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With its growing number of deployed devices and applications, the Internet of Things (IoT) raises significant challenges for network maintenance procedures. In this work, we address a problem of active fault detection in an IoT scenario, whereby a monitor can probe a remote device to acquire fresh information and facilitate fault detection. However, probing could significantly impact the system’s energy and communication resources. To this end, we utilize the Age of Information to measure the freshness of information at the monitor and adopt a semantics-aware communication approach between the monitor and the remote device. In semantics-aware communications, the processes of generating and transmitting information are treated jointly to consider the importance of information and the purpose of communication. We formulate the problem as a Partially Observable Markov Decision Process and show analytically that the optimal policy is of a threshold type. Finally, we use a computationally efficient stochastic approximation algorithm to approximate the optimal policy and present numerical results that exhibit the advantage of our approach compared to a conventional delay-based probing policy.

Abstract Background Extracellular vesicles (EVs), including small EVs (sEVs) such as exosomes, exhibit great potential for the diagnosis and treatment of brain disorders, representing a valuable tool for precision medicine. The latter demands high-quality human biospecimens, especially in complex disorders in which pathological and specimen heterogeneity, as well as diverse individual clinical profile, often complicate the development of precision therapeutic schemes and patient-tailored treatments. Thus, the collection and characterization of physiologically relevant sEVs are of the utmost importance. However, standard brain EV isolation approaches rely on tissue dissociation, which can contaminate EV fractions with intracellular vesicles. Methods Based on multiscale analytical platforms such as cryo-EM, label-free proteomics, advanced flow cytometry, and ExoView analyses, we compared and characterized the EV fraction isolated with this novel method with a classical digestion-based EV isolation procedure. Moreover, EV biogenesis was pharmacologically manipulated with either GW4869 or picrotoxin to assess the validity of the spontaneous-release method, while the injection of labelled-EVs into the mouse brain further supported the integrity of the isolated vesicles. Results We hereby present an efficient purification method that captures a sEV-enriched population spontaneously released by mouse and human brain tissue. In addition, we tested the significance of the release method under conditions where biogenesis/secretion of sEVs was pharmacologically manipulated, as well as under animals’ exposure to chronic stress, a clinically relevant precipitant of brain pathologies, such as depression and Alzheimer’s disease. Our findings show that the released method monitors the drug-evoked inhibition or enhancement of sEVs secretion while chronic stress induces the secretion of brain exosomes accompanied by memory loss and mood deficits suggesting a potential role of sEVs in the brain response to stress and related stress-driven brain pathology. Conclusions Overall, the spontaneous release method of sEV yield may contribute to the characterization and biomarker profile of physiologically relevant brain-derived sEVs in brain function and pathology. Video Abstract

Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. Early detection/diagnosis is vital for the prognosis of HCC, whereas diagnosis at late stages is associated with very low survival rate. Early diagnosis is based on 6-month surveillance of the patient and the use of at least two imaging modalities. The aim of this study was to investigate diagnostic markers for the detection of early HCC based on proteome analysis, microRNAs (miRNAs) and circulating tumor cells (CTCs) in the blood of patients with cirrhosis or early or advanced HCC. We studied 89 patients with HCC, of whom 33 had early HCC and 28 were cirrhotic. CTCs were detected by real-time quantitative reverse transcription PCR and immunofluorescence using the markers epithelial cell adhesion molecule (EPCAM), vimentin, alpha fetoprotein (aFP) and surface major vault protein (sMVP). Expression of the five most common HCC-involved miRNAs (miR-122, miR-200a, miR-200b, miR-221, miR-222) was examined in serum using quantitative real time PCR (qRT-PCR). Finally, patient serum was analyzed via whole proteome analysis (LC/MS). Of 53 patients with advanced HCC, 27 (51%) had detectable CTCs. Among these, 10/27 (37%) presented evidence of mesenchymal or intermediate stage cells (vimentin and/or sMVP positive). Moreover, 5/17 (29%) patients with early HCC and 2/28 (7%) cirrhotic patients had detectable CTCs. Patients with early or advanced HCC exhibited a significant increase in miR-200b when compared to cirrhotic patients. Our proteome analysis indicated that early HCC patients present a significant upregulation of APOA2, APOC3 proteins when compared to cirrhotic patients. When taken in combination, this covers the 100% of the patients with early HCC. miR-200b, APOA2 and APOC3 proteins are sensitive markers and can be potentially useful in combination for the early diagnosis of HCC.

