The role of growth in metabolic scaling: a case study across habitats and life histories

All life processes are powered by metabolism, and thus the metabolic rate of organisms provide a measure of their pace of life. Metabolic rate is linked to body size by many biological processes, involving self-maintenance, biomass production, and activity, all three ultimately related to fitness. Explaining the degree of variation in metabolic rate with body size has therefore become a central topic for ecologists, yet the mechanism(s) underlying this relationship, often termed metabolic scaling, remain enigmatic. In this thesis, I investigate the variation in metabolic scaling in response to different ecological and organismal factors in a broad diversity of ectotherms from extremely different habitats. First, using a meta-analytic approach, I determine the change in metabolic scaling within species of ectothermic vertebrates under both increasing temperature and activity level, exploring differences between air- (i.e., reptiles and amphibians) and water-breathing organisms (i.e., teleost fish and elasmobranchs). I demonstrate that scaling slopes become shallower as metabolic level (i.e., the elevation of the metabolic rate vs. body mass relationship) increases with warming only in water-breathers, whereas slopes steepen as metabolic level increases with locomotory activity only in air-breathers. I explain these contrasting findings by combining various, complementary hypotheses involving mechanisms that evolved to protect aerobic scope in fish. Second, I show that allometric (log-log) metabolic scaling slopes decrease with increased maximum growth rates across species of teleost fish, suggesting that growth demands influence metabolic scaling. Using a theoretical model, I then characterise the energetic demands at rest in these teleost species, and show that growth costs remain largely invariant with species body size, lifestyle, and evolutionary history. These results highlight that systematic differences in metabolic scaling are important to understand different energy allocation strategies of species. Last, I examine ontogenetic shifts and sexual differences in metabolic scaling in a model crustacean species (Artemia franciscana), showing that variation in scaling slopes can be affected by changes in costs of biomass production between ontogenetic phases and reproductive modes. The potential roles of the cellular mode of growth on production costs and hence on metabolic scaling in this species are discussed. Overall, this thesis combines multiple mechanisms including evolutionary adaptations, plastic responses, and metabolic costs of various organismal activities, to explain the variation in the mass-scaling of energy use among ectotherms and at various levels of biological organisation. Such a multi-mechanistic perspective may be crucial not only for a comprehensive understanding of metabolic scaling, but also to predict the impact of global change on animal communities

Development of a moisture-in-solid-insulation sensor for power transformers

Moisture is an important variable that must be kept under control to guarantee a safe operation of power transformers. Because of the hydrophilic character of cellulose, water mainly remains in the solid insulation, while just a few parts per million are dissolved in oil. The distribution of moisture between paper and oil is not static, but varies depending on the insulation temperature, and thus, water migration processes take place continuously during transformers operation. In this work, a sensor is presented that allows the determination of the moisture content of the transformer solid insulation in the steady state and during the moisture migration processes. The main objective of the design is that the electrodes of the sensor should not obstruct the movement of water from the solid insulation to the oil, so the proposed prototype uses a metallic-mesh electrode to do the measurements. The measurement setup is based on the characterization of the insulation dielectric response by means of the frequency dielectric spectroscopy (FDS) method. The sensitivity of the proposed sensor has been tested on samples with a moisture content within 1% to 5%, demonstrating the good sensitivity and repeatability of the measurements.This work has been supported by the Spanish Government under Contract DPI2012-35819

Habitat differences filter functional diversity of low dispersive microscopic animals (Acari, Halacaridae)

We are starting to appreciate that microscopic animals are not as widespread as previously thought, but we still ignore to what extent and through which mechanisms the environment selects for specific communities or traits in microscopic animals. We here analyse the functional diversity of marine mite communities living in a seagrass meadow across two habitats: the leaves and the matte. The strictly benthic lifestyle and the conserved morphology of mites allow for unambiguous characterisation of their functional traits, while the discrete nature of the two habitats alleviates the uncertainty in their ecological characterisation. Our results show that habitat filters the distribution of certain traits favouring a higher diversity, dispersion, and evenness of functional traits in the matte than in the leaves. We further observed temporal variations in the functional diversity of communities, following the changes in biomass and structure of seagrass leaves. However, despite the stark differences between the two habitats, the filtering effect is partial and affects mostly relative species abundances. Our study emphasises the need of moving from a taxonomical towards a functional view of ecological studies of microscopic organisms. This integrative approach is key to achieve a mechanistic understanding of their habitat and distribution patterns.Peer reviewe

A dataset of Tanaidacea from the Iberian Peninsula and surrounding areas

We describe a dataset on the crustacean Order Tanaidacea from the coasts of the Iberian Peninsula and surrounding seas, including the archipelagos of the Azores, Madeira, Savage, and the Canary Islands. The dataset gathers the records from all available sources published between 1828 to 2019, which were collected following a standardized Google Scholar search and cross checking each article’s reference lists. For each record, the dataset includes taxonomic, geographical, and ecological information, as well as remarks regarding the sampling methods. The dataset was further completed with 52 additional unpublished records obtained from screening the collections of the University Complutense of Madrid gathered from 35 shallow water surveys. Furthermore, 698 records from different oceanographic deep-sea campaigns have also been included. In total, 3456 records from 186 species in 22 families have been compiled. The dataset organises the current published and unpublished knowledge on tanaidaceans in the area and, by making it open access, it will allow comparisons of the distribution of tanaidaceans in zoogeographic studies.&nbsp

