Human adaptation to heat in the context of climate change: A conceptual framework.

Climate change is causing serious damage to natural and social systems, as well as having an impact on human health. Among the direct effects of climate change is the rise in global surface temperatures and the increase in the frequency, duration, intensity and severity of heat waves. In addition, understanding of the adaptation process of the exposed population remains limited, posing a challenge in accurately estimating heat-related morbidity and mortality. In this context, this study seeks to establish a conceptual framework that would make it easier to understand and organise knowledge about human adaptation to heat and the factors that may influence this process. An inductive approach based on grounded theory was used, through the analysis of case studies connecting concepts. The proposed conceptual framework is made up of five components (climate change, vulnerability, health risks of heat, axes of inequality and health outcomes), three heat-adaptation domains (physiological, cultural and political), two levels (individual and social), and the pre-existing before a heat event. The application of this conceptual framework facilitates the assistance of decision-makers in planning and implementing effective adaptation measures. Recognizing the importance of addressing heat adaptation as a health problem that calls for political solutions and social changes. Accordingly, this requires a multidisciplinary approach that would foster the participation and collaboration of multiple actors for the purpose of proposing effective measures to address the health impact of the rise in temperature.

Creation of an Isogenic Human iPSC-Based RGC Model of Dominant Optic Atrophy Harboring the Pathogenic Variant c.1861C>T (p.Gln621Ter) in the OPA1 Gene.

Autosomal dominant optic atrophy (ADOA) is a rare progressive disease mainly caused by mutations in OPA1, a nuclear gene encoding for a mitochondrial protein that plays an essential role in mitochondrial dynamics, cell survival, oxidative phosphorylation, and mtDNA maintenance. ADOA is characterized by the degeneration of retinal ganglion cells (RGCs). This causes visual loss, which can lead to legal blindness in many cases. Nowadays, there is no effective treatment for ADOA. In this article, we have established an isogenic human RGC model for ADOA using iPSC technology and the genome editing tool CRISPR/Cas9 from a previously generated iPSC line of an ADOA plus patient harboring the pathogenic variant NM_015560.3: c.1861C>T (p.Gln621Ter) in heterozygosis in OPA1. To this end, a protocol based on supplementing the iPSC culture media with several small molecules and defined factors trying to mimic embryonic development has been employed. Subsequently, the created model was validated, confirming the presence of a defect of intergenomic communication, impaired mitochondrial respiration, and an increase in apoptosis and ROS generation. Finally, we propose the analysis of OPA1 expression by qPCR as an easy read-out method to carry out future drug screening studies using the created RGC model. In summary, this model provides a useful platform for further investigation of the underlying pathophysiological mechanisms of ADOA plus and for testing compounds with potential pharmacological action.

Defining the maximum nitrogen surplus in water management plans to recover nitrate polluted aquifers in Spain.

Nitrate pollution in aquifers is a global concern. Spain has developed a national strategy to recover nitrate polluted aquifers aligned with the European Union (EU) policies, specifically through the water planning under the EU Water Framework Directive. River basin management plans use PATRICAL model results to define the maximum nitrogen surplus in each polluted aquifer for the first time. The maximum nitrogen surplus allows to reach the good status in each aquifer and the model provides the number of years required. Around 30% of the aquifers in Spain is currently heavily polluted by nitrates. Model results show that 90% of these aquifers can be recovered in next 6-12 years by increasing nitrogen use efficiency and reducing nitrogen losses around 50%, which is in line with the EU Farm to Fork Strategy. The remaining aquifers require additional reductions to achieve the good status. In Spain this increase in nitrogen efficiency can be obtained with different measures including 30% reduction of current fertilization.

Pathophysiology of Cerebellar Degeneration in Mitochondrial Disorders: Insights from the Harlequin Mouse.

