TRPA1 Role in Inflammatory Disorders: What Is Known So Far?

The transient receptor potential ankyrin 1 (TRPA1), a member of the TRP superfamily of channels, is primarily localized in a subpopulation of primary sensory neurons of the trigeminal, vagal, and dorsal root ganglia, where its activation mediates neurogenic inflammatory responses. TRPA1 expression in resident tissue cells, inflammatory, and immune cells, through the indirect modulation of a large series of intracellular pathways, orchestrates a range of cellular processes, such as cytokine production, cell differentiation, and cytotoxicity. Therefore, the TRPA1 pathway has been proposed as a protective mechanism to detect and respond to harmful agents in various pathological conditions, including several inflammatory diseases. Specific attention has been paid to TRPA1 contribution to the transition of inflammation and immune responses from an early defensive response to a chronic pathological condition. In this view, TRPA1 antagonists may be regarded as beneficial tools for the treatment of inflammatory conditions.     

Leptin Signaling in Obesity and Colorectal Cancer

Obesity and colorectal cancer (CRC) are among the leading diseases causing deaths in the world, showing a complex multifactorial pathology. Obesity is considered a risk factor in CRC development through inflammation, metabolic, and signaling processes. Leptin is one of the most important adipokines related to obesity and an important proinflammatory marker, mainly expressed in adipose tissue, with many genetic variation profiles, many related influencing factors, and various functions that have been ascribed but not yet fully understood and elucidated, the most important ones being related to energy metabolism, as well as endocrine and immune systems. Aberrant signaling and genetic variations of leptin are correlated with obesity and CRC, with the genetic causality showing both inherited and acquired events, in addition to lifestyle and environmental risk factors; these might also be related to specific pathogenic pathways at different time points. Moreover, mutation gain is a crucial factor enabling the genetic process of CRC. Currently, the inconsistent and insufficient data related to leptin’s relationship with obesity and CRC indicate the necessity of further related studies. This review summarizes the current knowledge on leptin genetics and its potential relationship with the main pathogenic pathways of obesity and CRC, in an attempt to understand the molecular mechanisms of these associations, in the context of inconsistent and contradictory data. The understanding of these mechanisms linking obesity and CRC could help to develop novel therapeutic targets and prevention strategies, resulting in a better prognosis and management of these diseases.     

Systematic Review and Meta-Analysis of Mass Spectrometry Proteomics Applied to Human Peripheral Fluids to Assess Potential Biomarkers of Schizophrenia

Mass spectrometry (MS)-based techniques can be a powerful tool to identify neuropsychiatric disorder biomarkers, improving prediction and diagnosis ability. Here, we evaluate the efficacy of MS proteomics applied to human peripheral fluids of schizophrenia (SCZ) patients to identify disease biomarkers and relevant networks of biological pathways. Following PRISMA guidelines, a search was performed for studies that used MS proteomics approaches to identify proteomic differences between SCZ patients and healthy control groups (PROSPERO database: CRD42021274183). Nineteen articles fulfilled the inclusion criteria, allowing the identification of 217 differentially expressed proteins. Gene ontology analysis identified lipid metabolism, complement and coagulation cascades, and immune response as the main enriched biological pathways. Meta-analysis results suggest the upregulation of FCN3 and downregulation of APO1, APOA2, APOC1, and APOC3 in SCZ patients. Despite the proven ability of MS proteomics to characterize SCZ, several confounding factors contribute to the heterogeneity of the findings. In the future, we encourage the scientific community to perform studies with more extensive sampling and validation cohorts, integrating omics with bioinformatics tools to provide additional comprehension of differentially expressed proteins. The produced information could harbor potential proteomic biomarkers of SCZ, contributing to individualized prognosis and stratification strategies, besides aiding in the differential diagnosis.     

Liver Steatosis: A Marker of Metabolic Risk in Children

Obesity is one of the greatest health challenges affecting children of all ages and ethnicities. Almost 19% of children and adolescents worldwide are overweight or obese, with an upward trend in the last decades. These reports imply an increased risk of fat accumulation in hepatic cells leading to a series of histological hepatic damages gathered under the acronym NAFLD (Non-Alcoholic Fatty Liver Disease). Due to the complex dynamics underlying this condition, it has been recently renamed as ‘Metabolic Dysfunction Associated Fatty Liver Disease (MAFLD)’, supporting the hypothesis that hepatic steatosis is a key component of the large group of clinical and laboratory abnormalities of Metabolic Syndrome (MetS). This review aims to share the latest scientific knowledge on MAFLD in children in an attempt to offer novel insights into the complex dynamics underlying this condition, focusing on the novel molecular aspects. Although there is still no treatment with a proven efficacy for this condition, starting from the molecular basis of the disease, MAFLD’s therapeutic landscape is rapidly expanding, and different medications seem to act as modifiers of liver steatosis, inflammation, and fibrosis.     

Alchemical Design of Pharmacological Chaperones with Higher Affinity for Phenylalanine Hydroxylase

Phenylketonuria (PKU) is a rare metabolic disease caused by variations in a human gene, PAH, encoding phenylalanine hydroxylase (PAH), and the enzyme converting the essential amino acid phenylalanine into tyrosine. Many PKU-causing variations compromise the conformational stability of the encoded enzyme, decreasing or abolishing its catalytic activity, and leading to an elevated concentration of phenylalanine in the blood, which is neurotoxic. Several therapeutic approaches have been developed to treat the more severe manifestations of the disorder, but they are either not entirely effective or difficult to adhere to throughout life. In a search for novel pharmacological chaperones to treat PKU, a lead compound was discovered (compound IV) that exhibited promising in vitro and in vivo chaperoning activity on PAH. The structure of the PAH-IV complex has been reported. Here, using alchemical free energy calculations (AFEC) on the structure of the PAH-IV complex, we design a new generation of compound IV-analogues with a higher affinity for the enzyme. Seventeen novel analogues were synthesized, and thermal shift and isothermal titration calorimetry (ITC) assays were performed to experimentally evaluate their stabilizing effect and their affinity for the enzyme. Most of the new derivatives bind to PAH tighter than lead compound IV and induce a greater thermostabilization of the enzyme upon binding. Importantly, the correspondence between the calculated alchemical binding free energies and the experimentally determined ΔΔG_b values is excellent, which supports the use of AFEC to design pharmacological chaperones to treat PKU using the X-ray structure of their complexes with the target PAH enzyme.     

