Stress recovery in geometrically nonlinear membranes by a Hu-Washizu finite element formulation

A class of mixed finite elements based on the Hu-Washizu functional is introduced as a strategy to reduce the spurious stress phenomena encountered with standard or displacement-based formulations for geometrically exact membranes. Selected examples compare the performance of this class of elements with that of the standard formulation and demonstrate that reduction of spurious stresses is obtained and that the stresses are more accurate than those optimally sampled in the standard formulation.     

Spanish Melon Landraces: Revealing Useful Diversity by Genomic,Morphological, and Metabolomic Analysis

Spain is a secondary centre of the diversification of the melon (Cucumis melo L.), with high diversity represented in highly appreciated landraces belonging to the Flexuosus and Ibericus groups. A collection of 47 accessions of Flexuosus, Chate, Piel de Sapo, Tendral, Amarillo, Blanco, and Rochet was analysed using a genotyping-by-sequencing (GBS) approach. A total of 66,971 quality SNPs were identified. Genetic analysis differentiated Ibericus accessions and exotic materials (Ameri, Momordica, Kachri, and Agrestis), while Flexuous accessions shared ancestry between them. Within the Ibericus group, no clear genomic distinction could be identified for the different landraces evaluated, with accessions of different landraces showing high genetic similarity. The morphological characterization confirmed that the external colour and fruit shape had been used as recognition patterns for Spanish melon landraces, but variability within a landrace exists. Differences were found in the sugars and acid and volatile profiles of the materials. Flexuosus and Chate melons at the immature commercial stage accumulated malic acid and low levels of hexoses, while Ibericus melons accumulated high contents of sucrose and citric acid. Specific trends could be identified in the Ibericus landraces. Tendral accumulated low levels of sugars and citric acid and high of malic acid, maintaining higher firmness, Rochet reached higher levels of sugars, and Amarillo tended to lower malic acid contents. Interestingly, high variability was found within landraces for the acidic profile, offering possibilities to alter taste tinges. The main volatile organic compounds (VOCs) in Flexuosus and Chate were aldehydes and alcohols, with clear differences between both groups. In the Ibericus landraces, general trends for VOC accumulation could be identified, but, again, a high level of variation exists. This situation highlights the necessity to develop depuration programs to promote on-farm in situ conservation and, at the same time, offers opportunities to establish new breeding program targets and to take advantage of these sources of variation.     

Functionalized Hydrogels for Cartilage Repair: The Value of Secretome-Instructive Signaling

Cartilage repair has been a challenge in the medical field for many years. Although treatments that alleviate pain and injury are available, none can effectively regenerate the cartilage. Currently, regenerative medicine and tissue engineering are among the developed strategies to treat cartilage injury. The use of stem cells, associated or not with scaffolds, has shown potential in cartilage regeneration. However, it is currently known that the effect of stem cells occurs mainly through the secretion of paracrine factors that act on local cells. In this review, we will address the use of the secretome—a set of bioactive factors (soluble factors and extracellular vesicles) secreted by the cells—of mesenchymal stem cells as a treatment for cartilage regeneration. We will also discuss methodologies for priming the secretome to enhance the chondroregenerative potential. In addition, considering the difficulty of delivering therapies to the injured cartilage site, we will address works that use hydrogels functionalized with growth factors and secretome components. We aim to show that secretome-functionalized hydrogels can be an exciting approach to cell-free cartilage repair therapy.     

NMDA and P2X7 Receptors Require Pannexin 1 Activation to Initiate and Maintain Nociceptive Signaling in the Spinal Cord of Neuropathic Rats

