Nutrients and pathways that regulate health span and life span

Both life span and health span are influenced by genetic, environmental and lifestyle factors. With the genetic influence on human life span estimated to be about 20\u201325%, epigenetic changes play an important role in modulating individual health status and aging. Thus, a main part of life expectance and healthy aging is determined by dietary habits and nutritional factors. Excessive or restricted food consumption have direct effects on health status. Moreover, some dietary interventions including a reduced intake of dietary calories without malnutrition, or a restriction of specific dietary component may promote health benefits and decrease the incidence of aging-related comorbidities, thus representing intriguing potential approaches to improve healthy aging. However, the relationship between nutrition, health and aging is still not fully understood as well as the mechanisms by which nutrients and nutritional status may affect health span and longevity in model organisms. The broad effect of different nutritional conditions on health span and longevity occurs through multiple mechanisms that involve evolutionary conserved nutrient-sensing pathways in tissues and organs. These pathways interacting each other include the evolutionary conserved key regulators mammalian target of rapamycin, AMP-activated protein kinase, insulin/insulin-like growth factor 1 pathway and sirtuins. In this review we provide a summary of the main molecular mechanisms by which different nutritional conditions, i.e., specific nutrient abundance or restriction, may affect health span and life span

Three-Dimensional CFD Simulation of a Proton Exchange Membrane Electrolysis Cell

The energy shift towards carbon-free solutions is creating an ever-growing engineering interest in electrolytic cells, i.e., devices to produce hydrogen from water-splitting reactions. Among the available technologies, Proton Exchange Membrane (PEM) electrolysis is the most promising candidate for coping with the intermittency of renewable energy sources, thanks to the short transient period granted by the solid thin electrolyte. The well-known principle of PEM electrolysers is still unsupported by advanced engineering practices, such as the use of multidimensional simulations able to elucidate the interacting fluid dynamics, electrochemistry, and heat transport. A methodology for PEM electrolysis simulation is therefore needed. In this study, a model for the multidimensional simulation of PEM electrolysers is presented and validated against a recent literature case. The study analyses the impact of temperature and gas phase distribution on the cell performance, providing valuable insights into the understanding of the physical phenomena occurring inside the cell at the basis of the formation rate of hydrogen and oxygen. The simulations regard two temperature levels (333 K and 353 K) and the complete polarization curve is numerically predicted, allowing the analysis of the overpotentials break-up and the multi-phase flow in the PEM cell. An in-house developed model for macro-homogeneous catalyst layers is applied to PEM electrolysis, allowing independent analysis of overpotentials, investigation into their dependency on temperature and analysis of the cathodic gas–liquid stratification. The study validates a comprehensive multi-dimensional model for PEM electrolysis, relevantly proposing a methodology for the ever-growing urgency for engineering optimization of such devices

Industry 4.0 Driven Result-oriented PSS: An Assessment in the Energy Management

Sustainability is a current challenge and all sectors, including the buildings one, are being called upon to provide a solution to mitigate climate change. The state of the art of energy management using Information and Communication Technologies (ICT) technology in building systems industry is characterized by a traditional monitoring approach which could assess the energy consumption of the building but that cannot manage and act the required action to improve the energy management according to a demand side approach. The aim of this paper is to overcome this traditional monitoring approach, presenting Simon, a new model proposed by Evogy, enabling a result-oriented product service system (PSS) for buildings through cyber physical systems, artificial intelligence, and internet of things adoption. The main findings highlight the benefits associated with the Simon model by virtue of digital-based predictive maintenance on the real system. In addition, its adoption allows the PSS provider to aggregate energy demand from the plethora of buildings and, according to digital technologies, not only monitor consumption but also implement equipment. Finally, the application case highlights the benefits are different and thus stands as a best practice for combining sustainability and digitization

Induced pluripotent stem cell-based models: Are we ready for that heart in a dish?

Non present

Altered functional properties of a missense variant in the TRESK K+ channel (KCNK18) associated with migraine and intellectual disability

Mutations in the KCNK18 gene that encodes the TRESK K2P potassium channel have previously been linked with typical familial migraine with aura. Recently, an atypical clinical case has been reported in which a male individual carrying the p.Trp101Arg (W101R) missense mutation in the KCNK18 gene was diagnosed with intellectual disability and migraine with brainstem aura. Here we report the functional characterization of this new missense variant. This mutation is located in a highly conserved residue close to the selectivity filter, and our results show although these mutant channels retain their K+ selectivity and calcineurin-dependent regulation, the variant causes an overall dramatic loss of TRESK channel function as well as an initial dominant-negative effect when co-expressed with wild-type channels in Xenopus laevis oocytes. The dramatic functional consequences of this mutation thereby support a potentially pathogenic role for this variant and provide further insight into the relationship between the structure and function of this ion channel

An integrated 0D/1D/3D numerical framework to predict performance, emissions, knock and heat transfer in ICEs fueled with NH3–H2 mixtures: The conversion of a marine Diesel engine as case study

