Abstract

Abstract
Bone injury healing is an orchestrated process that starts with an inflammatory phase followed by repair and remodelling of the bone defect. The initial inflammation is characterized by local changes in immune cell populations and molecular mediators, including microRNAs (miRNAs). However, the systemic response to bone injury remains largely uncharacterized. Thus, this study aimed to profile the changes in the plasma miRnome after bone injury and determine its biological implications. Methods: A rat model of femoral bone defect was used, and animals were evaluated at days 3 and 14 after injury. Non-operated (NO) and sham operated animals were used as controls. Blood and spleen were collected and peripheral blood mononuclear cells (PBMC) and plasma were separated. Plasma miRnome was determined by RT-qPCR array and bioinformatics Ingenuity pathway analysis (IPA) was performed. Proliferation of bone marrow mesenchymal stem/stromal cells (MSC) was evaluated by Ki67 staining and high-throughput cell imaging. Candidate miRNAs were evaluated in splenocytes by RT-qPCR, and proteins found in the IPA analysis were analysed in splenocytes and PBMC by Western blot. Results: Bone injury resulted in timely controlled changes to the miRNA expression profile in plasma. At day 3 there was a major down-regulation of miRNA levels, which was partially recovered by day 14 post-injury. Interestingly, bone injury led to a significant up-regulation of let-7a, let-7d and miR-21 in plasma and splenocytes at day 14 relative to day 3 after bone injury, but not in sham operated animals. IPA predicted that most miRNAs temporally affected were involved in cellular development, proliferation and movement. MSC proliferation was analysed and found significantly increased in response to plasma of animals days 3 and 14 post-injury, but not from NO animals. Moreover, IPA predicted that miRNA processing proteins Ago2 and Dicer were specifically inhibited at day 3 post-injury, with Ago2 becoming activated at day 14. Protein levels of Ago2 and Dicer in splenocytes were increased at day 14 relative to day 3 post-bone injury and NO animals, while in PBMC, levels were reduced at day 3 (albeit Dicer was not significant) and remained low at day 14. Ephrin receptor B6 followed the same tendency as Ago2 and Dicer, while Smad2/3 was significantly decreased in splenocytes from day 14 relative to NO and day 3 post-bone injury animals. Conclusion: Results show a systemic miRNA response to bone injury that is regulated in time and is related to inflammation resolution and the start of bone repair/regeneration, unravelling candidate miRNAs to be used as biomarkers in the monitoring of healthy bone healing and as therapeutic targets for the development of improved bone regeneration therapies.

Abstract
The varied phenotypes of obstructive sleep apnea (OSA) poses critical challenges, resulting in missed or delayed diagnosis. In this work, we applied k-modes, aiming to identify groups of OSA patients, based on demographic, physical examination, clinical history, and comorbidities characterization variables (n=41) collected from 318 patients. Missing values were imputed with k-nearest neighbours (k-NN) and chi-square test was held. Thirteen variables were inserted in cluster analysis, resulting in three clusters. Cluster 1 were middle-aged men, while Cluster 3 were the oldest men and Cluster 2 mainly middle-aged women. Cluster 3 weighted the most, whereas Cluster 1 weighted the least. The same effect was described in increased neck circumference. The percentages of variables driving sleepiness, congestive heart failure, arrhythmias and pulmonary hypertension were very low (<20%) and OSA severity was more common in mild level. Our results suggest that it is possible to phenotype OSA patients in an objective way, as also, different (although not considered innovative) visualizations improve the recognition of this common sleep pathology.

Abstract

Abstract

Abstract
In the last decades, the weight of renewable energies sources (RES-E) in the electricity generation mix of most European countries has considerably increased, constituting an important contribution to the transition towards a low-carbon economy. Until very recently, RES-E were supported by favorable investment mechanisms specially designed to endorse investment in RES-E. More recently, as RES-E are becoming increasingly more competitive (especially wind and solar photovoltaic), RES-E are starting to be remunerated according to market mechanisms. This has generated a lively debate on the economic pros and cons of dispatching RES-E in the market. This paper contributes to this debate by developing a game theoretical model in the context of which we analyze how the inclusion of RES-E in the electricity wholesale market affects equilibrium outcomes under demand and supply uncertainty. Then, we examine how the inclusion of RES-E in the electricity wholesale market impacts firms' incentives to invest in conventional energy sources, characterizing the optimal investment under demand and supply uncertainty. We find that, when RES-E capacity and asymmetry in firms' marginal production costs are sufficiently high, RES-E producers may strategically reduce the market price, in order to evict the less efficient conventional source in that period. Although, in the short-run, this strategy may actually favor energy consumers (since prices are lower), the expectations of inactivity periods (regardless of whether they arise for strategic or market reasons) may negatively affect investment in back-up capacity, possibly leading to an increase in future prices (since less back-up capacity is available). Finally, we provide an analytical characterization of optimal investment levels in conventional energy sources under demand and supply uncertainty.