MORPH: A Reference Architecture for Configuration and Behaviour Self-Adaptation

An architectural approach to self-adaptive systems involves runtime change of system configuration (i.e., the system's components, their bindings and operational parameters) and behaviour update (i.e., component orchestration). Thus, dynamic reconfiguration and discrete event control theory are at the heart of architectural adaptation. Although controlling configuration and behaviour at runtime has been discussed and applied to architectural adaptation, architectures for self-adaptive systems often compound these two aspects reducing the potential for adaptability. In this paper we propose a reference architecture that allows for coordinated yet transparent and independent adaptation of system configuration and behaviour

Inhibitor binding mode and allosteric regulation of Na+-glucose symporters.

Sodium-dependent glucose transporters (SGLTs) exploit sodium gradients to transport sugars across the plasma membrane. Due to their role in renal sugar reabsorption, SGLTs are targets for the treatment of type 2 diabetes. Current therapeutics are phlorizin derivatives that contain a sugar moiety bound to an aromatic aglycon tail. Here, we develop structural models of human SGLT1/2 in complex with inhibitors by combining computational and functional studies. Inhibitors bind with the sugar moiety in the sugar pocket and the aglycon tail in the extracellular vestibule. The binding poses corroborate mutagenesis studies and suggest a partial closure of the outer gate upon binding. The models also reveal a putative Na+ binding site in hSGLT1 whose disruption reduces the transport stoichiometry to the value observed in hSGLT2 and increases inhibition by aglycon tails. Our work demonstrates that subtype selectivity arises from Na+-regulated outer gate closure and a variable region in extracellular loop EL5

Erythropoietin (EPO) increases myelin gene expression in CG4 oligodendrocyte cells through the classical EPO receptor

Erythropoietin (EPO) has protective effects in neurodegenerative and neuroinflammatory diseases, including in animal models of multiple sclerosis, where EPO decreases disease severity. EPO also promotes neurogenesis and is protective in models of toxic demyelination. In this study, we asked whether EPO could promote neurorepair by also inducing remyelination. In addition, we investigated whether the effect of EPO could be mediated by the classical erythropoietic EPO receptor (EPOR), since it is still questioned if EPOR is functional in non-hematopoietic cells. Using CG4 cells, a line of rat oligodendrocyte precursor cells, we found that EPO increases the expression of myelin genes (myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP)). EPO had no effect in wild-type CG4 cells, which do not express EPOR, whereas it increased MOG and MBP expression in cells engineered to overexpress EPOR (CG4-EPOR). This was reflected in a marked increase in MOG protein levels, as detected by western blot. In these cells, EPO induced by 10-fold the early growth response gene 2 (Egr2), which is required for peripheral myelination. However, Egr2 silencing with a siRNA did not reverse the effect of EPO, indicating that EPO acts through other pathways. In conclusion, EPO induces the expression of myelin genes in oligodendrocytes and this effect requires the presence of EPOR. This study demonstrates that EPOR can mediate neuroreparative effects

Vitamins D3 and D2 have marked but different global effects on gene expression in a rat oligodendrocyte precursor cell line

Background: Vitamin D deficiency increases the risk of developing multiple sclerosis (MS) but it is unclear whether vitamin D supplementation improves the clinical course of MS, and there is uncertainty about the dose and form of vitamin D (D2 or D3) to be used. The mechanisms underlying the effects of vitamin D in MS are not clear. Vitamin D3 increases the rate of differentiation of primary oligodendrocyte precursor cells (OPCs), suggesting that it might help remyelination in addition to modulating the immune response. Here we analyzed the transcriptome of differentiating rat CG4 OPCs treated with vitamin D2 or with vitamin D3 at 24 h and 72 h following onset of differentiation. Methods: Gene expression in differentiating CG4 cells in response to vitamin D2 or D3 was quantified using Agilent DNA microarrays (n=4 replicates), and the transcriptome data were processed and analysed using the R software environment. Differential expression between the experimental conditions was determined using LIMMA, applying the Benjamini and Hochberg multiple testing correction to p-values, and significant genes were grouped into co-expression clusters by hierarchical clustering. The functional significance of gene groups was explored by pathway enrichment analysis using the clusterProfiler package. Results: Differentiation alone changed the expression of about 10% of the genes at 72 h compared to 24 h. Vitamin D2 and D3 exerted different effects on gene expression, with D3 influencing 1,272 genes and D2 574 at 24 h. The expression of the vast majority of these genes was either not changed in differentiating cells not exposed to vitamin D or followed the same trajectory as the latter. D3-repressed genes were enriched for Gene Ontology (GO) categories including transcription factors and the Notch pathway, while D3-induced genes were enriched for the Ras pathway. Conclusions: This study shows that vitamin D3, compared with D2, changes the expression of a larger number of genes in OLs. Identification of genes affected by D3 in OLs should help to identify mechanisms mediating its action in MS

