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Osteoarthritis is characterized by enzymatic breakdown of the articular cartilage via the disruption of chondrocyte homeostasis, ultimately resulting in the destruction of the articular surface. Decades of research have highlighted the importance of inflammation in osteoarthritis progression, with inflammatory cytokines shifting resident chondrocytes into a pro-catabolic state. Inflammation can result in poor outcomes for cells implanted for cartilage regeneration. Therefore, a method to promote the growth of new cartilage and protect the implanted cells from the pro-inflammatory cytokines found in the joint space is required. In this study, we fabricate two gel types: polymer network hydrogels composed of chondroitin sulfate and hyaluronic acid, glycosaminoglycans (GAGs) known for their anti-inflammatory and prochondrogenic activity, and interpenetrating networks of GAGs and collagen I. Compared to a collagen-only hydrogel, which does not provide an anti-inflammatory stimulus, chondrocytes in GAG hydrogels result in reduced production of pro-inflammatory cytokines and enzymes as well as preservation of collagen II and aggrecan expression. Overall, GAG-based hydrogels have the potential to promote cartilage regeneration under pro-inflammatory conditions. Further, the data have implications for the use of GAGs to generally support tissue engineering in pro-inflammatory environments.

Sodium glucose cotransporter-2 inhibitors (SGLT2i), originally developed for type II diabetes mellitus, have recently been approved for the treatment of heart failure in both diabetic and non-diabetic patients due to their significant cardiovascular benefits. Beyond their established role in diabetes and heart failure management, current research is exploring the potential applications of SGLT2 inhibitors in the field of cardio-oncology. This interest is driven by dual possible benefits: cardioprotection against the adverse effects of antitumor therapies and inherent antitumor properties. Patients affected by cancer often face the challenge of managing cardiovascular toxicity induced by antineoplastic treatments. SGLT2 inhibitors have shown promise in mitigating toxicities, thereby enhancing the cardiovascular health of these patients. Additionally, emerging evidence suggests that SGLT2 inhibitors may possess direct antitumor effects, further contributing to their therapeutic potential in oncology. This review aims to provide a comprehensive overview of the molecular mechanisms through which SGLT2 inhibitors exert their cardioprotective and antitumor effects. Furthermore, we will examine the current body of evidence supporting the use of these inhibitors in a cardio-oncology setting.

This brief introduction sets the stage for the central aim of this issue of Ethics in Progress devoted to Hegel: to underscore the enduring relevance of his thought, in particular his Philosophy of Nature and his Realphilosophie, in addressing contemporary challenges. While Hegel may appear to some as an abstract thinker, seemingly surpassed by the demands of our era, the core elements of his philosophy – particularly the dialectical method, his reflections on the complex relationship between Natur (nature) and Geist (spirit), and key concepts such as Anerkennung (recognition) and Wille (will) – continue to provide a vital conceptual framework for addressing pressing issues of our time. These include the environmental crisis and the evolving dynamics between humanity, nature, and emerging technologies like artificial intelligence. Consequently, this issue strives to approach Hegel through the lens of our contemporary experience, not to distort or “denaturalize” his thought, nor to fall into the trap of anachronism, but to breathe new life into the concept. By doing so, it invites the reader to listen anew to what Hegel’s philosophy might still teach us today.

Melamine has several domestic and industrial uses as a flame retardant or in the manufacture of melamine–formaldehyde resins. Based on available scientific literature data, the French Agency for Food, Environmental and Occupational Health & Safety (ANSES) included this substance in the list of “chemicals that may present endocrine disruptor (ED) properties”, and the substance was prioritized to assess whether it should be classified as an ED in European Union (EU) regulations for hazard identification. This review reports the assessment of melamine based on relevant studies from the registration dossier under REACH, and peer-reviewed literature. Among the various adverse effects, reproductive, neurodevelopmental, and thyroid effects were analyzed in particular, because they could be the consequence of an endocrine disruption. The different modes of action (endocrine or non-endocrine) potentially leading to these effects were scrutinized to understand whether the WHO definition for ED and the criteria for hazard identification were met. It was concluded that the reproductive effect on spermatogenesis was not a consequence of endocrine activity. A biologically plausible link between this effect and endocrine activity was not established, and other modes of action (oxidative stress or altered energy metabolism) could be involved. Similarly, thyroid and neurodevelopmental effects appeared at higher doses than those leading to renal toxicity. Our assessment confirms that melamine is a reprotoxic substance but does not support ED classification. This assessment illustrates the scientific and regulatory challenges in differentiating specific endocrine disruption from an indirect endocrine effect resulting from non-ED mediated systemic toxicity.

Abstract The energy efficiency of Artificial Intelligence (AI) systems is a crucial and actual issue that may have an important impact on an ecological, economic and technological level. Spiking Neural Networks (SNNs) are strongly suggested as valid candidates able to overcome Artificial Neural Networks (ANNs) in this specific contest. In this study, the proposal involves the review and comparison of energy consumption of the popular Artificial Neural Network architectures implemented on the CPU and GPU hardware compared with Spiking Neural Networks implemented in specialized memristive hardware and biological neural network human brain. As a result, the energy efficiency of Spiking Neural Networks can be indicated from 5 to 8 orders of magnitude. Some Spiking Neural Networks solutions are proposed including continuous feedback‐driven self‐learning approaches inspired by biological Spiking Neural Networks as well as pure memristive solutions for Spiking Neural Networks.

