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Software user manual of the Turbidity spectrometry (TUS) sensordeveloped by IRIS Technology Solutions S.L. within the NanoPAT project. TUS is an online real-time characterisation solution for nanoparticle production processes.

Software user manual of the Turbidity spectrometry (TUS) sensordeveloped by IRIS Technology Solutions S.L. within the NanoPAT project. TUS is an online real-time characterisation solution for nanoparticle production processes.

El amor siempre ha sido objeto de reflexión de filósofos, tema privilegiado de poetas, artistas y moralistas de toda índole e inclinación. Desde el siglo XVII, la propia historia del cuerpo, de la concepción de las pasiones y las emociones ha ido “descarnado” el amor, separándolo de los procesos corporales, fisiológicos. Antes de llegar a aquel momento crítico de la historia de la cultura europea, hubo ciertamente quienes defendieron un amor separado del cuerpo, pero lejos de resultar algo obvio, tuvieron que defender sus argumentos ante una profunda tradición científica y filosófica que consideraba el amor una patología inseparable de los procesos fisiológicos. En este artículo se hace un repaso por el concepto de hereos, aegritudo amoris, para presentar un texto de Francesco Patrizi da Cherso (s. XVI), Il Delfino, overo del bacio, que constituye una de las más claras exposiciones de una concepción fisiológica del amor, una naturalización del amor que sorprende y resulta especialmente interesante por su síntesis con la tradición platónica.

Background The AMP-activated protein kinase (AMPK) is a major regulator of cellular energetics which plays key role in acute metabolic response and in long-term adaptation to stress. Recent works have also suggested non-metabolic effects. Methods To decipher AMPK roles in the heart, we generated a cardio-specific inducible model of gene deletion of the main cardiac catalytic subunit of AMPK (Ampkα2) in mice. This allowed us to avoid the eventual impact of AMPK-KO in peripheral organs. Results Cardio-specific Ampkα2 deficiency led to a progressive left ventricular systolic dysfunction and the development of cardiac fibrosis in males. We observed a reduction in complex I-driven respiration without change in mitochondrial mass or in vitro complex I activity, associated with a rearrangement of the cardiolipins and reduced integration of complex I into the electron transport chain supercomplexes. Strikingly, none of these defects were present in females. Interestingly, suppression of estradiol signaling by ovariectomy partially mimicked the male sensitivity to AMPK loss, notably the cardiac fibrosis and the rearrangement of cardiolipins, but not the cardiac function that remained protected. Conclusion Our results confirm the close link between AMPK and cardiac mitochondrial function, but also highlight links with cardiac fibrosis. Importantly, we show that AMPK is differently involved in these processes in males and females, which may have clinical implications for the use of AMPK activators in the treatment of heart failure., Highlights AMPK is a metabolic sensor of cellular energy which regulates energy homeostasis.We generated a cardiac-specific inducible deletion of Ampkα2 and demonstrated that this deletion induces mild cardiac dysfunction in male only.Cardiac dysfunction observed in males was associated with cardiac fibrosis and cardiac cardiolipin remodeling that are not seen in females.Although no significant cardiac function alteration was noticed in ovariectomized female Ampkα2ciKO mice, these latter exhibited cardiac fibrosis and mild cardiolipins remodeling.Our results show a higher dependence on AMPK signaling fibrosis and cardiolipin biosynthesis/maturation in males, either due to the absence of female hormones protection or/and to the action of male hormones. This may contribute to the known difference in cardiovascular risk and outcome between sexes.

El granuloma anular maculoso es una variante rara de granuloma anular, que representa un desafío diagnóstico. Su incidencia se desconoce y se presenta con mayor frecuencia en las mujeres de entre 40 y 70 años. Se asocia a las mismas entidades y responde a los mismos tratamientos que las otras variantes clínicas de granuloma anular. Se presentan los casos de 5 mujeres con diagnóstico de granuloma anular maculoso, que recibieron diferentes tratamientos tópicos y sistémicos, con respuestas clínicas variables.

