Biomarkers in Glycogen Storage Diseases: An Update

Glycogen storage diseases (GSDs) are a group of 19 hereditary diseases caused by a lack of one or more enzymes involved in the synthesis or degradation of glycogen and are characterized by deposits or abnormal types of glycogen in tissues. Their frequency is very low and they are considered rare diseases. Except for X-linked type IX, the different types are inherited in an autosomal recessive pattern. In this study we reviewed the literature from 1977 to 2020 concerning GSDs, biomarkers, and metabolic imbalances in the symptoms of some GSDs. Most of the reported studies were performed with very few patients. Classification of emerging biomarkers between different types of diseases (hepatics GSDs, McArdle and PDs and other possible biomarkers) was done for better understanding. Calprotectin for hepatics GSDs and urinary glucose tetrasaccharide for Pompe disease have been approved for clinical use, and most of the markers mentioned in this review only need clinical validation, as a final step for their routine use. Most of the possible biomarkers are implied in hepatocellular adenomas, cardiomyopathies, in malfunction of skeletal muscle, in growth retardation, neutropenia, osteopenia and bowel inflammation. However, a few markers have lost interest due to a great variability of results, which is the case of biotinidase, actin alpha 2, smooth muscle, aorta and fibroblast growth factor receptor 4. This is the first review published on emerging biomarkers with a potential application to GSDs.     

Microencapsulated Bifidobacterium bifidum and Lactobacillus gasseri in Combination with Quercetin Inhibit Colorectal Cancer Development in ApcMin/+ Mice

Recent studies have suggested that flavonoids such as quercetin and probiotics such as Bifidobacterium bifidum (Bf) and Lactobacillus gasseri (Lg) could play a relevant role in inhibiting colon cancer cell growth. Our study investigated the role of dietary supplementation with microencapsulated probiotics (Bf and Lg) along with quercetin in the development of mouse colorectal cancer (CRC). Methods: Adenomatous polyposis coli/multiple intestinal neoplasia (Apc^Min/+) mice were fed a standard diet or the same diet supplemented with microencapsulated probiotics (Bf and Lg strains, 10⁷ CFU/100 g food) or both probiotics strains plus microencapsulated quercetin (15 mg/100 g food) for 73 days. Changes in body and organ weights, energy metabolism, intestinal microbiota, and colon tissue were determined. The expression of genes related to the Wnt pathway was also analyzed in colon samples. Results: Dietary supplementation with microencapsulated probiotics or microencapsulated probiotics plus quercetin reduced body weight loss and intestinal bleeding in Apc^Min/+ mice. An improvement in energy expenditure was observed after 8 weeks but not after 10 weeks of treatment. A supplemented diet with microencapsulated Bf and Lg reduced the number of aberrant crypt foci (ACF) and adenomas by 45% and 60%, respectively, whereas the supplementation with Bf, Lg and quercetin decreased the number of ACF and adenomas by 57% and 80%, respectively. Microencapsulated Bf and Lg in combination with quercetin could exert inhibition of the canonical Wnt/β-catenin signaling pathway in the colon of Apc^Min/+ mice Conclusions: The administration of microencapsulated Bf and Lg, individually or in combination with quercetin, inhibits the CRC development in Apc^Min/+ mice.     

Human-Induced Neural and Mesenchymal Stem Cell Therapy Combined with a Curcumin Nanoconjugate as a Spinal Cord Injury Treatment

We currently lack effective treatments for the devastating loss of neural function associated with spinal cord injury (SCI). In this study, we evaluated a combination therapy comprising human neural stem cells derived from induced pluripotent stem cells (iPSC-NSC), human mesenchymal stem cells (MSC), and a pH-responsive polyacetal–curcumin nanoconjugate (PA-C) that allows the sustained release of curcumin. In vitro analysis demonstrated that PA-C treatment protected iPSC-NSC from oxidative damage in vitro, while MSC co-culture prevented lipopolysaccharide-induced activation of nuclear factor-κB (NF-κB) in iPSC-NSC. Then, we evaluated the combination of PA-C delivery into the intrathecal space in a rat model of contusive SCI with stem cell transplantation. While we failed to observe significant improvements in locomotor function (BBB scale) in treated animals, histological analysis revealed that PA-C-treated or PA-C and iPSC-NSC + MSC-treated animals displayed significantly smaller scars, while PA-C and iPSC-NSC + MSC treatment induced the preservation of β-III Tubulin-positive axons. iPSC-NSC + MSC transplantation fostered the preservation of motoneurons and myelinated tracts, while PA-C treatment polarized microglia into an anti-inflammatory phenotype. Overall, the combination of stem cell transplantation and PA-C treatment confers higher neuroprotective effects compared to individual treatments.     

Genetic Contribution of Endometriosis to the Risk of Developing Hormone-Related Cancers

Endometriosis is a common gynecological disorder that has been associated with endometrial, breast and epithelial ovarian cancers in epidemiological studies. Since complex diseases are a result of multiple environmental and genetic factors, we hypothesized that the biological mechanism underlying their comorbidity might be explained, at least in part, by shared genetics. To assess their potential genetic relationship, we performed a two-sample mendelian randomization (2SMR) analysis on results from public genome-wide association studies (GWAS). This analysis confirmed previously reported genetic pleiotropy between endometriosis and endometrial cancer. We present robust evidence supporting a causal genetic association between endometriosis and ovarian cancer, particularly with the clear cell and endometrioid subtypes. Our study also identified genetic variants that could explain those associations, opening the door to further functional experiments. Overall, this work demonstrates the value of genomic analyses to support epidemiological data, and to identify targets of relevance in multiple disorders.     