Transumbilical versus transvaginal retrieval of surgical specimens at laparoscopy: a randomized trial.

Objective We sought to compare transumbilical (TU) and transvaginal (TV) route for retrieval of surgical specimens at laparoscopy. Study design Women scheduled for a laparoscopic resection of an adnexal mass were randomized to have their surgical specimen removed either through a posterior colpotomy (n = 34) or the umbilical port site (n = 32). Group allocation was concealed from patients and bedside clinicians. The primary outcome was postoperative incisional pain assessed by a 10-cm visual analog scale at 1, 3, and 24 hours after surgery. Results TV retrieval caused less postoperative pain than TU specimen extraction at each time point (visual analog scale score at 1 hour: 2.6 \ub1 2.9 vs 1.2 \ub1 2.0, P = .03; at 3 hours: 2.4 \ub1 2.0 vs 1.4 \ub1 2.0, P = .02; and at 24 hours: 1.1 \ub1 1.5 vs 0.5 \ub1 1.4, P = .02). A higher proportion of women in the TU group than in the TV group indicated the umbilicus as the most painful area at 1 and 3 hours postoperatively. Two months after surgery, the participants scored similarly as to their overall satisfaction, cosmetic outcome, and dyspareunia upon resumption of intercourse. Conclusion A TV approach for specimen removal after laparoscopic resection of adnexal masses offers the advantage of less postoperative pain than TU retrieva

Interleukin-1 Induces Tumor Necrosis Factor (TNF) in Human Peripheral Blood Mononuclear Cells In Vitro and a Circulating TNF-like Activity in Rabbits

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Anisotropic dark energy stars

A model of compact object coupled to inhomogeneous anisotropic dark energy is studied. It is assumed a variable dark energy that suffers a phase transition at a critical density. The anisotropic Lambda-Tolman-Oppenheimer-Volkoff equations are integrated to know the structure of these objects. The anisotropy is concentrated on a thin shell where the phase transition takes place, while the rest of the star remains isotropic. The family of solutions obtained depends on the coupling parameter between the dark energy and the fermion matter. The solutions share several features in common with the gravastar model. There is a critical coupling parameter that gives non-singular black hole solutions. The mass-radius relations are studied as well as the internal structure of the compact objects. The hydrodynamic stability of the models is analyzed using a standard test from the mass-radius relation. For each permissible value of the coupling parameter there is a maximum mass, so the existence of black holes is unavoidable within this model.Comment: 12 pages, 6 figures, final manuscript, Accepted for publication in Astrophysics & Space Scienc

Miniaturised Wireless Power Transfer Systems for Neurostimulation: A Review

In neurostimulation, wireless power transfer is an efficient technology to overcome several limitations affecting medical devices currently used in clinical practice. Several methods were developed over the years for wireless power transfer. In this review article, we report and discuss the three most relevant methodologies for extremely miniaturised implantable neurostimulator: ultrasound coupling, inductive coupling and capacitive coupling. For each powering method, the discussion starts describing the physical working principle. In particular, we focus on the challenges given by the miniaturisation of the implanted integrated circuits and the related ad-hoc solutions for wireless power transfer. Then, we present recent developments and progresses in wireless power transfer for biomedical applications. Last, we compare each technique based on key performance indicators to highlight the most relevant and innovative solutions suitable for neurostimulation, with the gaze turned towards miniaturisation