Supplemental Digital Content is available in the text., Background: Orai1 is a critical ion channel subunit, best recognized as a mediator of store-operated Ca2+ entry (SOCE) in nonexcitable cells. SOCE has recently emerged as a key contributor of cardiac hypertrophy and heart failure but the relevance of Orai1 is still unclear. Methods: To test the role of these Orai1 channels in the cardiac pathophysiology, a transgenic mouse was generated with cardiomyocyte-specific expression of an ion pore-disruptive Orai1R91W mutant (C-dnO1). Synthetic chemistry and channel screening strategies were used to develop 4-(2,5-dimethoxyphenyl)-N-[(pyridin-4-yl)methyl]aniline (hereafter referred to as JPIII), a small-molecule Orai1 channel inhibitor suitable for in vivo delivery. Results: Adult mice subjected to transverse aortic constriction (TAC) developed cardiac hypertrophy and reduced ventricular function associated with increased Orai1 expression and Orai1-dependent SOCE (assessed by Mn2+ influx). C-dnO1 mice displayed normal cardiac electromechanical function and cellular excitation-contraction coupling despite reduced Orai1-dependent SOCE. Five weeks after TAC, C-dnO1 mice were protected from systolic dysfunction (assessed by preserved left ventricular fractional shortening and ejection fraction) even if increased cardiac mass and prohypertrophic markers induction were observed. This is correlated with a protection from TAC-induced cellular Ca2+ signaling alterations (increased SOCE, decreased [Ca2+]i transients amplitude and decay rate, lower SR Ca2+ load and depressed cellular contractility) and SERCA2a downregulation in ventricular cardiomyocytes from C-dnO1 mice, associated with blunted Pyk2 signaling. There was also less fibrosis in heart sections from C-dnO1 mice after TAC. Moreover, 3 weeks treatment with JPIII following 5 weeks of TAC confirmed the translational relevance of an Orai1 inhibition strategy during hypertrophic insult. Conclusions: The findings suggest a key role of cardiac Orai1 channels and the potential for Orai1 channel inhibitors as inotropic therapies for maintaining contractility reserve after hypertrophic stress.

Heart failure (HF) is a complex syndrome in which death rates are >50%. The main causes of death among HF patients are pump failure and ventricular arrhythmias, but severe bradycardia is also a common cause of sudden cardiac death, pointing to sinoatrial node (SAN) dysfunction. SAN pacemaker activity is regulated by voltage-clock and Ca2+-clock mechanisms and, although voltage-clock dysfunction in SAN has been largely proved in HF, Ca2+-clock dysfunction mechanisms in SAN remains unraveled. Here, we used an HF model in mice with transverse aortic constriction (TAC) and, using telemetry, saw slower heart rhythm under autonomic nervous system blockade. Then, by confocal microscopy, we analyzed Ca2+ handling in HF SAN tissue and found that intracellular Ca2+ transients rate were slower together with less frequency of Ca2+ sparks than in SHAM SAN tissue. Next, we studied protein expression of key excitation–contraction coupling proteins and found reduced expression of the Na+/Ca2+ exchanger and reduced phosphorylated status of ryanodine receptor and phospholamban in the CaMKII sites for the SAN in TAC mice. Finally, the application of the CaMKII inhibitor, KN93, caused less effect in slowing the Ca2+ transient rates in HF SAN tissue, confirming the reduced CaMKII activation. In conclusion, our data demonstrates a reduction in CaMKII activation in the Ca2+-clock function of the SAN tissue in a mouse model of HF.

