Perinatal Obesity Induces Hepatic Growth Restriction with Increased DNA Damage Response,Senescence, and Dysregulated Igf-1-Akt-Foxo1 Signaling in Male Offspring of Obese Mice

Maternal obesity predisposes for hepato-metabolic disorders early in life. However, the underlying mechanisms causing early onset dysfunction of the liver and metabolism remain elusive. Since obesity is associated with subacute chronic inflammation and accelerated aging, we test the hypothesis whether maternal obesity induces aging processes in the developing liver and determines thereby hepatic growth. To this end, maternal obesity was induced with high-fat diet (HFD) in C57BL/6N mice and male offspring were studied at the end of the lactation [postnatal day 21 (P21)]. Maternal obesity induced an obese body composition with metabolic inflammation and a marked hepatic growth restriction in the male offspring at P21. Proteomic and molecular analyses revealed three interrelated mechanisms that might account for the impaired hepatic growth pattern, indicating prematurely induced aging processes: (1) Increased DNA damage response (γH2AX), (2) significant upregulation of hepatocellular senescence markers (Cdnk1a, Cdkn2a); and (3) inhibition of hepatic insulin/insulin-like growth factor (IGF)-1-AKT-p38-FoxO1 signaling with an insufficient proliferative growth response. In conclusion, our murine data demonstrate that perinatal obesity induces an obese body composition in male offspring with hepatic growth restriction through a possible premature hepatic aging that is indicated by a pathologic sequence of inflammation, DNA damage, senescence, and signs of a possibly insufficient regenerative capacity.     

Differential Expression of Proteins in an Atypical Presentation of Autoimmune Lymphoproliferative Syndrome

Autoimmune lymphoproliferative syndrome (ALPS) is a rare disease defined as a defect in the lymphocyte apoptotic pathway. Currently, the diagnosis of ALPS is based on clinical aspects, defective lymphocyte apoptosis and mutations in Fas, FasL and Casp 10 genes. Despite this, ALPS has been misdiagnosed. The aim of this work was to go one step further in the knowledge of the disease, through a molecular and proteomic analysis of peripheral blood mononuclear cells (PBMCs) from two children, a 13-year-old girl and a 6-year-old boy, called patient 1 and patient 2, respectively, with clinical data supporting the diagnosis of ALPS. Fas, FasL and Casp10 genes from both patients were sequenced, and a sample of the total proteins from patient 1 was analyzed by label-free proteomics. Pathway analysis of deregulated proteins from PBMCs was performed on the STRING and PANTHER bioinformatics databases. A mutation resulting in an in-frame premature stop codon and protein truncation was detected in the Fas gene from patient 2. From patient 1, the proteomic analysis showed differences in the level of expression of proteins involved in, among other processes, cell cycle, regulation of cell cycle arrest and immune response. Noticeably, the most down-regulated protein is an important regulator of the cell cycle process. This could be an explanation of the disease in patient 1.     

Elevation of Tear MMP-9 Concentration as a Biomarker of Inflammation in Ocular Pathology by Antibody Microarray Immunodetection Assays

Matrix metalloproteinases are a family of enzymes fundamental in inflammatory processes. Between them, MMP-9 is up-regulated during inflammation; thus, its quantification in non-invasive fluids is a promising approach for inflammation identification. To this goal, a biomarker quantification test was developed for ocular inflammation detection using anti-MMP-9 antibody microarrays (AbMAs). After validation with eight healthy control tear samples characterized by ELISA, 20 samples were tested from individuals diagnosed with ocular inflammation due to: cataracts, glaucoma, meibomian gland dysfunction, allergy, or dry eye. Concentration values of tear MMP-9 were obtained for each sample, and 12 patients surpassed the pathological threshold (30 ng/mL). A significant elevation of MMP-9 concentration in the tears of glaucoma patients compared with healthy controls was observed. In order to evaluate the diagnostic ability, an ROC curve analysis was performed using our data, determining the optimal threshold for the test at 33.6 ng/mL of tear MMP-9. In addition, a confusion matrix was applied, estimating sensitivity at 60%, specificity at 88%, and accuracy at 68%. In conclusion, we demonstrated that the AbMAs system allows the quantification of MMP-9 in pathologies that involve inflammation of the ocular surface.     

Synthesis and Biological Evaluation of Small Molecules as Potential Anticancer Multitarget Agents

Twenty-six triazole-based derivatives were designed for targeting both PD-L1 (programmed death receptor ligand 1) and VEGFR-2 (vascular endothelial growth factor receptor 2). These compounds were synthetized and biologically evaluated as multitarget inhibitors of VEGFR-2, PD-L1 and c-Myc proteins. The antiproliferative activity of these molecules on several tumor cell lines (HT-29, A-549, and MCF-7) and on the non-tumor cell line HEK-293 was determined. The effects on the abovementioned biological targets were evaluated for some selected compounds. Compound 23, bearing a p-chlorophenyl group, showed better results than sorafenib in regard to the downregulation of VEGFR-2 and a similar effect to BMS-8 on both PD-L1 and c-Myc proteins. The antiangiogenic and antivascular activities of chloro derivatives were also established by endothelial microtube formation assay on Matrigel^®.     