By means of a proteomic approach, we assessed the pathways involved in cerebellar neurodegeneration in a mouse model (Harlequin, Hq) of mitochondrial disorder. A differential proteomic profile study (iTRAQ) was performed in cerebellum homogenates of male Hq and wild-type (WT) mice 8 weeks after the onset of clear symptoms of ataxia in the Hq mice (aged 5.2 ± 0.2 and 5.3 ± 0.1 months for WT and Hq, respectively), followed by a biochemical validation of the most relevant changes. Additional groups of 2-, 3- and 6-month-old WT and Hq mice were analyzed to assess the disease progression on the proteins altered in the proteomic study. The proteomic analysis showed that beyond the expected deregulation of oxidative phosphorylation, the cerebellum of Hq mice showed a marked astroglial activation together with alterations in Ca2+ homeostasis and neurotransmission, with an up- and downregulation of GABAergic and glutamatergic neurotransmission, respectively, and the downregulation of cerebellar "long-term depression", a synaptic plasticity phenomenon that is a major player in the error-driven learning that occurs in the cerebellar cortex. Our study provides novel insights into the mechanisms associated with cerebellar degeneration in the Hq mouse model, including a complex deregulation of neuroinflammation, oxidative phosphorylation and glutamate, GABA and amino acids' metabolism.

Effect of climate change on the water quality of Mediterranean rivers and alternatives to improve its status.

Surface water (SW) quality is particularly vulnerable to increased concentrations of nutrients, and this issue may be exacerbated by climate change. Knowledge of the effects of temperature and rainfall on SW quality is required to take the necessary measures to achieve good SW status in the future. To address this, the aims of this study were threefold: (1) to assess how a changing climate may alter the nitrate, ammonium, phosphorus and biological oxygen demand status (BOD5) of SW; (2) assess the relationship between water quality and flow; and (3) simulate diffuse and point source pollution reduction scenarios in the Júcar River Basin District in the Mediterranean region. A regionalised long-term climate scenario was used following one Representative Concentration Pathway (RCP8.5) with the data incorporated into the coupling of hydrological and water quality models. According to these climate change scenarios, SW with poor nitrate, ammonium, phosphorus and BOD5 status are expected to increase in the future by factors of 1.3, 1.9, 4 and 4, respectively. Furthermore, median ammonium and phosphorus concentration may be doubled in months with low flows. Additional measures are required to maintain current status in the water bodies, and it is necessary to reduce at least 25% of diffuse nitrate pollution, and 50% of point loads of ammonium, phosphorus, and BOD5.

Psychological Implicit Motives Construct as an Emergent Fractal Attractor from Intermittent Neurophysiological Responses: Simulation and Entropy-like Characterization.

Implicit Motives are non-conscious needs that drive human behavior towards the achievement of incentives that are affectively incited. Repeated affective experiences providing satisfying rewards have been held responsible for the building of Implicit Motives. Responses to rewarding experiences have a biological basis via close connections with neurophysiological systems controlling neurohormone release. We propose an iteration random function system acting in a metric space to model experience-reward interactions. This model is based on key facts of Implicit Motive theory reported in a broad number of studies. The model shows how (random) responses produced by intermittent random experiences create a well-defined probability distribution on an attractor, thus providing an insight into the underlying mechanism leading to the emergence of Implicit Motives as psychological structures. Implicit Motives' robustness and resilience properties appear theoretically explained by the model. The model also provides uncertainty entropy-like parameters to characterize Implicit Motives which hopefully might be useful, beyond the mere theoretical frame, when used in combination with neurophysiological methods.

Preferent Diaphragmatic Involvement in TK2 Deficiency: An Autopsy Case Study.

