The Role of Tricellulin in Epithelial Jamming and Unjamming via Segmentation of Tricellular Junctions

Collective cellular behavior in confluent monolayers supports physiological and pathological processes of epithelial development, regeneration, and carcinogenesis. Here, the attainment of a mature and static tissue configuration or the local reactivation of cell motility involve a dynamic regulation of the junctions established between neighboring cells. Tricellular junctions (tTJs), established at vertexes where three cells meet, are ideally located to control cellular shape and coordinate multicellular movements. However, their function in epithelial tissue dynamic remains poorly defined. To investigate the role of tTJs establishment and maturation in the jamming and unjamming transitions of epithelial monolayers, a semi-automatic image-processing pipeline is developed and validated enabling the unbiased and spatially resolved determination of the tTJ maturity state based on the localization of fluorescent reporters. The software resolves the variation of tTJ maturity accompanying collective transitions during tissue maturation, wound healing, and upon the adaptation to osmolarity changes. Altogether, this work establishes junctional maturity at tricellular contacts as a novel biological descriptor of collective responses in epithelial monolayers

Changes in urinary metabolomic profile during relapsing renal vasculitis

Current biomarkers of renal disease in systemic vasculitis lack predictive value and are insensitive to early damage. To identify novel biomarkers of renal vasculitis flare, we analysed the longitudinal urinary metabolomic profile of a rat model of anti-neutrophil cytoplasmic antibody (ANCA) vasculitis. Wistar-Kyoto (WKY) rats were immunised with human myeloperoxidase (MPO). Urine was obtained at regular intervals for 181 days, after which relapse was induced by re-challenge with MPO. Urinary metabolites were assessed in an unbiased fashion using nuclear magnetic resonance (NMR) spectroscopy, and analysed using partial least squares discriminant analysis (PLS-DA) and partial least squares regression (PLS-R). At 56 days post-immunisation, we found that rats with vasculitis had a significantly different urinary metabolite profile than control animals; the observed PLS-DA clusters dissipated between 56 and 181 days, and re-emerged with relapse. The metabolites most altered in rats with active or relapsing vasculitis were trimethylamine N-oxide (TMAO), citrate and 2-oxoglutarate. Myo-inositol was also moderately predictive. The key urine metabolites identified in rats were confirmed in a large cohort of patients using liquid chromatography-mass spectrometry (LC-MS). Hypocitraturia and elevated urinary myo-inositol remained associated with active disease, with the urine myo-inositol:citrate ratio being tightly correlated with active renal vasculitis

The Internet of Things as Smart City Enabler:The Cases of Palo Alto, Nice and Stockholm

Part 5: Smart Cities and Smart HomesInternational audienceDue to rapid urbanization, city populations are rapidly increasing all over the world creating new problems and challenges. Solving some of these problems requires innovative approaches; one increasingly popular approach is to transform cities to Smart Cities. Smart Cities implement innovative approaches based on IoT technologies and convert many services to digital services. These services are implemented within the different components of a Smart City, helping city administrators to improve the life of the citizens, addressing different service, security and administrative challenges. The objective of this paper is to explore and determine how three well-known cities - Nice, Palo Alto and Stockholm - implemented the Smart City concept. The study indicates that a successful implementation of a Smart City model requires addressing a number of critical challenges: citizen involvement, business collaboration and strong leadership prove to be key success factors in the Smart City development process

Accurate detection of spontaneous seizures using a generalized linear model with external validation

Objective Seizure detection is a major facet of electroencephalography (EEG) analysis in neurocritical care, epilepsy diagnosis and management, and the instantiation of novel therapies such as closed-loop stimulation or optogenetic control of seizures. It is also of increased importance in high-throughput, robust, and reproducible pre-clinical research. However, seizure detectors are not widely relied upon in either clinical or research settings due to limited validation. In this study, we create a high-performance seizure-detection approach, validated in multiple data sets, with the intention that such a system could be available to users for multiple purposes. Methods We introduce a generalized linear model trained on 141 EEG signal features for classification of seizures in continuous EEG for two data sets. In the first (Focal Epilepsy) data set consisting of 16 rats with focal epilepsy, we collected 1012 spontaneous seizures over 3 months of 24/7 recording. We trained a generalized linear model on the 141 features representing 20 feature classes, including univariate and multivariate, linear and nonlinear, time, and frequency domains. We tested performance on multiple hold-out test data sets. We then used the trained model in a second (Multifocal Epilepsy) data set consisting of 96 rats with 2883 spontaneous multifocal seizures. Results From the Focal Epilepsy data set, we built a pooled classifier with an Area Under the Receiver Operating Characteristic (AUROC) of 0.995 and leave-one-out classifiers with an AUROC of 0.962. We validated our method within the independently constructed Multifocal Epilepsy data set, resulting in a pooled AUROC of 0.963. We separately validated a model trained exclusively on the Focal Epilepsy data set and tested on the held-out Multifocal Epilepsy data set with an AUROC of 0.890. Latency to detection was under 5 seconds for over 80% of seizures and under 12 seconds for over 99% of seizures. Significance This method achieves the highest performance published for seizure detection on multiple independent data sets. This method of seizure detection can be applied to automated EEG analysis pipelines as well as closed loop interventional approaches, and can be especially useful in the setting of research using animals in which there is an increased need for standardization and high-throughput analysis of large number of seizures