espanolLa Enfermedad mano pie boca es una patologia exantematica viral muy contagiosa, de predominio en la edad pediatrica. Sus agentes etiologicos mas frecuentes son los virus Coxsackie y Enterovirus. Se caracteriza clinicamente por la presencia de fiebre, erosiones en mucosa bucal y exantema maculo vesicular en regiones acrales. Generalmente se autolimita, pero puede presentar complicaciones severas con compromiso neurologico, pulmonar y cardiaco. Se han observado brotes mundiales, por lo que actualmente es considerada un problema de salud publica emergente, tanto en poblaciones pediatricas como adultos. Se presentan casos de pacientes adultos inmunocompetentes con transmision intrafamiliar de Coxsackie B, sin complicaciones severas. Estos casos muestran la importancia de la prevencion para evitar brotes epidemicos, ademas de destacar la presentacion infrecuente en adultos inmunocompetentes EnglishHand foot and mouth disease is a very contagious viral exanthematous disease, predominantly in the pediatric age. Its most frequent etiologic agents are Coxsackie virus and Enterovirus. It is clinically characterized by fever accompanied or followed by erosions in the oral cavity, and vesicular exanthema in acral regions, usually self-limited, but can present severe complications with neurological, pulmonary and cardiac compromise. Due to recent outbreaks, it is considered an emerging public health concern, not only in pediatric population, but also in adults. We present cases of immunocompetent adult patients with intrafamilial transmission of Coxsackie B, without severe complications. These cases highlight the need for preventive measures that may inhibit epidemic outbreaks, in addition to highlighting the infrequent presentation in immunocompetent adults.

The paper presents the application of a holistic approach to corrosion prediction that overcomes classical pitfalls in corrosion testing and modelling at high pressure, high temperature and high CO2 conditions. Thermodynamic modelling of field and lab conditions allows for more accurate predictions by a novel CO2/H2S general corrosion model validated by laboratory tests. In the proposed workflow, autoclave tests at high pressure and temperature are designed after modeling corrosion in a rigorous thermodynamic framework including fluid-dynamic modelling; the modeled steps include preparation, gas loading and heating of fluid samples at high CO2 concentration, and high flow velocities. An autoclave setup is proposed and validated to simultaneously test different conditions. Corrosion rates are extrapolated to compute service life of the materials and guide material selection. The results from the model and tests extend the application of selected stainless steel grade beyond the threshold conditions calculated by simplistic models and guidelines. Consideration of fugacities and true aqueous compositions allows for accurate thermodynamic representation of field conditions. Computation by rigorous fluid dynamics of shear stress, multiphase flow and heat transfer effects inside completion geometry lead to a proper interpretation of corrosion mechanisms and models to apply. In the case study used to showcase the workflow, conventional stainless steel is validated for most of the tubing. It is observed that some sections of the system in static condition are not exposed to liquid water, allowing for safe use of carbon steel, while as for other critical parts, more noble materials are deemed necessary. Harsh environments pose a challenge to the application of conventional steel materials. The workflow applied to the case study allows accurate representation and application of materials in its application limit region, allowing for safe use of carbon steel or less noble stainless steels in those areas of the completion where corrosion is limited by multiphase fluid-dynamics, heat transfer or the both. The approximation is validated for real case study under high CO2 content, and is considered also valid in the transportation of higher amounts of CO2, for example, in CCUS activities.

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We present a Compositional Eulerian model to forecast the evolution of oil spills in the sea. The model allows studying the fate of not only the oil concentration but also of each component (e.g., volatile, non-volatile, water in the oil). Therefore, the problem is formulated as a conservation equation for each component, plus an equation to estimate the age of the oil, which allows us to assess weathering processes (e.g., evaporation, natural dispersion, emulsion) and the associated changes in oil properties. We describe an efficient implementation, using second order numerical schemes for advection and nonlinear diffusion terms, to reduce numerical diffusion. We perform numerical experiments, based on real and synthetic cases, to illustrate and validate the capabilities of our model to forecast the evolution of oil spills and to perform environmental risk analysis in the case of a potential accident., This work was carried out thanks to the financial support from the Spanish “Ministry of Science and Innovation” under Project PID2019-106337GB-I00 and the National University of Mexico Project PASPA, DGAPA . We also thank Nelson del Castillo, for his support in the elaboration of this article. Comments by two anonymous reviewers have contributed to improving the final version of the paper. Some of the figures proposed in this work include maps from the Google Map website (see, for instance, https://www.google.com/maps).