Our goal was to analyze postmortem tissues of an adult patient with late-onset thymidine kinase 2 (TK2) deficiency who died of respiratory failure. Compared with control tissues, we found a low mtDNA content in the patient's skeletal muscle, liver, kidney, small intestine, and particularly in the diaphragm, whereas heart and brain tissue showed normal mtDNA levels. mtDNA deletions were present in skeletal muscle and diaphragm. All tissues showed a low content of OXPHOS subunits, and this was especially evident in diaphragm, which also exhibited an abnormal protein profile, expression of non-muscular ß-actin and loss of GAPDH and α-actin. MALDI-TOF/TOF mass spectrometry analysis demonstrated the loss of the enzyme fructose-bisphosphate aldolase, and enrichment for serum albumin in the patient's diaphragm tissue. The TK2-deficient patient's diaphragm showed a more profound loss of OXPHOS proteins, with lower levels of catalase, peroxiredoxin 6, cytosolic superoxide dismutase, p62 and the catalytic subunits of proteasome than diaphragms of ventilated controls. Strong overexpression of TK1 was observed in all tissues of the patient with diaphragm showing the highest levels. TK2 deficiency induces a more profound dysfunction of the diaphragm than of other tissues, which manifests as loss of OXPHOS and glycolytic proteins, sarcomeric components, antioxidants and overactivation of the TK1 salvage pathway that is not attributed to mechanical ventilation.

Effects of the pandemic crisis on entrepreneurship and sustainable development.

The COVID-19 pandemic has caused an economic crisis in advanced economies greater than the 2008 economic crisis, as the latest Organisation for Economic Co-operation and Development (OECD) forecasts indicate. Entrepreneurship activity is an important factor to be considered to reduce this negative. The objective of this paper is to analyze the factors that favor entrepreneurship in the COVID-19 pandemic situation and explore the relationship between entrepreneurship and sustainable development. Monetary, fiscal, competitiveness, and business expectations are factors to consider. To achieve this objective, we reviewed the specialized literature and proposed an economic model to verify the relationships between the relevant variables. The estimation of this model uses the Partial Least Squares (PLS) method. This study looks at select OECD countries where data on entrepreneurial activity are available and there are calculations by the OECD for the economic projections for 2020.

Increased dNTP pools rescue mtDNA depletion in human POLG-deficient fibroblasts.

Polymerase γ catalytic subunit (POLG) gene encodes the enzyme responsible for mitochondrial DNA (mtDNA) synthesis. Mutations affecting POLG are the most prevalent cause of mitochondrial disease because of defective mtDNA replication and lead to a wide spectrum of clinical phenotypes characterized by mtDNA deletions or depletion. Enhancing mitochondrial deoxyribonucleoside triphosphate (dNTP) synthesis effectively rescues mtDNA depletion in different models of defective mtDNA maintenance due to dNTP insufficiency. In this study, we studied mtDNA copy number recovery rates following ethidium bromide-forced depletion in quiescent fibroblasts from patients harboring mutations in different domains of POLG. Whereas control cells spontaneously recovered initial mtDNA levels, POLG-deficient cells experienced a more severe depletion and could not repopulate mtDNA. However, activation of deoxyribonucleoside (dN) salvage by supplementation with dNs plus erythro-9-(2-hydroxy-3-nonyl) adenine (inhibitor of deoxyadenosine degradation) led to increased mitochondrial dNTP pools and promoted mtDNA repopulation in all tested POLG-mutant cells independently of their specific genetic defect. The treatment did not compromise POLG fidelity because no increase in multiple deletions or point mutations was detected. Our study suggests that physiologic dNTP concentration limits the mtDNA replication rate. We thus propose that increasing mitochondrial dNTP availability could be of therapeutic interest for POLG deficiency and other conditions in which mtDNA maintenance is challenged.-Blázquez-Bermejo, C., Carreño-Gago, L., Molina-Granada, D., Aguirre, J., Ramón, J., Torres-Torronteras, J., Cabrera-Pérez, R., Martín, M. Á., Domínguez-González, C., de la Cruz, X., Lombès, A., García-Arumí, E., Martí, R., Cámara, Y. Increased dNTP pools rescue mtDNA depletion in human POLG-deficient fibroblasts.

The Mitochondrial Isoform of FASTK Modulates Nonopsonic Phagocytosis of Bacteria by Macrophages via Regulation of Respiratory Complex I.