Abstract Tau accumulation is clearly linked to pathogenesis in Alzheimer’s disease and other Tauopathies. However, processes leading to Tau fibrillization and reasons for its pathogenicity remain largely elusive. Mical emerged as a novel interacting protein of human Tau expressed in Drosophila brains. Mical is characterized by the presence of a flavoprotein monooxygenase domain that generates redox potential with which it can oxidize target proteins. In the well-established Drosophila Tauopathy model, we use genetic interactions to show that Mical alters Tau interactions with microtubules and the Actin cytoskeleton and greatly affects Tau aggregation propensity and Tau-associated toxicity and dysfunction. Exploration of the mechanism was pursued using a Mical inhibitor, a mutation in Mical that selectively disrupts its monooxygenase domain, Tau transgenes mutated at cysteine residues targeted by Mical and mass spectrometry analysis to quantify cysteine oxidation. The collective evidence strongly indicates that Mical’s redox activity mediates the effects on Tau via oxidation of Cys322. Importantly, we also validate results from the fly model in human Tauopathy samples by showing that MICAL1 is up-regulated in patient brains and co-localizes with Tau in Pick bodies. Our work provides mechanistic insights into the role of the Tau cysteine residues as redox-switches regulating the process of Tau self-assembly into inclusions in vivo, its function as a cytoskeletal protein and its effect on neuronal toxicity and dysfunction.

Summary: The term “terroir” has been widely employed to link differential geographic phenotypes with sensorial signatures of agricultural food products, influenced by agricultural practices, soil type, and climate. Nowadays, the geographical indications labeling has been developed to safeguard the quality of plant-derived food that is linked to a certain terroir and is generally considered as an indication of superior organoleptic properties. As the dynamics of agroecosystems are highly intricate, consisting of tangled networks of interactions between plants, microorganisms, and the surrounding environment, the recognition of the key molecular components of terroir fingerprinting remains a great challenge to protect both the origin and the safety of food commodities. Furthermore, the contribution of microbiome as a potential driver of the terroir signature has been underestimated. Herein, we present a first comprehensive view of the multi-omic landscape related to transcriptome, proteome, epigenome, and metagenome of the popular Protected Geographical Indication potatoes of Naxos.

Introduction: Despite the significant progress that has been made during the last decade, Greece still faces the effects of road traffic accidents (RTAs) to a great extent every year. This study represents an epidemiological approach to road traffic injuries (RTIs) presenting to a secondary hospital in a geographical area with very low-quality road network; it aims to indicate possible preventive measures and actions. Methods: The present study was conducted in Rethymnon General Hospital between January 2018 and February 2020. Data from all trauma patients who presented to the emergency department (ED) after RTAs were retrospectively collected from patient medical records. The severity of injury sustained by road traffic victims was graded using the Injury Severity Score (ISS). Results: During the study period, 1582 trauma patients presented to the ED after RTAs. There were 1079 men and 503 women and the median age was 30 years. In total, 818 motorcycle-related injuries (51.7%), 497 automobile-related injuries (31.4%), 165 bicycle-related injuries (10.4%) and 102 pedestrian injuries (6.4%) were documented. Of the 1582 trauma patients, 58.2% (921) presented with injuries to the extremities, 35.3% (554) presented with thoracic injuries, 34.4% (541) presented with head injuries, 30% (475) presented with spinal column injuries, 17.4% (271) presented with facial injuries, 12.9% (203) presented with abdominal injuries and 10.3% (162) presented with pelvic injuries. A significant increase in the number of incidents was noticed during the tourist season. Median ISS was 2 (IQR=4). 53.7% of patients who were transferred to the hospital by ambulance had an ISS≤4. In 41 cases, transportation to a tertiary hospital was necessary, six patients had emergency operations and 13 others died in the ED. The median length of hospital stay was 3 (IQR=6) days. Conclusion: Actions that could possibly mitigate the burden of RTIs in the district of Rethymnon include upgrading the level of law enforcement, implementing educational strategies and information campaigns against inappropriate ambulance use, encouraging facilities to develop trauma registries and ensuring adequate hospital staffing.

Molar incisor hypomineralization is a complex developmental enamel defect that affects the permanent dentition of children with significant functional and aesthetic implications. Saliva is an ideal diagnostic tool and ensures patients’ compliance by diminishing the discomfort especially in pediatric population. Lately, salivary proteome analysis has progressively evolved in various biomedical disciplines. As changes in saliva composition are associated with oral diseases, it is reasonable to assume that the saliva proteome of MIH-affected children might be altered compared to healthy children. This study analyzed the human and microbial salivary proteome in children with MIH in order to identify salivary markers indicative of the pathology. The conducted proteomic analysis generated a comprehensive dataset comprising a total of 1515 high confidence identifications and revealed a clear discrimination between the two groups. Statistical comparison identified 142 differentially expressed proteins, while the pathway analysis indicated deregulation of inflammation, immune response mechanisms, and defense response to bacteria in MIH patients. Bacterial proteome analysis showed a lower diversity for the microbial species, which highlights the dysbiotic environment established in the MIH pathology.

