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.     

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.     

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.     

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.     

Europe should stop taxing innovation

After nearly 48 years of failure to create the EU patent, language issues and the design of a centralised patent-litigation court still dominate headlines. But behind these issues there are high financial stakes and control power to play for. The recent EU Council deal on an ‘enhanced’ European patent system does not solve the above problems, and has not eliminated lingering governance issues. The risk for Europe is that a final patent agreement might be reached that does not cure the system of its major ills, and thus does not bring about any significant improvement for those that need it most: entrepreneurs and innovative companies starting out on the innovation process. The creation of an effective single EU patent requires (i) English-only post-grant translation, (ii) the end of nationally granted patents, (iii) phasing-out of the current ‘European patent’, (iv) lower fees for young innovative companies, and (v) a radical shake-up of the governance of the European Patent Office.     

Treatment of uncertain material interfaces in compressible flows

To treat uncertain interface position is an important issue for complex applications. In this paper, we address the characterization of randomly perturbed interfaces between fluids thanks to stochastic modeling and uncertainty quantification through the 2D Euler system. The perturbed interface is modeled as a random field and represented by a Karhunen–Loève expansion. The stochastic 2D Euler system is solved applying Polynomial Chaos theory through the Intrusive Polynomial Moment Method (IPMM). This stochastic resolution method is fully explained and studied (theoretically and numerically). Stochastic Richtmyer–Meshkov unstable flows are solved and presented for several configurations of the uncertain interface (different rugosities) between the fluids. The probability density functions of the mass density of the fluid in the vicinity of the interface are computed built and compared for the different simulations: the system exhibits strong sensitivity with respect to the stochastic initially leading modes.     

Microstructure of Low C Steel Isothermally Transformed in the M S to M f Temperature Range

An isothermal transformation was observed when a fully austenitized lean-alloyed, low C steel was quenched to a temperature in the M _S to M _f temperature range and held at the quenching temperature. The dilatometric analysis revealed that the isothermal transformation was distinct from the bainitic transformation. Internal friction (IF) measurements and X-ray diffraction (XRD) analysis showed that the dislocation density in the isothermal transformation product was larger than in lower bainite, and lower than in athermal martensite. Microstructural analysis by transmission electron microscopy (TEM) revealed that the isothermal transformation product had a specific microstructure consisting of large lath-type constituent units with wavy boundaries, with a Nishiyama?CWassermann orientation relationship (NW OR) with respect to the parent austenite. The isothermal transformation below M _S proceeds by the thickening of athermally formed laths.     

Edge degree-of-sharpness and free-stream turbulence scale effects on the aerodynamics of a bridge deck

This paper discusses the sensitivity of the aerodynamic behavior of a trapezoidal-shaped bridge deck cross-section to its lower corner degree-of-sharpness and to the incoming flow turbulence integral length scale in conjunction with low turbulence intensity. Since these features are hard to set and measure in experimental facilities, the aerodynamic behavior of the body has been investigated through the computational simulation of the flow around it. The results are given in term of force coefficients, Strouhal number, pressure distribution along its surface, and the mean and instantaneous flow patterns. Dramatic changes in the force coefficients and Strouhal number occur following small changes in the parameter values. These changes have been found to be due to significant modifications in the topological structure of the flow. Special emphasis has been given to the analysis of the separation and reattachment points, the recirculation bubble length, the vortex shedding mechanisms and the wake structures. On the basis of the results, four aerodynamic regimes have been pointed out in analogy with the well-known individual Re number regimes. Some of these regimes have also been recognized on the deck section with the considered sharpest and smoothest lower edge treatments, i.e. for the highest and lowest degrees-of-sharpness.