Phagocytosis is a pivotal process by which innate immune cells eliminate bacteria. In this study, we explore novel regulatory mechanisms of phagocytosis driven by the mitochondria. Fas-activated serine/threonine kinase (FASTK) is an RNA-binding protein with two isoforms, one localized to the mitochondria (mitoFASTK) and the other isoform to cytosol and nucleus. The mitoFASTK isoform has been reported to be necessary for the biogenesis of the mitochondrial ND6 mRNA, which encodes an essential subunit of mitochondrial respiratory complex I (CI, NADH:ubiquinone oxidoreductase). This study investigates the role and the mechanisms of action of FASTK in phagocytosis. Macrophages from FASTK─/─ mice exhibited a marked increase in nonopsonic phagocytosis of bacteria. As expected, CI activity was specifically reduced by almost 50% in those cells. To explore if decreased CI activity could underlie the phagocytic phenotype, we tested the effect of CI inhibition on phagocytosis. Indeed, treatment with CI inhibitor rotenone or short hairpin RNAs against two CI subunits (NDUFS3 and NDUFS4) resulted in a marked increase in nonopsonic phagocytosis of bacteria. Importantly, re-expression of mitoFASTK in FASTK-depleted macrophages was sufficient to rescue the phagocytic phenotype. In addition, we also report that the decrease in CI activity in FASTK─/─ macrophages is associated with an increase in phosphorylation of the energy sensor AMP-activated protein kinase (AMPK) and that its inhibition using Compound C reverted the phagocytosis phenotype. Taken together, our results clearly demonstrate for the first time, to our knowledge, that mitoFASTK plays a negative regulatory role on nonopsonic phagocytosis of bacteria in macrophages through its action on CI activity.

Subclinical hypothyroidism in childhood, treatment or only follow-up?

BACKGROUND: Subclinical hypothyroidism (SH) is defined as serum levels of thyroid-stimulating hormone (TSH) above the upper limit with normal concentrations of free T4 (fT4). Its management remains challenging. The aim of the study was to evaluate clinical and laboratory findings as well as the clinical course of children with SH followed in a third level hospital. Sixty-five patients aged between 2 and 18 years old were retrospectively studied. METHODS: The patients were followed for a median period of 9 months (range 6 months to 24 months). Those who normalized TSH levels were discharged (Group 1). If TSH persisted mildly elevated (5-10µUI/mL) with normal fT4 and negative TPOAb/TgAb, they were classified as Group 2 and followed semi-annually without treatment. Those patients whose TSH raised ≥10µUI/mL or who maintained TSH 5-10µUI/mL and positive TPOAb/TgAb were considered suitable for thyroxin therapy (Group 3, G3). RESULTS: In 89% of our patients, TSH concentrations spontaneously reverted to normality or remained stable without treatment (Groups 1 and 2), whereas less than 11% progressed to clinical hypothyroidism (Group 3). Baseline TSH was significantly lower in group 1 than in group 3. In group 3 the prevalence of female sex (71%) was higher and TPO antibodies were present in 85% of patients. The risk of developing overt hypothyroidism in patients with positive anti-thyroid antibodies respect to those who normalized TSH was 45 (95%CI 6.5-312.5). CONCLUSION: Baseline TSH, female sex and the presence of thyroid autoimmunity were the best predictors of the evolution to SH over time.

Preclinical Research in Glycogen Storage Diseases: A Comprehensive Review of Current Animal Models.

GSD are a group of disorders characterized by a defect in gene expression of specific enzymes involved in glycogen breakdown or synthesis, commonly resulting in the accumulation of glycogen in various tissues (primarily the liver and skeletal muscle). Several different GSD animal models have been found to naturally present spontaneous mutations and others have been developed and characterized in order to further understand the physiopathology of these diseases and as a useful tool to evaluate potential therapeutic strategies. In the present work we have reviewed a total of 42 different animal models of GSD, including 26 genetically modified mouse models, 15 naturally occurring models (encompassing quails, cats, dogs, sheep, cattle and horses), and one genetically modified zebrafish model. To our knowledge, this is the most complete list of GSD animal models ever reviewed. Importantly, when all these animal models are analyzed together, we can observe some common traits, as well as model specific differences, that would be overlooked if each model was only studied in the context of a given GSD.