Autotaxin (ATX) is a secreted lysophospholipase D catalyzing the extracellular production of lysophosphatidic acid (LPA), a growth factor-like signaling lysophospholipid. ATX and LPA signaling have been incriminated in the pathogenesis of different chronic inflammatory diseases and various types of cancer. In this report, deregulated ATX and LPA levels were detected in the spinal cord and plasma of mice during the development of experimental autoimmune encephalomyelitis (EAE). Among the different sources of ATX expression in the inflamed spinal cord, F4/80+ CD11b+ cells, mostly activated macrophages and microglia, were found to express ATX, further suggesting an autocrine role for ATX/LPA in their activation, an EAE hallmark. Accordingly, ATX genetic deletion from CD11b+ cells attenuated the severity of EAE, thus proposing a pathogenic role for the ATX/LPA axis in neuroinflammatory disorders.

Recent studies have linked the activity of ER aminopeptidase 2 (ERAP2) to increased efficacy of immune-checkpoint inhibitor cancer immunotherapy, suggesting that pharmacological inhibition of ERAP2 could have important therapeutic implications. To explore the effects of ERAP2 inhibition on the immunopeptidome of cancer cells, we treated MOLT-4 T lymphoblast leukemia cells with a recently developed selective ERAP2 inhibitor, isolated Major Histocompatibility class I molecules (MHCI), and sequenced bound peptides by liquid chromatography tandem mass spectrometry. Inhibitor treatment induced significant shifts on the immunopeptidome so that more than 20% of detected peptides were either novel or significantly upregulated. Most of the inhibitor-induced peptides were 9mers and had sequence motifs and predicted affinity consistent with being optimal ligands for at least one of the MHCI alleles carried by MOLT-4 cells. Such inhibitor-induced peptides could serve as triggers for novel cytotoxic responses against cancer cells and synergize with the therapeutic effect of immune-checkpoint inhibitors.

HuR is an abundant RNA-binding protein acting as a post-transcriptional regulator of many RNAs including mRNAs encoding inflammatory mediators, cytokines, death signalers and cell cycle regulators. In the context of intestinal pathologies, elevated HuR is considered to enhance the stability and the translation of pro-tumorigenic mRNAs providing the rationale for its pharmacological targeting. However, HuR also possesses specific regulatory functions for innate immunity and cytokine mRNA control which can oppose intestinal inflammation and tumor promotion. Here, we aim to identify contexts of intestinal inflammation where the innate immune and the epithelial functions of HuR converge or diverge. To address this, we use a disease-oriented phenotypic approach using mice lacking HuR either in intestinal epithelia or myeloid-derived immune compartments. These mice were compared for their responses to (a) Chemically induced Colitis; (b) Colitis- associated Cancer (CAC); (c) T-cell mediated enterotoxicity; (d) Citrobacter rodentium-induced colitis; and (e) TNF-driven inflammatory bowel disease. Convergent functions of epithelial and myeloid HuR included their requirement for suppressing inflammation in chemically induced colitis and their redundancies in chronic TNF-driven IBD and microbiota control. In the other contexts however, their functions diversified. Epithelial HuR was required to protect the epithelial barrier from acute inflammatory or infectious degeneration but also to promote tumor growth. In contrast, myeloid HuR was required to suppress the beneficial inflammation for pathogen clearance and tumor suppression. This cellular dichotomy in HuR's functions was validated further in mice engineered to express ubiquitously higher levels of HuR which displayed diminished pathologic and beneficial inflammatory responses, resistance to epithelial damage yet a heightened susceptibility to CAC. Our study demonstrates that epithelial and myeloid HuR affect different cellular dynamics in the intestine that need to be carefully considered for its pharmacological exploitation and points toward potential windows for harnessing HuR functions in intestinal inflammation.

The Internet-of-things facilitates the development of many groundbreaking applications. A large number of these applications involve mobile end nodes and a sparsely deployed network of base stations that operate as gateways to the Internet. Most of the mobile nodes, at least within city areas, are connected through low power wide area networking technologies (LPWAN) using public frequencies. Mobility and sparse network coverage result in long delays and intermittent connectivity for the end nodes. Disruption Tolerant Networks and utilization of heterogeneous wireless interfaces have emerged as key technologies to tackle the problem at hand. The first technology renders communication resilient to intermittent connectivity by storing and carrying data while the later increases the communication opportunities of the end nodes and at the same time reduces energy consumption whenever short-range communication is possible. However, one has to consider that end nodes are typically both memory and energy constrained devices which makes finding an energy efficient data transmission policy for heterogeneous disruption tolerant networks imperative. In this work we utilize information related to the spatial availability of network resources and localization information to formulate the problem at hand as a dynamic programming problem. Next, we utilize the framework of Markov Decision Processes to derive approximately optimal and suboptimal data transmission policies. We also prove that we can achieve improved packet transmission policies and reduce energy consumption, extending battery lifetime. This is achieved by knowing the spatial availability of heterogeneous network resources combined with the mobile node’s location information. Numerical resultsshow significant gains achieved by utilizing the derived approximately optimal and suboptimal policies.