Clinical, neuroimaging, and molecular spectrum of TECPR2‐associated hereditary sensory and autonomic neuropathy with intellectual disability

Bi‐allelic TECPR2 variants have been associated with a complex syndrome with features of both a neurodevelopmental and neurodegenerative disorder. Here, we provide a comprehensive clinical description and variant interpretation framework for this genetic locus. Through international collaboration, we identified 17 individuals from 15 families with bi‐allelic TECPR2‐variants. We systemically reviewed clinical and molecular data from this cohort and 11 cases previously reported. Phenotypes were standardized using Human Phenotype Ontology terms. A cross‐sectional analysis revealed global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections, and central/nocturnal hypopnea as core manifestations. A review of brain magnetic resonance imaging scans demonstrated a thin corpus callosum in 52%. We evaluated 17 distinct variants. Missense variants in TECPR2 are predominantly located in the N‐ and C‐terminal regions containing β‐propeller repeats. Despite constituting nearly half of disease‐associated TECPR2 variants, classifying missense variants as (likely) pathogenic according to ACMG criteria remains challenging. We estimate a pathogenic variant carrier frequency of 1/1221 in the general and 1/155 in the Jewish Ashkenazi populations. Based on clinical, neuroimaging, and genetic data, we provide recommendations for variant reporting, clinical assessment, and surveillance/treatment of individuals with TECPR2‐associated disorder. This sets the stage for future prospective natural history studies

Mechanisms and management of loss of response to anti-TNF therapy for patients with Crohn's disease: 3-year data from the prospective, multicentre PANTS cohort study