Embryonic Trophectoderm Secretomics Reveals Chemotactic Migration and Intercellular Communication of Endometrial and Circulating MSCs in Embryonic Implantation

Embryonic implantation is a key step in the establishment of pregnancy. In the present work, we have carried out an in-depth proteomic analysis of the secretome (extracellular vesicles and soluble proteins) of two bovine blastocysts embryonic trophectoderm primary cultures (BBT), confirming different epithelial–mesenchymal transition stages in these cells. BBT-secretomes contain early pregnancy-related proteins and angiogenic proteins both as cargo in EVs and the soluble fraction. We have demonstrated the functional transfer of protein-containing secretome between embryonic trophectoderm and maternal MSC in vitro using two BBT primary cultures eight endometrial MSC (eMSC) and five peripheral blood MSC (pbMSC) lines. We observed that eMSC and pbMSC chemotax to both the soluble fraction and EVs of the BBT secretome. In addition, in a complementary direction, we found that the pattern of expression of implantation proteins in BBT-EVs changes depending on: (i) their epithelial–mesenchymal phenotype; (ii) as a result of the uptake of eMSC- or pbMSC-EV previously stimulated or not with embryonic signals (IFN-τ); (iii) because of the stimulation with the endometrial cytokines present in the uterine fluid in the peri-implantation period.     

Coverage and invariability in fuzzy systems

This paper presents a new complex system systemic. Here, we are working in a fuzzy environment, so we have to adapt all the previous concepts and results that were obtained in a non-fuzzy environment, for this fuzzy case. The direct and indirect influences between variables will provide the basis for obtaining fuzzy and/or non-fuzzy relationships, so that the concepts of coverage and invariability between sets of variables will appear naturally. These two concepts and their interconnections will be analyzed from the viewpoint of algebraic properties of inclusion, union and intersection (fuzzy and non-fuzzy), and also for the loop concept, which, as we shall see, will be of special importance.     

CHARACTERIZATION OF EVA-BASED ADHESIVES CONTAINING DIFFERENT AMOUNTS OF ROSIN ESTER OR POLYTERPENE TACKIFIER

Different amounts (50-170 php--parts per hundred parts of EVA, 33-63 wt%) of two tackifiers (hydrogenated rosin ester, polyterpene resin) were added to an ethylene vinyl acetate (EVA) copolymer containing 28 wt% vinyl acetate. The EVA and the tackifier were characterized using infrared (IR) spectroscopy, DSC measurements, and stress-controlled plate-plate rheology. The properties and compatibility of the EVA-tackifier mixtures were studied using DSC, DMTA, and stress-controlled plate-plate rheology. Immediate adhesion was measured as a quantification of tack, and the T-peel strength of roughened styrene-butadiene rubber/EVA-tackifier adhesive joints was also obtained. The increase in the amount of tackifier noticeably changed the crystallinity of polyethylene blocks in the EVA, and the temperature at the cross-over between the curves of the storage and loss moduli as a function of the temperature was displaced to a lower value. Whereas the hydrogenated rosin ester was compatible with the amorphous ethylene vinyl acetate copolymer regions of the EVA (Tg value increased) reducing its crystallinity, the polyterpene resin was compatible with the polyethylene blocks of the EVA (T g value was not modified), increasing its crystallinity. Immediate adhesion of the EVA-tackifier mixtures was improved by adding both hydrogenated rosin ester and polyterpene tackifiers. On the other hand, there was an optimum tackifier content at which the maximum T-peel strength value was obtained.     

Event-driven,pattern-based methodology for cost-effective development of standardized personal health devices

Experiences applying standards in personal health devices (PHDs) show an inherent trade-off between interoperability and costs (in terms of processing load and development time). Therefore, reducing hardware and software costs as well as time-to-market is crucial for standards adoption. The ISO/IEEE11073 PHD family of standards (also referred to as X73PHD) provides interoperable communication between PHDs and aggregators. Nevertheless, the responsibility of achieving inexpensive implementations of X73PHD in limited resource microcontrollers falls directly on the developer. Hence, the authors previously presented a methodology based on patterns to implement X73-compliant PHDs into devices with low-voltage low-power constraints. That version was based on multitasking, which required additional features and resources. This paper therefore presents an event-driven evolution of the patterns-based methodology for cost-effective development of standardized PHDs. The results of comparing between the two versions showed that the mean values of decrease in memory consumption and cycles of latency are 11.59% and 45.95%, respectively. In addition, several enhancements in terms of cost-effectiveness and development time can be derived from the new version of the methodology. Therefore, the new approach could help in producing cost-effective X73-compliant PHDs, which in turn could foster the adoption of standards.     

Mobile digcovery: discovering and interacting with the world through the Internet of things

The application of Internet-enabled devices in the real world for the development of Smart Cities, environmental monitoring, bus tracking, and parking requires scalability, extensibility, and integration of emerging resources to reach a suitable ecosystem for data acquisition and interaction with citizens. Internet of things needs to offer efficient support for global communications and access to services and information. It needs to enable homogeneous and seamless machine-to-machine communication for different solutions and applications. This work presents an homogeneous and suitable mechanism for global resource discovery, device access for deployed smart objects in different scenarios, and sensors and devices from end users (participative sensing). The integration of legacy and sensors already available from smart buildings and smart objects is presented. For this purpose, a resolution infrastructure called “digcovery” is defined for maximizing efficiency and sustainability of deployments. Digcovery architecture offers the framework to allow users to register/include their own sensors into a common infrastructure and access/discover the available resources through mobile digcovery. Mobile digcovery exploits the context-awareness, geo-location, and identification technologies available in mobile platforms such as smartphones to discover, interact, and access the resources through its ElasticSearch engine.