Lysosomes are crucial for degradation and recycling of damaged proteins and cellular components. Therapeutic strategies enhancing lysosomal function are a promising approach for aging and age-related neurodegenerative diseases. Here, we show that an FDA approved drug sodium polystyrene sulfonate (SPS), used to reduce high blood potassium in humans, enhances lysosomal function both in C. elegans and in human neuronal cells. Enhanced lysosomal function following SPS treatment is accompanied by the suppression of proteotoxicity caused by expression of the neurotoxic peptides Aβ and TAU. Additionally, treatment with SPS imparts health benefits as it significantly increases lifespan in C. elegans. Overall our work supports the potential use of SPS as a prospective geroprotective intervention.

ABSTRACT Limiting the availability of transition metals at infection sites serves as a critical defense mechanism employed by the innate immune system to combat microbial infections. Pseudomonas aeruginosa exhibits a remarkable ability to thrive in zinc-deficient environments, facilitated by intricate cellular responses governed by numerous genes regulated by the zinc-responsive transcription factor Zur. Many of these genes have unknown functions, including those within the predicted PA2911-PA2914 and PA4063-PA4066 operons. A structural bioinformatics investigation revealed that PA2911-PA2914 comprises a TonB-dependent outer membrane receptor and inner membrane ABC-permeases responsible for importing metal-chelating molecules, whereas PA4063-PA4066 contains genes encoding a MacB transporter, likely involved in the export of large molecules. Molecular genetics and biochemical experiments, feeding assays, and intracellular metal content measurements support the hypothesis that PA2911-PA2914 and PA4063-PA4066 are engaged in the import and export of the pyochelin-cobalt complex, respectively. Notably, cobalt can reduce zinc demand and promote the growth of P. aeruginosa strains unable to import zinc, highlighting pyochelin-mediated cobalt import as a novel bacterial strategy to counteract zinc deficiency. These results unveil an unexpected role for pyochelin in zinc homeostasis and challenge the traditional view of this metallophore exclusively as an iron transporter.IMPORTANCEThe mechanisms underlying the remarkable ability of Pseudomonas aeruginosa to resist the zinc sequestration mechanisms implemented by the vertebrate innate immune system to control bacterial infections are still far from being fully understood. This study reveals that the Zur-regulated gene clusters PA2911-2914 and PA4063-PA4066 encode systems for the import and export of cobalt-bound pyochelin, respectively. This proves to be a useful strategy to counteract conditions of severe zinc deficiency since cobalt can replace zinc in many proteins. The discovery that pyochelin may contribute to cellular responses to zinc deficiency leads to a reevaluation of the paradigm that pyochelin is a siderophore involved exclusively in iron acquisition and suggests that this molecule has a broader role in modulating the homeostasis of multiple metals.

In this study, the effect of start of injection (SOI) timing is investigated on a single cylinder spark ignited (SI) internal combustion engine (ICE) fueled with hydrogen, using Computational Fluid Dynamics (CFD) simulations. Mixing fields and combustion behaviors at different relative air-fuel ratios (λ) and injection strategies are discussed. Direct injection (DI) cases with three different SOI timings for each λ are compared against port-fuel injection (PFI) cases modeled assuming perfectly premixed charge at the intake plenum. Results for the investigated cases show that PFI cases at λ = 2 and λ = 3 have very high combustion efficiency while at λ = 3.5 partial burn occurs (only 70% of the fuel is oxidized). In DI cases, combustion efficiency decreases compared to corresponding premixed situations, as expected, but significant improvements are obtained by advancing the SOI timing towards the end of the intake stroke. In addition, early SOI timings tend to reduce the duration of initial combustion stage, CA0-10, which correlates with ignition repeatability, therefore suggesting potential benefits on combustion stability under very lean conditions. The method and results of this work can be used as a guideline for developing efficient hydrogen injection strategies.

Should the appliances change to adapt to new conditions in the current scenario of a compromised environmental situation? The human needs to cook food, wash dishes and do laundry are the same, but society and our relationship with mother nature have changed radically. Although many contributions to the design for sustainability, the changes in the design sector and the market are not always visible. This paper is part of a research project on the design of appliances for the circular economy scenario and intends to understand Is there the need to re-design the current one, design new ones, or invent something else? How to decide? Are we considering all the aspects? The problem was tackled using a systemic design approach. The result is a framework that contains the data collected by the research steps, maps all the implications that the design of appliances in the circular economy scenario should consider in the process, and visualises the complexity of the topic.

Purpose: Intraoperative electron radiotherapy (IOeRT) is considered the first clinical translation of FLASH with electrons. A crucial aspect is represented by the precise dose monitoring and measurement; to this aim, we propose a method fully based on Monte Carlo (MC) simulation that uses as input the beam current measurement and the beam optics simulation. To validate this approach, we chose the NOVAC11 (produced by Sordina IORT Technologies SpA) accelerator, which provides a well-studied model.Methods: We used FLUKA and FRED MC software to simulate in detail the geometry of the NOVAC11 and the coupled applicator usually adopted in clinical practice to deliver the dose in the surgical bed. The simulation results of the longitudinal and off-axis profiles and dose per pulse obtained in a water phantom with different applicators are compared to the experimental data.Results: A very good agreement not only for the relative dosimetry in both the longitudinal and off-axis profiles, with a gamma index pass rate of 100% with 3%/3 mm acceptance criteria, but also for the absolute dosimetry was obtained.Conclusion: The results completely validate the MC description of the system and provide a reliable evaluation of the dose per pulse and output factor with an accuracy of the order of few % for different sets of applicator diameters and lengths.