Energy-aware lazy scheduling algorithm for energy-harvesting sensor nodes

The main problem in dealing with energy-harvesting (EH) sensor nodes is represented by the scarcity and non-stationarity of powering, due to the nature of the renewable energy sources. In this work, the authors address the problem of task scheduling in processors located in sensor nodes powered by EH sources. Some interesting solutions have appeared in the literature in the recent past, as the lazy scheduling algorithm (LSA), which represents a performing mix of scheduling effectiveness and ease of implementation. With the aim of achieving a more efficient and conservative management of energy resources, a new improved LSA solution is here proposed. Indeed, the automatic ability of foreseeing at run-time the task energy starving (i.e. the impossibility of finalizing a task due to the lack of power) is integrated within the original LSA approach. Moreover, some modifications have been applied in order to reduce the LSA computational complexity and thus maximizing the amount of energy available for task execution. The resulting technique, namely energy-aware LSA, has then been tested in comparison with the original one, and a relevant performance improvement has been registered both in terms of number of executable tasks and in terms of required computational burden.     

Needs and desires: transcending the ‘bipolar tendency’

The paper connects two of the concerns of this special issue: the way to transcend the ‘bipolar tendency’ of the market culture and to ‘deal with the swings between prophesies of doom that serve only to paralyse us further, and the unbridled consumerism that makes things worse’, and how to remain human when being mediated by technology in contrast to how we are in the presence of others. Our contribution is based on an extensive conception of human beings (HBs). HBs cannot be considered only as cognitive subjects but also in their anthropological integrity. What we mean by this that they think and feel, they share concepts and emotions, they plan and desire. It implies that any attempt at reducing this complexity is a way to diminish human beings and their capabilities. HBs need meaningful course of actions to manage complexity and to tackle alternatives. Meanings come from purposeful activities, and people’s purposes are based not only on utilitarian or rational enquiries but also on what they consider right and good, according to their vision of the world. This is also the key to overcome the ‘bipolar tendency’.     

The ECHORD project proposals analysis – Research profiles,collaboration patterns and research topic trends

This paper investigates the research profiles, collaboration patterns and research topic trends which can be identified in the proposals submitted to the ECHORD (European Clearing House for Open Robotics Development) FP7 project. On a country level, clusters were identified and characterized by patterns of proposal production per inhabitant, score and international cooperation. Belgium and Sweden constitute a cluster characterized by high proposal production, with very high scores and extensive international collaboration. Belgium also excels from another cluster analysis, being as the only country where 100% of proposals involve industry–academia cooperation and obtain scores above 10. Other findings show that single partner proposals have significantly lower quality than multi-partner proposals but, on the other hand, the number of countries involved shows no influence on the quality of the proposals. Despite the high number of industrial participants present on the proposals, it is observed that they play secondary roles in the proposals, with a very low number projects leaded by companies. Also, it is observed that partnerships between research institutions (non-universities) are the most successful. Concerning topics of the proposals, the technology human–robot interface and the product vision robot for small-scale manufacturing are the most significant. Finally, the paper shows clusters of institutions extracted from the giant network of relations obtained from the ECHORD set of proposals.     

On the detection of card-sharing traffic through wavelet analysis and Support Vector Machines

In the last years, the interest in methods and techniques for circumventing the security of the available digital video broadcasting systems is continuously increasing. Digital TV providers are struggling to restrict access to their video contents only to authorized users, by deploying more and more sophisticated conditional access systems. At the state-of-the-art, the most significant menace is the card-sharing activity which exploits a known weakness allowing an authorized subscriber to provide access to digital contents to a potentially large group of unauthorized ones connected over a communication network. This is usually realized by using ad hoc customized devices. Detecting the presence of these illegal systems on a network, by recognizing their related traffic is an issue of primary importance. Unfortunately, to avoid the identification of such traffic, payload obfuscation strategies based on encryption are often used, hindering packet inspection techniques.This paper presents a strategy for the detection of card-sharing traffic, empowered by machine-learning-driven traffic classification techniques and based on the natural capability of wavelet analysis to decompose a traffic time series into several component series associated with particular time and frequency scales and hence allowing its observation at different frequency component levels and with different resolutions. These ideas have been used for the proof-of-concept implementation of an SVM-based binary classification scheme that relies only on time regularities of the traffic and not on the packet contents and hence is immune to payload obfuscation techniques.     

A Java Framework to Specify Faultloads for Fault Injection Campaigns

In an operational environment, the identification and reproduction of faults may be hard to be done, specially in complex systems. Use of fault injection accelerates this process, improving the test of fault tolerance mechanisms. However, there are a significant amount of fault injectors available, using several different approaches. This diversity of tools, each one with different methods to describe faultloads for fault injection campaigns, imposes severe obstacles to the efficient use of such fault injectors. In this context, this paper presents jFaultload, which applies Java for the specification of faultloads and translates them to specific formats that are appropriate to each available fault injector. Fault injectors for communication systems were integrated in the environment and completes the test scenario. The service under test used to demonstrate the usability and expressiveness of our solution is a video streaming session using RTP Protocol.