Pannexin 1 (Panx1) is involved in the spinal central sensitization process in rats with neuropathic pain, but its interaction with well-known, pain-related, ligand-dependent receptors, such as NMDA receptors (NMDAR) and P2X7 purinoceptors (P2X7R), remains largely unexplored. Here, we studied whether NMDAR- and P2X7R-dependent nociceptive signaling in neuropathic rats require the activation of Panx1 channels to generate spinal central sensitization, as assessed by behavioral (mechanical hyperalgesia) and electrophysiological (C-reflex wind-up potentiation) indexes. Administration of either a selective NMDAR agonist i.t. (NMDA, 2 mM) or a P2X7R agonist (BzATP, 150 μM) significantly increased both the mechanical hyperalgesia and the C-reflex wind-up potentiation, effects that were rapidly reversed (minutes) by i.t. administration of a selective pannexin 1 antagonist (10panx peptide, 300 μM), with the scores even reaching values of rats without neuropathy. Accordingly, 300 μM 10panx completely prevented the effects of NMDA and BzATP administered 1 h later, on mechanical hyperalgesia and C-reflex wind-up potentiation. Confocal immunofluorescence imaging revealed coexpression of Panx1 with NeuN protein in intrinsic dorsal horn neurons of neuropathic rats. The results indicate that both NMDAR- and P2X7R-mediated increases in mechanical hyperalgesia and C-reflex wind-up potentiation require neuronal Panx1 channel activation to initiate and maintain nociceptive signaling in neuropathic rats.     

Evaluation and Characterization of Post-Stroke Lung Damage in a Murine Model of Cerebral Ischemia

After stroke and other brain injuries, there is a high incidence of respiratory complications such as pneumonia or acute lung injury. The molecular mechanisms that drive the brain-lung interaction post-stroke have not yet been elucidated. We performed transient middle cerebral artery occlusion (MCAO) and sham surgery on C57BL/6J mice and collected bronchoalveolar lavage fluid (BALF), serum, brain, and lung homogenate samples 24 h after surgery. A 92 proteins-panel developed by Olink Proteomics^® was used to analyze the content in BALF and lung homogenates. MCAO animals had higher protein concentration levels in BALF than sham-controls, but these levels did not correlate with the infarct volume. No alteration in alveolar-capillary barrier permeability was observed. A total of 12 and 14 proteins were differentially expressed between the groups (FDR < 0.1) in BALF and lung tissue homogenates, respectively. Of those, HGF, TGF-α, and CCL2 were identified as the most relevant to this study. Their protein expression patterns were verified by ELISA. This study confirmed that post-stroke lung damage was not associated with increased lung permeability or cerebral ischemia severity. Furthermore, the dysregulation of HGF, TGF-α, and CCL2 in BALF and lung tissue after ischemia could play an important role in the molecular mechanisms underlying stroke-induced lung damage.     

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.     

From latex specifications to parallel codes

The advent of multicore systems, joined to the potential acceleration of the graphics processing units, has given us a low cost computation capability unprecedented. The new systems alleviate some well-known important architectural problems at the expense of a considerable increment of the programmability wall. Heterogeneity, at both the architectural and programming levels, poses a great challenge to programmers. As a contribution, we propose a development methodology for the automatic source-to-source transformation on specific domains. This methodology is successfully instantiated as a framework to solve Dynamic Programming problems. As a result of applying our framework, the end user (a physicist, a mathematician or a biologist) can express her problem through a latex equation and automatically derive efficient parallel codes for current homogeneous or heterogeneous architectures. The approach allows an easy portability to new emergent architectures.     

Collective intelligence as mechanism of medical diagnosis: The iPixel approach

Collective intelligence (CI) is an active field of research, which capitalizes the knowledge of human collectives in order to create, to innovate and to invent. There are two important mechanisms to implement CI: recommender and reputation systems. Recommender systems are used to provide filtered information from a large amount of elements. The recommendations are intended to provide interesting elements to users. Recommendation systems can be developed using different techniques and algorithms where the selection of these techniques depends on the area in which they will be applied. This work presents iPixel Recommender Engine, which is focused on the medical field. iPixel Recommendation Engine supports the process of differential diagnosis by recommending mammographic evaluations. Each mammogram is collectively tagged by the users’ community with a semantic sense; this feature allows iPixel acquires collective knowledge. iPixel can associate more than one feature with each mammogram. This work also presents a qualitative evaluation, where the basic features that a recommendation system should have in the medical field were obtained. Finally, a comparison was carried out with other similar recommender systems in order to know the Pixel advantages.