This is the final version. Available from Elsevier via the DOI in this record. Background We sought to report the effectiveness of infliximab and adalimumab over the first 3 years of treatment and to define the factors that predict anti-TNF treatment failure and the strategies that prevent or mitigate loss of response. Methods Personalised Anti-TNF therapy in Crohn’s disease (PANTS) is a UK-wide, multicentre, prospective observational cohort study reporting the rates of effectiveness of infliximab and adalimumab in anti-TNF-naive patients with active luminal Crohn’s disease aged 6 years and older. At the end of the first year, sites were invited to enrol participants still receiving study drug into the 2-year PANTS-extension study. We estimated rates of remission across the whole cohort at the end of years 1, 2, and 3 of the study using a modified survival technique with permutation testing. Multivariable regression and survival analyses were used to identify factors associated with loss of response in patients who had initially responded to anti-TNF therapy and with immunogenicity. Loss of response was defined in patients who initially responded to anti-TNF therapy at the end of induction and who subsequently developed symptomatic activity that warranted an escalation of steroid, immunomodulatory, or anti-TNF therapy, resectional surgery, or exit from study due to treatment failure. This study was registered with ClinicalTrials.gov, NCT03088449, and is now complete. Findings Between March 19, 2014, and Sept 21, 2017, 389 (41%) of 955 patients treated with infliximab and 209 (32%) of 655 treated with adalimumab in the PANTS study entered the PANTS-extension study (median age 32·5 years [IQR 22·1–46·8], 307 [51%] of 598 were female, and 291 [49%] were male). The estimated proportion of patients in remission at the end of years 1, 2, and 3 were, for infliximab 40·2% (95% CI 36·7–43·7), 34·4% (29·9–39·0), and 34·7% (29·8–39·5), and for adalimumab 35·9% (95% CI 31·2–40·5), 32·9% (26·8–39·2), and 28·9% (21·9–36·3), respectively. Optimal drug concentrations at week 14 to predict remission at any later timepoints were 6·1–10·0 mg/L for infliximab and 10·1–12·0 mg/L for adalimumab. After excluding patients who had primary non-response, the estimated proportions of patients who had loss of response by years 1, 2, and 3 were, for infliximab 34·4% (95% CI 30·4–38·2), 54·5% (49·4–59·0), and 60·0% (54·1–65·2), and for adalimumab 32·1% (26·7–37·1), 47·2% (40·2–53·4), and 68·4% (50·9–79·7), respectively. In multivariable analysis, loss of response at year 2 and 3 for patients treated with infliximab and adalimumab was predicted by low anti-TNF drug concentrations at week 14 (infliximab: hazard ratio [HR] for each ten-fold increase in drug concentration 0·45 [95% CI 0·30–0·67], adalimumab: 0·39 [0·22–0·70]). For patients treated with infliximab, loss of response was also associated with female sex (vs male sex; HR 1·47 [95% CI 1·11–1·95]), obesity (vs not obese 1·62 [1·08–2·42]), baseline white cell count (1·06 [1·02–1·11) per 1 × 10⁹ increase in cells per L), and thiopurine dose quartile. Among patients treated with adalimumab, carriage of the HLA-DQA1*05 risk variant was associated with loss of response (HR 1·95 [95% CI 1·17–3·25]). By the end of year 3, the estimated proportion of patients who developed anti-drug antibodies associated with undetectable drug concentrations was 44·0% (95% CI 38·1–49·4) among patients treated with infliximab and 20·3% (13·8–26·2) among those treated with adalimumab. The development of antidrug antibodies associated with undetectable drug concentrations was significantly associated with treatment without concomitant immunomodulator use for both groups (HR for immunomodulator use: infliximab 0·40 [95% CI 0·31–0·52], adalimumab 0·42 [95% CI 0·24–0·75]), and with carriage of HLA-DQA1*05 risk variant for infliximab (HR for carriage of risk variant: infliximab 1·46 [1·13–1·88]) but not for adalimumab (HR 1·60 [0·92–2·77]). Concomitant use of an immunomodulator before or on the day of starting infliximab was associated with increased time without the development of anti-drug antibodies associated with undetectable drug concentrations compared with use of infliximab alone (HR 2·87 [95% CI 2·20–3·74]) or introduction of an immunomodulator after anti-TNF initiation (1·70 [1·11–2·59]). In years 2 and 3, 16 (4%) of 389 patients treated with infliximab and 11 (5%) of 209 treated with adalimumab had adverse events leading to treatment withdrawal. Nine (2%) patients treated with infliximab and two (1%) of those treated with adalimumab had serious infections in years 2 and 3. Interpretation Only around a third of patients with active luminal Crohn’s disease treated with an anti-TNF drug were in remission at the end of 3 years of treatment. Low drug concentrations at the end of the induction period predict loss of response by year 3 of treatment, suggesting higher drug concentrations during the first year of treatment, particularly during induction, might lead to better long-term outcomes. Anti-drug antibodies associated with undetectable drug concentrations of infliximab, but not adalimumab, can be predicted by carriage of HLA-DQA1*05 and mitigated by concomitant immunomodulator use for both drugs.Guts UKCrohn’s and Colitis UKCure Crohn’s ColitisAbbVieMerck Sharp and DohmeNapp PharmaceuticalsPfizerCelltrion Healthcar

Smart cities: a taxonomy for the efficient management of lighting in unpredicted environments

In recent years there has been a substantial increase in the number of outdoor lighting installations, the energy management of this has not been greatly improved and electricity consumption has skyrocketed. Most of it does not come from renewable energies with all the negative effects that this entails. With all this, public lighting can represent up to a total of 54% of the energy consumption of a municipality and up to 61% of its electricity consumption. This work focuses on the analysis of the factors to consider in the implementation and application of a lighting control system in a real environment for energy saving. The system should be based on the collection of data by the different sensors installed in the luminaries of the route oriented to the environment of the Smart Cities and the Intelligent Transport Systems (ITS). The main objective is to try to reduce the consumption of electrical energy as much as possible while maintaining the comfort that the road user feels in it. For this, the weak points of these systems will be searched and their elimination will be sought. A study will be made of the situation of the systems available today. The characteristics of these systems will be analysed. Based on the characteristics of the systems analysed, the necessary requirements of the system presented will be determined. The characteristics that will make this project different from the rest will be established. An architecture proposal that seeks to optimise the parameters analysed will be presented.Ávil