Umbilical Cord Blood (UCB) is an alternative source of hematopoietic stem cells for transplantation. A UCB bank is a multidisciplinary structure that is responsible for the recruitment, collection, processing, testing, cryopreservation, storage, listing, reservation, release, and distribution of units for administration. Also, UCB can be transferred for life-saving research. Before labor, adequate information and consent, including possibility of repurposing donation shall be performed. After delivery and using appropriate techniques placental blood can be collected and processed for therapeutic purposes. Cell processing normally consists of volume reduction to achieve a reasonable reduce of storage area. Automatic procedures have some advantages on reproducibility. A banking project starts with an establishment phase where banks should have a rapid growth to achieve their operational size. Then a maintenance phase follows, once the optimum inventory is achieved where UCB banks should focus in increasing quality and diversity. As consequence a decrease in numbers of newly added units are expected. The fact that less than 20% of collected units have more than 150x107 total nucleated cells, estimated to be the threshold for efficient inventories, challenge ethics of donation programs. Therefore, UCB banks need to research on alternative uses to add value to the surplus units and the available inventory. Finally, integration with other cell therapy services will reduce fix costs of operation and contribute sustainability.

Background: The cyclic AMP (adenosine monophosphate; cAMP)-hydrolyzing protein PDE4B (phosphodiesterase 4B) is a key negative regulator of cardiac β-adrenergic receptor stimulation. PDE4B deficiency leads to abnormal Ca 2+ handling and PDE4B is decreased in pressure overload hypertrophy, suggesting that increasing PDE4B in the heart is beneficial in heart failure. Methods: We measured PDE4B expression in human cardiac tissues and developed 2 transgenic mouse lines with cardiomyocyte-specific overexpression of PDE4B and an adeno-associated virus serotype 9 encoding PDE4B. Myocardial structure and function were evaluated by echocardiography, ECG, and in Langendorff-perfused hearts. Also, cAMP and PKA (cAMP dependent protein kinase) activity were monitored by Förster resonance energy transfer, L-type Ca 2+ current by whole-cell patch-clamp, and cardiomyocyte shortening and Ca 2+ transients with an Ionoptix system. Heart failure was induced by 2 weeks infusion of isoproterenol or transverse aortic constriction. Cardiac remodeling was evaluated by serial echocardiography, morphometric analysis, and histology. Results: PDE4B protein was decreased in human failing hearts. The first PDE4B-transgenic mouse line (TG15) had a ≈15-fold increase in cardiac cAMP-PDE activity and a ≈30% decrease in cAMP content and fractional shortening associated with a mild cardiac hypertrophy that resorbed with age. Basal ex vivo myocardial function was unchanged, but β-adrenergic receptor stimulation of cardiac inotropy, cAMP, PKA, L-type Ca 2+ current, Ca 2+ transients, and cell contraction were blunted. Endurance capacity and life expectancy were normal. Moreover, these mice were protected from systolic dysfunction, hypertrophy, lung congestion, and fibrosis induced by chronic isoproterenol treatment. In the second PDE4B-transgenic mouse line (TG50), markedly higher PDE4B overexpression, resulting in a ≈50-fold increase in cardiac cAMP-PDE activity caused a ≈50% decrease in fractional shortening, hypertrophy, dilatation, and premature death. In contrast, mice injected with adeno-associated virus serotype 9 encoding PDE4B (10 12 viral particles/mouse) had a ≈50% increase in cardiac cAMP-PDE activity, which did not modify basal cardiac function but efficiently prevented systolic dysfunction, apoptosis, and fibrosis, while attenuating hypertrophy induced by chronic isoproterenol infusion. Similarly, adeno-associated virus serotype 9 encoding PDE4B slowed contractile deterioration, attenuated hypertrophy and lung congestion, and prevented apoptosis and fibrotic remodeling in transverse aortic constriction. Conclusions: Our results indicate that a moderate increase in PDE4B is cardioprotective and suggest that cardiac gene therapy with PDE4B might constitute a new promising approach to treat heart failure.

In this work, we use an Eulerian mathematical model to forecast the movement of oil spills in the open sea and we design objective functions to obtain optimal trajectories for skimmer ships to clean and recover the oil. Here, we first validate the ability of this mathematical model to forecast the fate of the oil by comparing our results with satellite images. Then, we create a synthetic study case based on real data, and we show that following optimal trajectories greatly improves the amount of oil recovered at the whole area of study.