Single is better than double: theoretical and experimental comparison between two thermal poling configurations of optical fibers.

Thermal poling, a technique to create permanently effective second-order susceptibility in silica optical fibers, has a suite of applications including frequency conversion and mixing for high harmonic generation and phase sensitive amplification, optical switching and modulation, and polarization-entangled photon pair generation. In this work, we compare both theoretically and experimentally two different electrode configurations for poling optical fibers, namely double-anode and single-anode, for two different geometries of the cladding holes. This analysis reveals that the single-anode configuration is optimal, both for the absolute value of effective χ (2) created in the fiber core, and for the simplification of the fiber fabrication process.

Investigation of pesticides and their transformation products in the Júcar River Hydrographical Basin (Spain) by wide-scope high-resolution mass spectrometry screening.

The Water Framework Directive 2000/60/EC implemented by the European Union established as the main objectives to achieve a "good ecological and chemical status" of the surface water and a "good quantitative and chemical status" of groundwater bodies. One of the major pressures affecting water bodies comes from the use of pesticides and their potential presence in the water ecosystems. For this purpose, the reliable determination of pesticides and their transformation products (TPs) in natural waters (both surface and groundwater) is required. The high number of compounds potentially reaching the aquatic environment makes extraordinary difficult, if not impossible, to investigate all these compounds even using the most powerful analytical techniques. Among these, liquid chromatography coupled to high-resolution mass spectrometry is emphasized due to its strong potential for detection and identification of many organic contaminants thanks to the accurate-mass full spectrum acquisition data. This work focuses on wide-scope screening of many pesticides and their TPs in surface water and groundwater samples, collected between March and May 2017, in the Júcar River Hydrographical Basin, Spain. For this purpose, a home-made database containing more than 500 pesticides and TPs was employed. Analyses performed by liquid chromatography coupled to quadrupole-time of flight mass spectrometry (LC-QTOF MS) allowed the identification of up to 27 pesticides and 6 TPs. The most detected compounds in groundwater were the herbicides atrazine, simazine, terbuthylazine, and their TPs (atrazine-desethyl, terbumeton-desethyl and terbuthylazine-desethyl). Regarding surface water, the fungicides carbendazim, thiabendazole and imazalil, the herbicide terbutryn and the TP terbumeton-desethyl were also detected. These results illustrate the wide use of these compounds (in the present or in the recent past) in the area under study and the vulnerability of the water bodies, and are in accordance with previous findings in other water bodies of the different Spanish Hydrographic systems.

Assessment of DSMs Using Backpack-Mounted Systems and Drone Techniques to Characterise Ancient Underground Cellars in the Duero Basin (Spain).

In this study, a backpack-mounted 3D mobile scanning system and a fixed-wing drone (UAV) have been used to register terrain data on the same space. The study area is part of the ancient underground cellars in the Duero Basin. The aim of this work is to characterise the state of the roofs of these wine cellars by obtaining digital surface models (DSM) using the previously mentioned systems to detect any possible cases of collapse, using four geomatic products obtained with these systems. The results obtained from the process offer sufficient quality to generate valid DSMs in the study area or in a similar area. One limitation of the DSMs generated by backpack MMS is that the outcome depends on the distance of the points to the axis of the track and on the irregularities in the terrain. Specific parameters have been studied, such as the measuring distance from the scanning point in the laser scanner, the angle of incidence with regard to the ground, the surface vegetation, and any irregularities in the terrain. The registration speed and the high definition of the terrain offered by these systems produce a model that can be used to select the correct conservation priorities for this unique space.

Influence of time of residence on the sense of community and satisfaction with life in immigrants in Spain: The moderating effects of sociodemographic characteristics.

