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.     

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.     

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.     

FIB voltage contrast measurement for enhanced circuit repairs

Recent planar technologies with 3 metal layers or more challenge current physical design modification capacities using Focused Ion Beam tools. Image visibility on the FIB is drastically reduced, making accurate positioning and milling operations in the area of interest more difficult. Despite the complexity of FIB modifications, however, the demand for circuit modifications continues to increase. We will present a method which brings voltage contrast measurement capabilities to FIB systems. With this method, it is possible to verify the completion of FIB repairs.     

Chiral Se Nanobrooms with Wavelength and Polarization Sensitive Scattering

High-index dielectric nanostructures offer strong magnetic and electric resonances in the visible range and low optical losses, stimulating research interest in their use for light manipulation technologies. Lithographic fabrication of dielectric nanostructures, while providing precise control over the pattern dimensions, limits the scalability of this approach for practical applications due to an inefficient fabrication process and limited production quantity. Here, the colloidal synthesis of high-index chiral dielectric nanostructures with a broom-like geometry made from trigonal Se is demonstrated. The anisotropic morphology and crystal structure of Se nanobrooms enable both linearly and circularly polarized scattering, as well as spectrum variation along the particle axis, which is, to the authors’ knowledge, the first observation of such behavior from dielectric colloidal nanostructures. To show the versatility of the highly scattering Se NB suspensions, 2D and 3D printing of Se NB inks are demonstrated as a proof of concept. This approach provides a way to manipulate light using aqueous dispersions of high-index dielectric nanostructures, unlocking their potential to fit in various morphologies and dimensions in 2D and 3D for broad applications.