Pumping tests interpretation is an art that involves dealing with noise coming from multiple sources and conceptual model uncertainty. Interpretation is greatly helped by diagnostic plots, which include drawdown data and their derivative with respect to log-time, called log-derivative. Log-derivatives are especially useful to complement geological understanding in helping to identify the underlying model of fluid flow because they are sensitive to subtle variations in the response to pumping of aquifers and oil reservoirs. The main problem with their use lies in the calculation of the log-derivatives themselves, which may display fluctuations when data are noisy. To overcome this difficulty, we propose a variational regularization approach based on the minimization of a functional consisting of two terms: one ensuring that the computed log-derivatives honor measurements and one that penalizes fluctuations. The minimization leads to a diffusion-like differential equation in the log-derivatives, and boundary conditions that are appropriate for well hydraulics (i.e., radial flow, wellbore storage, fractal behavior, etc.). We have solved this equation by finite differences. We tested the methodology on two synthetic examples showing that a robust solution is obtained. We also report the resulting log-derivative for a real case.

Folding of the myosin head often requires the joint actions of Hsp90 and a dedicated UNC45, Cro1, She4 (UCS) domain-containing cochaperone protein. Relatively weak sequence conservation exists between the single UCS protein of simple eukaryotes (She4 in budding yeast) and the two UCS proteins of higher organisms (the general cell and smooth muscle UNC45s; UNC45-GC and UNC45-SM respectively). In vertebrates, UNC45-GC facilitates cytoskeletal function whereas the 55% identical UNC45-SM assists in the assembly of the contractile apparatus of cardiac and skeletal muscles. UNC45-SM, unlike UNC45-GC, shares with yeast She4 an IDSL sequence motif known to be a site of in vivo serine phosphorylation in yeast. Investigating this further, we found that both a non-phosphorylatable (S18A) and a phosphomimetic (S18E) mutant form of She4 could rescue the type 1 myosin localisation and endocytosis defects of the yeast she4Δ mutant at 39 °C. Nevertheless, at higher temperature (45 °C), only She4 (S18A), not She4(S18E), could substantially rescue the cell lysis defect of she4Δ mutant cells. In the yeast two-hybrid system, the non-phosphorylatable S18A and S251A mutant forms of She4 and UNC45-SM still displayed the stress-enhanced in vivo interaction with Hsp90 seen with the wild-type She4 and UNC45-SM. Such high-temperature enforcement to interaction was though lost with the phosphomimetic mutant forms (She4(S18E) and UNC45-SM (S251E)), an indication that phosphorylation might suppress these increases in She4/Hsp90 and UNC45-SM/Hsp90 interaction with stress.

Introduction Mitochondrial dysfunction plays a major role in the Heart Failure (HF) pathophysiology.The AMP activated protein kinase (AMPK) is activated by a high AMP-ADP/ATP ratio and regulates a number of metabolic pathways. Many studies have highlighted a protective role of AMPK in HF, but its relevance to cardiac tissue, its metabolic part and its sex specificity are not well established. Purpose Then, the aim of this study is to determine the role of AMPK in the healthy and failing heart in male and female mice. Methods We developed and validated a mouse strain with an adult-inducible cardiac-specific deletion of AMPKα2, the major cardiac isoform, using the Cre-Lox system (40mg/kg tamoxifen injection on two consecutive days at adult age). At four months after the deletion, cardiac contractility, morphology and metabolism were studied in control and KO mice from both sexes. Results We observed only in male KO mice a decrease of left ventricular ejection fraction (−10%), an increase of the total fibrosis (+64%) and defects in mitochondrial structures. Male KO mice also showed a reduced (−28%) mitochondrial respiration via complex I associated with a different cardiolipin species distribution. Conclusion Our results reveal in adult healthy hearts, a sex-specificity in the effects of AMPKα2 deletion, leading to impaired contractile function related to metabolic and non-metabolic alterations only in male mice.