probe for an interaction between the most abundant periplasmic cytochrome PpcA and the dodecahaem cytochrome GSU1996, one of the proposed nanowire cytochromes in G. sulfurreducens The perturbations on the haem methyl signals of GSU1996 and PpcA showed that the proteins form a transient redox complex in an interface that involves haem groups from two different domains located at the C-terminal of GSU1996. Overall, the present study provides for the first time a clear evidence for an interaction between periplasmic cytochromes that might be relevant for the EET and electron storage pathways in G. sulfurreducens.

Protective effects of farnesol on a Rhizobium strain exposed to cadmium.

Soil acts as a repository for many metals that human activity releases into the environment. Cadmium enters agricultural soils primarily from application of phosphate fertilizers and sewage sludge. Among soil bacteria, rhizobia have a great agronomic and environmental significance and are major contributors to a sustainable maintenance of soil fertility. However, the services that this group of microorganisms provides are affected by environmental constraints, such as Cd contamination. Bioactive compounds also influence soil microorganisms. Farnesol is a phytocompound with recognized bioactivity, inducing both beneficial and harmful effects. In this study, Rhizobium sp. strain E20-8 was exposed to sole or combined exposure to Cd and farnesol. Results showed that farnesol (25 and 200 µM) did not affect rhizobia; exposure to Cd (µM) inhibited rhizobia growth and induced several biomarkers of oxidative stress; exposure to the combination of farnesol and Cd reduced oxidative damage, and the highest concentration of farnesol tested reduced Cd accumulation and allowed a significant growth recovery. Farnesol protective effects on rhizobia exposed to Cd is novel information which can be used in the development of microbe-based environmental engineering strategies for restoration of metal contaminated areas.

Impact of Smoking Cessation on the Clinical Course of Crohn's Disease Under Current Therapeutic Algorithms: A Multicenter Prospective Study.

OBJECTIVES: Given the importance of tobacco smoking (TS) as the only environmental factor repeatedly linked to the development of the Crohn's disease (CD), it is surprising that very few prospective studies have assessed whether TS is associated with an increased frequency of clinical relapse. Our aim was to evaluate the current impact of TS on disease relapse and the clinical benefit of quitting smoking in the present era of widespread use of anti-TNF drugs and immunosuppressants. METHODS: This was a multicenter prospective cohort study, which included 573 CD patients in clinical remission with various smoking habits. All smokers were advised to quit. Patients not exposed to tobacco before inclusion (non- and former smokers), continuing smokers, and quitters were compared regarding differences in disease outcomes during a follow-up of 4 years. RESULTS: A total of 148 continuing smokers, 190 nonsmokers, 160 former smokers, and 75 quitters were included. In comparison with nonsmokers, continuing smokers relapsed more frequently with an incidence rate ratio of 1.53 (95% confidence interval (CI): 1.10-2.17). Former smokers and quitters had similar relapse incidences compared with nonsmokers. Smoking was an independent predictor for disease relapse in the multivariate analysis (hazard ratio: 1.58 (95% CI 1.20-2.09). In the time-dependent analysis, continuing smokers had earlier relapse, regardless of anti-TNF or immunosuppressant use. CONCLUSIONS: Continuing smokers have more disease relapses, and patients who quit smoking have a similar relapse incidence compared with nonsmokers.

BeCAS: biomedical concept recognition services and visualization.

SUMMARY: The continuous growth of the biomedical scientific literature has been motivating the development of text-mining tools able to efficiently process all this information. Although numerous domain-specific solutions are available, there is no web-based concept-recognition system that combines the ability to select multiple concept types to annotate, to reference external databases and to automatically annotate nested and intercepted concepts. BeCAS, the Biomedical Concept Annotation System, is an API for biomedical concept identification and a web-based tool that addresses these limitations. MEDLINE abstracts or free text can be annotated directly in the web interface, where identified concepts are enriched with links to reference databases. Using its customizable widget, it can also be used to augment external web pages with concept highlighting features. Furthermore, all text-processing and annotation features are made available through an HTTP REST API, allowing integration in any text-processing pipeline. AVAILABILITY: BeCAS is freely available for non-commercial use at http://bioinformatics.ua.pt/becas. CONTACTS: tiago.nunes@ua.pt or jlo@ua.pt.

Interleukin-33 and inflammatory bowel diseases: lessons from human studies.