Migration is an example of adaptation with enduring effects over time and in different cultures. Few studies have analyzed the effect of the sense of community (SOC) on satisfaction with life (SWL) over time while taking into account the moderating effects of sociodemographic characteristics. We propose a model that explains the influence of time of residence on the SOC and SWL. It was hypothesized that the SOC has a positive influence on SWL and that SWL is moderated by sociodemographic characteristics and cultural differences. Participants were 2,211 immigrants residing in Malaga (Spain). Results show a positive association between years of residence and the SOC and the SWL. A positive association was found between the SOC and SWL. This study shows the relevance of analyzing the moderating effects of sociodemographic characteristics in different immigrant groups rather than according to the migration process as a whole to develop specific intervention strategies.

On the Information Content of Coarse Data with Respect to the Particle Size Distribution of Complex Granular Media: Rationale Approach and Testing.

The particle size distribution (PSD) of complex granular media is seen as a mathematical measure supported in the interval of grain sizes. A physical property characterizing granular products used in the Andreasen and Andersen model of 1930 is re-interpreted in Information Entropy terms leading to a differential information equation as a conceptual approach for the PSD. Under this approach, measured data which give a coarse description of the distribution may be seen as initial conditions for the proposed equation. A solution of the equation agrees with a selfsimilar measure directly postulated as a PSD model by Martín and Taguas almost 80 years later, thus both models appear to be linked. A variant of this last model, together with detailed soil PSD data of 70 soils are used to study the information content of limited experimental data formed by triplets and its ability in the PSD reconstruction. Results indicate that the information contained in certain soil triplets is sufficient to rebuild the whole PSD: for each soil sample tested there is always at least a triplet that contains enough information to simulate the whole distribution.

Correction to: Manifesting heterozygotes in McArdle disease: a myth or a reality-role of statins.

Unfortunately the name of one of the authors was spelled incorrectly in the published original article. The correct name is Alejandro Santos-Lozano. The original article got updated.

Manifesting heterozygotes in McArdle disease: a myth or a reality-role of statins.

McArdle disease is an autosomal recessive condition caused by deficiency of the PYGM gene-encoded muscle isoform of glycogen phosphorylase. Some cases of "manifesting" heterozygotes or carriers (i.e., patients who show some McArdle-like symptoms or signs despite being carriers of only one mutated PYGM allele) have been reported in the literature but there is controversy, with misdiagnosis being a possibility. The purpose of our study was to determine if there are actually "manifesting" heterozygotes of McArdle disease and, if existing, whether statin treatment can trigger such condition. Eighty-one relatives of McArdle patients (among a total of 16 different families) were studied. We determined whether they were carriers of PYGM mutations and also collected information on exercise tests (second wind and modified Wingate anaerobic test) and statin intake. We found 50 carriers and 31 non-carriers of PYGM mutations. Although we found existence of heterozygotes manifesting some exercise-related muscle problems such as exacerbated myalgia or weakness, they only accounted for 14% of the carriers and muscle symptoms were milder than those commonly reported in patients. Further, no carrier (whether reporting symptoms or not) showed the second wind phenomenon or a flat blood lactate response to maximal-intensity exercise, both of which are hallmarks of McArdle disease. On the other hand, statin myotoxicity was not associated with muscle symptom onset.

Rhodamine-based sensor for real-time imaging of mitochondrial ATP in living fibroblasts.

Mitochondria are essential for the production and maintenance of ATP in the eukaryotic cell. To image and monitor intracellular ATP level without cell breakage, biological and chemical sensors were developed in the last years. Here, we have internalized a rhodamine-based sensor RSL+ into living cells and monitored the mitochondrial ATP levels in cultured mouse embryonic fibroblasts. To evaluate the robustness of the sensor we imaged the changes of the mitochondrial ATP levels under non-physiological conditions upon incubation with FCCP, oligomycin, azide, deoxyglucose or phosphoenolpyruvate; all compounds that interfere with ATP homeostasis of the cell. The ATP sensor allowed us to determine the mitochondrial ATP levels in human skin fibroblasts where we observe a similar amount of ATP compared to mouse embryonic fibroblasts. We propose the RSL+ to be a valuable tool for the assessment of mitochondrial dysfunction in human cells derived from mitochondrial OXPHOS patients and for basic studies on bioenergetics metabolism.