A Systematic Study of Restorative Crown-Materials Combinations for Dental Implants: Characterization of Mechanical Properties under Dynamic Loads

This study aimed to find the optimum mechanical characteristics of the restorative materials for the manufacture of implant crowns subjected to impact loading when different combinations of materials are used for the inner and outer crown. Several combinations of external–internal crown restorative materials were analyzed. The dynamic stresses at eight different zones of a dental implant subjected to an impact load and the influence of several mechanical properties, such as the Young’s modulus, Poisson’s ratio, density, and initial velocity, were analyzed and compared. A detailed 3D model was created, including the crown, the retention screw, the implant, and a mandible section. The model was then built by importing the 3D geometries from CAD software. The whole 3D model was carefully created in order to guarantee a finite element mesh that produced results adjusted to physical reality. Then, we conducted a numerical simulation using the finite element method (FEM). The results of the FEM analysis allowed for evaluating the effect that different combinations of restorative materials and mechanical properties had on the stress distribution in various regions of the implant. The choice of restorative material is a factor to be considered in order to preserve the integrity of osseointegration. Restorative materials transfer more or less stress to the dental implant and surrounding bone, depending on their stiffness. Therefore, an inadequate Young’s modulus of the rehabilitation material can affect the survival of the implant over time. Eight interactive graphics were provided on a web-based surface platform to help clinical dentists, researchers, and manufacturers to select the best restorative materials combination for the crown.     

Improving the Management of Endometrial Cancer Patients through the Use of Liquid Biopsy Analyses: A Case Report

Endometrial cancer (EC) is the 4th most common neoplasm of the female genital tract, with 15–20% of patients being of high risk of recurrence which leads to a significant decrease in patient survival. Current therapeutic options for patients with EC are poor, being the combined therapy of carboplatin and paclitaxel the standard of care, with limited efficacy. Therefore, new therapeutic options and better monitoring tools are needed to improve the management of the disease. In the current case report, we showcase the value of liquid biopsy analyses in a microsatellite instability EC patient with initially good prognosis that however underwent rapid progression disease within 6 months post-surgery; through the study of plasma cfDNA/ctDNA dynamics to assess the tumour evolution during treatment, as well as the study of the uterine aspirate as a valuable sample that captures the intra-tumour heterogeneity that allows a comprehensive genomic profiling of the disease to identify potential therapeutic options. Furthermore, preclinical models were generated at the time of tumour progression to assess the efficacy of the identified targeted therapies.     

Industrial application integration using the unification approach to agent-enabled semantic SOA

Within the enterprise, information infrastructure as the mean to bring together different software applications is the key component to enable cooperation and information and knowledge exchange in an open-distributed environment. The paper addresses the issues of industrial application integration in business processes using agent-enabled service-oriented architectures (SOA). In this paper, we show that agent-enabled SOA can play an important role for service integration. Our framework combines Web services (WS) and intelligent agent technologies orchestrated by a business process management system. This framework looks for unification of agent and WS service models, is grounded in a semantic SOA of an agent platform and is supported by the Component Agent Platform Over .NET Framework agent platform tools. We describe the architecture and illustrate the approach by an industrial application scenario from petroleum wells’ drilling.     

Random 3-SAT: The Plot Thickens

This paper presents an experimental investigation of the following questions: how does the average-case complexity of random 3-SAT, understood as a function of the order (number of variables) for fixed density (ratio of number of clauses to order) instances, depend on the density? Is there a phase transition in which the complexity shifts from polynomial to exponential in the order? Is the transition dependent or independent of the solver? Our experiment design uses three complete SAT solvers embodying different algorithms: GRASP, CPLEX, and CUDD. We observe new phase transitions for all three solvers, where the median running time shifts from polynomial in the order to exponential. The location of the phase transition appears to be solver-dependent. GRASP shifts from polynomial to exponential complexity near the density of 3.8, CPLEX shifts near density 3, while CUDD exhibits this transition between densities of 0.1 and 0.5. This experimental result underscores the dependence between the solver and the complexity phase transition, and challenges the widely held belief that random 3-SAT exhibits a phase transition in computational complexity very close to the crossover point.     

Matisse: A System-on-Chip Design Methodology Emphasizing Dynamic Memory Management

MATISSE is a design environment intended for developing systems characterized by a tight interaction between control and data-flow behavior, intensive data storage and transfer, and stringent real-time requirements. Matisse bridges the gap from a system specification, using a concurrent object-oriented language, to an optimized embedded single-chip hardware/software implementation. Matisse supports stepwise exploration and refinement of dynamic memory management, memory architecture exploration, and gradual incorporation of timing constraints before going to traditional tools for hardware synthesis, software compilation, and inter-processor communication synthesis. With this approach, specifications of embedded systems can be written in a high-level programming language using data abstraction. Application of MATISSE on telecom protocol processing systems in the ATM area shows significant improvements in area usage and power consumption.