Interleukin- (IL-) 33 is a widely expressed cytokine present in different cell types, such as epithelial, mesenchymal, and inflammatory cells, supporting a predominant role in innate immunity. IL-33 can function as a proinflammatory cytokine inducing Th2 type of immune response being involved with the defense against parasitic infections of the gastrointestinal tract. In addition, it has been proposed that IL-33 can act as a signaling molecule alerting the immune system of danger or tissue damage. Recently, in the intestinal mucosa, overexpression of IL-33 has been reported in samples from patients with inflammatory bowel diseases (IBD). This review highlights the available data regarding IL-33 in human IBD and discusses emerging roles for IL-33 as a key modulator of intestinal inflammation.

Reflections about Blockchain in Health Data Sharing: Navigating a Disruptive Technology.

A comprehensive analysis was performed, considering blockchain technology (BT) properties in digital health, addressing medicolegal, privacy, and regulatory considerations. Adherence to personal data protection and healthcare regulatory guidelines were analyzed and compared for GDPR (Europe), HIPAA (United States), CCPA (California), PIPEDA (Canada), the Privacy Act of 1988 (Australia), APPI (Japan), and LGPD (Brazil). Issues such as health systems, strengthening and aligning policy orientations and initiatives, and emphasizing the role of data analysis in shaping health policies were explored. The study addressed conflicts between the legal frameworks and blockchain, comparing and suggesting solutions like the revision of laws and the integration of compliance mechanisms. Additionally, it sought to enhance IT-health literacy by integrating the healthcare and legal domains. Ongoing collaboration between legal, health, and IT experts is essential for designing systems that effectively balance privacy rights and data protection while maximizing the benefits of disruptive technologies like blockchain.

Digital intraoral and radiologic records in forensic identification: Match with disruptive technology.

While clinical dentistry has seamlessly integrated the digital revolution, there is a gap in the technological capabilities of forensic dentistry.The study aimed to compare the superimposition accuracy of two different three-dimensional record formats, namely the intraoral scanner and cone beam computer tomography, in the context of forensic identification.The sample consisted of randomly selected adults (n=10) of both sexes aged between 20 and 50 years. Following the acquisition of data using the Medit i700 wireless scanner and the iCAT Tomograph with InVivo software, the records were analysed and compared through superimposition using Medit Scan Clinic software to assess the technical precision of anatomical identification details.The results obtained through the superimposition of dental and bone records following intra- and inter-observer analysis enabled an accurate comparison and identification of an individual. This method can differentiate between positive and negative matches, achieving exclusion results and offering a potential solution to overcoming the absence of a standardisation procedure in human identification.

Orofacial assessment as digital path for forensic and legal evidence record.

In forensic scenarios, such as armed conflicts or mass disasters, the oral cavity can be a valuable source of identification information relevant to legal issues. In many European Union countries, it is mandatory to register dental records for identification purposes. A pilot and quasi-experimental study was performed. The study aims to analyze two methodologies, photography and wireless intraoral (IO) laser scanner, in the scope of the orofacial record in forensic pathology, highlighting their impact on human identification. The IO scanner i700 (Medit, Lusobionic, Portugal) and Canon 5D-Full Frame equipment were used to record the individual status, living patients (n = 5), and forensic cases (n = 5). IO and extraoral anatomical structures were recorded following six parameters: time, mineralized and soft detail, communication, extra devices, and distortion. The statistical analysis was performed in accordance with a scoring system and Mann-Whitney (P < 0.05) analysis. The photography method recorded extraoral data for all samples (score range between 15 and 23). The time elapsed to complete an IO scan in forensic cases was shorter than with photography, without requiring additional sources of light or mirror devices. Living patients and corpses identified statistically significant differences. It can be concluded that laser scanners are a valuable tool in the field of forensic pathology and can be used to record and analyze anatomic-morphological data for identification purposes accurately. Key points: Human identification engages in orofacial details records.Photographic and laser scans record intraoral and extraoral anatomic structures.Forensic cases assessed by intraoral scanner technology are accurate and less time-consuming, optimizing the orofacial data for identification.

Long-Term Benefits of Photobiomodulation Therapy on Health-Related Quality of Life in Burning Mouth Syndrome Patients: A Prospective Study.