In the maritime transportation, e-fuels represent a valid alternative to fossil energy sour- ces, in order to accomplish the European Union goals in terms of climate neutrality. Among the e-fuels, the ammonia-hydrogen mixtures can play a leading role, as the combination of the two allows to exploit the advantages of each one, simultaneously compensating their gaps. The main goal of the present publication is the proposal of a robust numerical frame- work based on 0D, 1D and 3D tools for CFD analyses of internal combustion engines fueled with ammonia-hydrogen mixtures. The 1D engine model provides boundary conditions for the multi-dimensional in- vestigations and estimates the overall engine performance. 3D in-cylinder detailed ana- lyses are proficiently used to predict combustion efficiency (via the well-established G-equation model supported by laminar flame speed correlations for both ammonia and hydrogen) and emissions (with a detailed chemistry based approach). Heat transfer and knock tendency are evaluated as well, by in-house developed models. As for the 0D/1D chemical kinetics calculations, firstly they support 3D analyses (for example via the gen- eration of ignition delay time tables). Moreover, they allow insights on aspects such as NOx formation, to individuate mixture qualities able to strongly reduce the emissions

Kcnj16 (Kir5.1) gene ablation causes subfertility and increases the prevalence of morphologically abnormal spermatozoa

The ability of spermatozoa to swim towards an oocyte and fertilize it depends on precise K+ permeability changes. Kir5.1 is an inwardly-rectifying potassium (Kir) channel with high sensitivity to intracellular H+ (pHi) and extracellular K+ concentration [K+ ]o, and hence provides a link between pHi and [K+ ]o changes and membrane potential. The intrinsic pHi sensitivity of Kir5.1 suggests a possible role for this channel in the pHi-dependent processes that take place during fertilization. However, despite the localization of Kir5.1 in murine spermatozoa, and its increased expression with age and sexual maturity, the role of the channel in sperm morphology, maturity, motility, and fertility is unknown. Here, we confirmed the presence of Kir5.1 in spermatozoa and showed strong expression of Kir4.1 channels in smooth muscle and epithelial cells lining the epididymal ducts. In contrast, Kir4.2 expression was not detected in testes. To examine the possible role of Kir5.1 in sperm physiology, we bred mice with a deletion of the Kcnj16 (Kir5.1) gene and observed that 20% of Kir5.1 knock-out male mice were infertile. Furthermore, 50% of knock-out mice older than 3 months were unable to breed. By contrast, 100% of wild-type (WT) mice were fertile. The genetic inactivation of Kcnj16 also resulted in smaller testes and a greater percentage of sperm with folded flagellum compared to WT littermates. Nevertheless, the abnormal sperm from mutant animals displayed increased progressive motility. Thus, ablation of the Kcnj16 gene identifies Kir5.1 channel as an important element contributing to testis development, sperm flagellar morphology, motility, and fertility. These findings are potentially relevant to the understanding of the complex pHi-and [K+ ]o-dependent interplay between different sperm ion channels, and provide insight into their role in fertilization and infertility

Basal and IL-1β enhanced chondrocyte chemotactic activity on monocytes are co-dependent on both IKKα and IKKβ NF-κB activating kinases

IKKα and IKKβ are essential kinases for activating NF-κB transcription factors that regulate cellular differentiation and inflammation. By virtue of their small size, chemokines support the crosstalk between cartilage and other joint compartments and contribute to immune cell chemotaxis in osteoarthritis (OA). Here we employed shRNA retroviruses to stably and efficiently ablate the expression of each IKK in primary OA chondrocytes to determine their individual contributions for monocyte chemotaxis in response to chondrocyte conditioned media. Both IKKα and IKKβ KDs blunted both the monocyte chemotactic potential and the protein levels of CCL2/MCP-1, the chemokine with the highest concentration and the strongest association with monocyte chemotaxis. These findings were mirrored by gene expression analysis indicating that the lowest levels of CCL2/MCP-1 and other monocyte-active chemokines were in IKKαKD cells under both basal and IL-1β stimulated conditions. We find that in their response to IL-1β stimulation IKKαKD primary OA chondrocytes have reduced levels of phosphorylated NFkappaB p65pSer536 and H3pSer10. Confocal microscopy analysis revealed co-localized p65 and H3pSer10 nuclear signals in agreement with our findings that IKKαKD effectively blunts their basal level and IL-1β dependent increases. Our results suggest that IKKα could be a novel OA disease target

An Experimental and Simulation Study of Early Flame Development in a Homogeneous-Charge Spark-Ignition Engine

An integrated experimental and Large-Eddy Simulation (LES) study is presented for homogeneous premixed combustion in a spark-ignition engine. The engine is a single-cylinder two-valve optical research engine with transparent liner and piston: the Transparent Combustion Chamber (TCC) engine. This is a relatively simple, open engine configuration that can be used for LES model development and validation by other research groups. Pressure-based combustion analysis, optical diagnostics and LES have been combined to generate new physical insight into the early stages of combustion. The emphasis has been on developing strategies for making quantitative comparisons between high-speed/high-resolution optical diagnostics and LES using common metrics for both the experiments and the simulations, and focusing on the important early flame development period. Results from two different LES turbulent combustion models are presented, using the same numerical methods and computational mesh. Both models yield Cycle-to-Cycle Variations (CCV) in combustion that are higher than what is observed in the experiments. The results reveal strengths and limitations of the experimental diagnostics and the LES models, and suggest directions for future diagnostic and simulation efforts. In particular, it has been observed that flame development between the times corresponding to the laminar-to-turbulent transition and 1% mass-burned fraction are especially important in establishing the subsequent combustion event for each cycle. This suggests a range of temporal and spatial scales over which future experimental and simulation efforts should focus