Immune microenvironment dysfunctions enable malignification at the onset of myelodysplastic syndromes

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MDM2 Antagonist Improves Therapeutic Activity of Azacitidine in Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia

Failure of hypomethylation agent (HMA) treatments is an important issue in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Recent studies indicated that function of wildtype TP53 positively impacts outcome of HMA treatments. We investigated the combination of the HMA azacitidine (AZA) with DS-3032b and DS-5272, novel antagonists of the TP53 negative regulator MDM2, in cellular and animal models of MDS and CMML. In TP53 wildtype myeloid cell line, combinational effects of DS-3032b or DS-5272 with AZA were observed. In Tet2-knockout mouse model of MDS and CMML, DS-5272 and AZA combination ameliorated disease-like phenotype. RNA-Seq analysis in mouse bone marrow hematopoietic stem and progenitors indicated that DS-5272 and AZA combination caused down-regulation of leukemia stem cell marker genes and activation of pathways of TP53 function and stability. These findings demonstrate that combining an MDM2 antagonist with AZA has potential to improve AZA treatment in TP53 wildtype MDS and CMML

Hematopoietic Stem Cells With Granulo-Monocytic Differentiation State Overcome Venetoclax Sensitivity in Patients With Myelodysplastic Syndromes

The molecular mechanisms of venetoclax-based therapy failure in patients with acute myeloid leukemia were recently clarified, but the mechanisms by which patients with myelodysplastic syndromes (MDS) acquire secondary resistance to venetoclax after an initial response remain to be elucidated. Here, we show an expansion of MDS hematopoietic stem cells (HSCs) with a granulo-monocytic-biased transcriptional differentiation state in MDS patients who initially responded to venetoclax but eventually relapsed. While MDS HSCs in an undifferentiated cellular state are sensitive to venetoclax treatment, differentiation towards a granulo-monocytic-biased transcriptional state, through the acquisition or expansion of clones with STAG2 or RUNX1 mutations, affects HSCs\u27 survival dependence from BCL2-mediated anti-apoptotic pathways to TNFα-induced pro-survival NF-κB signaling and drives resistance to venetoclax-mediated cytotoxicity. Our findings reveal how hematopoietic stem and progenitor cell (HSPC) can eventually overcome therapy-induced depletion and underscore the importance of using close molecular monitoring to prevent HSPC hierarchical change in MDS patients enrolled in clinical trials of venetoclax

Targeting MCL1-Driven Anti-apoptotic Pathways Overcomes Blast Progression After Hypomethylating Agent Failure in Chronic Myelomonocytic Leukemia

RAS pathway mutations, which are present in 30% of patients with chronic myelomonocytic leukemia (CMML) at diagnosis, confer a high risk of resistance to and progression after hypomethylating agent (HMA) therapy, the current standard of care for the disease. Here, using single-cell, multi-omics technologies, we seek to dissect the biological mechanisms underlying the initiation and progression of RAS pathway-mutated CMML. We identify that RAS pathway mutations induce transcriptional reprogramming of hematopoietic stem and progenitor cells (HSPCs) and downstream monocytic populations in response to cell-intrinsic and -extrinsic inflammatory signaling that also impair the functions of immune cells. HSPCs expand at disease progression after therapy with HMA or the BCL2 inhibitor venetoclax and rely on the NF-κB pathway effector MCL1 to maintain survival. Our study has implications for the development of therapies to improve the survival of patients with RAS pathway-mutated CMML

Glioblastoma on a microfluidic chip: Generating pseudopalisades and enhancing aggressiveness through blood vessel obstruction events

Background: Glioblastoma (GBM) is one of the most lethal tumor types. Hypercellular regions, named pseudo- palisades, are characteristic in these tumors and have been hypothesized to be waves of migrating glioblastoma cells.These “waves” of cells are thought to be induced by oxygen and nutrient depletion caused by tumor-induced blood vessel occlusion. Although the universal presence of these structures in GBM tumors suggests that they may play an instrumental role in GBM’s spread and invasion, the recreation of these structures in vitro has remained challenging. Methods: Here we present a new microfluidic model of GBM that mimics the dynamics of pseudopalisade forma- tion.To do this, we embedded U-251 MG cells within a collagen hydrogel in a custom-designed microfluidic device. By controlling the medium flow through lateral microchannels, we can mimic and control blood-vessel obstruction events associated with this disease. Results: Through the use of this new system, we show that nutrient and oxygen starvation triggers a strong migratory process leading to pseudopalisade generation in vitro.These results validate the hypothesis of pseudo- palisade formation and show an excellent agreement with a systems-biology model based on a hypoxia-driven phenomenon. Conclusions: This paper shows the potential of microfluidic devices as advanced artificial systems capable of mod- eling in vivo nutrient and oxygen gradients during tumor evolution