Background/Objectives: Burning Mouth Syndrome (BMS) patients experience a reduction in health-related quality of life and an increased intake of medication. Photobiomodulation with low-level laser therapy has been demonstrated to be an efficacious treatment for BMS. However, its long-term benefits remain relatively unknown. This study aimed to evaluate the impact of prolonged Photobiomodulation with low-level laser therapy on BMS patients by examining the efficacy of an outpatient protocol in a real-world setting. Methods: A prospective study was designed to address the research question. Photobiomodulation was performed, irradiating the affected areas once every two weeks for 12 months. Health-related quality of life was assessed using the EQ-5D-5L questionnaire at the initial consultation and after 6 months and 12 months of treatment. Additionally, the patients' pharmacological profile was also monitored. Nonparametric statistical analysis was performed (p < 0.05 was considered statistically significant). Results: The study was completed by 15 individuals, comprising 14 females and 1 male. The results indicated a statistically significant improvement (p < 0.001) in four of the five dimensions of the health-related quality of life questionnaire, namely self-care, usual activities, pain/discomfort, and anxiety/depression, along with the patients' perceived health level. A total of 13 participants reported suspending or reducing their intake of medications for Burning Mouth Syndrome. Conclusions: Therefore, Photobiomodulation with low-level laser therapy has a positive effect on improving patients' quality of life and reducing BMS symptoms, contributing to a subsequent reduction or suspension of previous medications. These findings support the efficacy of the applied protocol. Given the innovative methodology and promising results, further research is warranted.

Maralixibat in progressive familial intrahepatic cholestasis (MARCH-PFIC): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) is a group of autosomal recessive disorders, the most prevalent being BSEP deficiency, resulting in disrupted bile formation, cholestasis, and pruritus. Building on a previous phase 2 study, we aimed to evaluate the efficacy and safety of maralixibat-an ileal bile acid transporter inhibitor-in participants with all types of PFIC. METHODS: MARCH-PFIC was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study conducted in 29 community and hospital centres across 16 countries in Europe, the Americas, and Asia. We recruited participants aged 1-17 years with PFIC with persistent pruritus (>6 months; average of ≥1·5 on morning Itch-Reported Outcome [Observer; ItchRO(Obs)] during the last 4 weeks of screening) and biochemical abnormalities or pathological evidence of progressive liver disease, or both. We defined three analysis cohorts. The BSEP (or primary) cohort included only those with biallelic, non-truncated BSEP deficiency without low or fluctuating serum bile acids or previous biliary surgery. The all-PFIC cohort combined the BSEP cohort with participants with biallelic FIC1, MDR3, TJP2, or MYO5B deficiencies without previous surgery but regardless of bile acids. The full cohort had no exclusions. Participants were randomly assigned (1:1) to receive oral maralixibat (starting dose 142·5 µg/kg, then escalated to 570 µg/kg) or placebo twice daily for 26 weeks. The primary endpoint was the mean change in average morning ItchRO(Obs) severity score between baseline and weeks 15-26 in the BSEP cohort. The key secondary efficacy endpoint was the mean change in total serum bile acids between baseline and the average of weeks 18, 22, and 26 in the BSEP cohort. Efficacy analyses were done in the intention-to-treat population (all those randomly assigned) and safety analyses were done in all participants who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT03905330, and EudraCT, 2019-001211-22. FINDINGS: Between July 9, 2019, and March 4, 2022, 125 patients were screened, of whom 93 were randomly assigned to maralixibat (n=47; 14 in the BSEP cohort and 33 in the all-PFIC cohort) or placebo (n=46; 17 in the BSEP cohort and 31 in the all-PFIC cohort), received at least one dose of study drug, and were included in the intention-to-treat and safety populations. The median age was 3·0 years (IQR 2·0-7·0) and 51 (55%) of 93 participants were female and 42 (45%) were male. In the BSEP cohort, least-squares mean change from baseline in morning ItchRO(Obs) was -1·7 (95% CI -2·3 to -1·2) with maralixibat versus -0·6 (-1·1 to -0·1) with placebo, with a significant between-group difference of -1·1 (95% CI -1·8 to -0·3; p=0·0063). Least-squares mean change from baseline in total serum bile acids was -176 µmol/L (95% CI -257 to -94) for maralixibat versus 11 µmol/L (-58 to 80) for placebo, also representing a significant difference of -187 µmol/L (95% CI -293 to -80; p=0·0013). The most common adverse event was diarrhoea (27 [57%] of 47 patients on maralixibat vs nine [20%] of 46 patients on placebo; all mild or moderate and mostly transient). There were five (11%) participants with serious treatment-emergent adverse events in the maralixibat group versus three (7%) in the placebo group. No treatment-related deaths occurred. INTERPRETATION: Maralixibat improved pruritus and predictors of native liver survival in PFIC (eg, serum bile acids). Maralixibat represents a non-surgical, pharmacological option to interrupt the enterohepatic circulation and improve the standard of care in patients with PFIC. FUNDING: Mirum Pharmaceuticals.

The EU-ADR Web Platform: delivering advanced pharmacovigilance tools.

PURPOSE: Pharmacovigilance methods have advanced greatly during the last decades, making post-market drug assessment an essential drug evaluation component. These methods mainly rely on the use of spontaneous reporting systems and health information databases to collect expertise from huge amounts of real-world reports. The EU-ADR Web Platform was built to further facilitate accessing, monitoring and exploring these data, enabling an in-depth analysis of adverse drug reactions risks. METHODS: The EU-ADR Web Platform exploits the wealth of data collected within a large-scale European initiative, the EU-ADR project. Millions of electronic health records, provided by national health agencies, are mined for specific drug events, which are correlated with literature, protein and pathway data, resulting in a rich drug-event dataset. Next, advanced distributed computing methods are tailored to coordinate the execution of data-mining and statistical analysis tasks. This permits obtaining a ranked drug-event list, removing spurious entries and highlighting relationships with high risk potential. RESULTS: The EU-ADR Web Platform is an open workspace for the integrated analysis of pharmacovigilance datasets. Using this software, researchers can access a variety of tools provided by distinct partners in a single centralized environment. Besides performing standalone drug-event assessments, they can also control the pipeline for an improved batch analysis of custom datasets. Drug-event pairs can be substantiated and statistically analysed within the platform's innovative working environment. CONCLUSIONS: A pioneering workspace that helps in explaining the biological path of adverse drug reactions was developed within the EU-ADR project consortium. This tool, targeted at the pharmacovigilance community, is available online at https://bioinformatics.ua.pt/euadr/.

Inflammasome in intestinal inflammation and cancer.

The activation of specific cytosolic pathogen recognition receptors, the nucleotide-binding-oligomerization-domain- (NOD-) like receptors (NLRs), leads to the assembly of the inflammasome, a multimeric complex platform that activates caspase-1. The caspase-1 pathway leads to the upregulation of important cytokines from the interleukin (IL)-1 family, IL-1ß , and IL-18, with subsequent activation of the innate immune response. In this review, we discuss the molecular structure, the mechanisms behind the inflammasome activation, and its possible role in the pathogenesis of inflammatory bowel diseases and intestinal cancer. Here, we show that the available data points towards the importance of the inflammasome in the innate intestinal immune response, being the complex involved in the maintenance of intestinal homeostasis, correct intestinal barrier function and efficient elimination of invading pathogens.

Induction of dsRNA-activated protein kinase links mitochondrial unfolded protein response to the pathogenesis of intestinal inflammation.

OBJECTIVE: Inflammatory bowel diseases (IBDs) feature multiple cellular stress responses, including endoplasmic reticulum (ER) unfolded protein responses (UPRs). UPRs represent autoregulatory pathways that adjust organelle capacity to cellular demand. A similar mechanism, mitochondrial UPR (mtUPR), has been described for mitochondria. ER UPR in intestinal epithelial cells (IECs) contributes to the development of intestinal inflammation, and since mitochondrial alterations and dysfunction are implicated in the pathogenesis of IBDs, the authors characterised mtUPR in the context of intestinal inflammation. METHODS: Truncated ornithine transcarbamylase was used to selectively induce mtUPR in a murine IEC line. Dextran sodium sulphate (DSS) was administered to PKR (double-stranded-RNA-activated protein kinase) knockout mice to induce IEC stress in vivo and to test for their susceptibility to DSS-induced colitis. Expression levels of the mitochondrial chaperone chaperonin 60 (CPN60) and PKR were quantified in IECs from patients with IBDs and from murine models of colitis using immunohistochemistry and Western blot analysis. RESULTS: Selective mtUPR induction by truncated ornithine transcarbamylase transfection triggered the phosphorylation of eukaryotic translation initiation factor (eIF) 2α and cJun through the recruitment of PKR. Using pharmacological inhibitors and small inhibitory RNA, the authors identified mtUPR-induced eIF2α phosphorylation and transcription factor activation (cJun/AP1) as being dependent on the activities of the mitochondrial protease ClpP and the cytoplasmic kinase PKR. Pkr(-/-) mice failed to induce CPN60 in IECs upon DSS treatment at early time points and subsequently showed an almost complete resistance to DSS-induced colitis. Under inflammatory conditions, primary IECs from patients with IBDs and two murine models of colitis exhibited a strong induction of the mtUPR marker protein CPN60 associated with enhanced expression of PKR. CONCLUSION: PKR integrates mtUPR into the disease-relevant ER UPR via eIF2α phosphorylation and AP1 activation. Induction of mtUPR and PKR was observed in IECs from murine models and patients with IBDs. The authors' results indicate that PKR might link mitochondrial stress to intestinal inflammation.