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The endocrine disruptor chlorpyrifos alters hypothalamic Npy and Agrp expression via ERβ-dependent regulation in vitro and in vivo
No full textIntroduction: Obesity represents a global health concern, with the hypothalamus playing a central role in regulating energy balance. Chlorpyrifos (CPF), a widely used organophosphate pesticide, is now recognized as an endocrine-disrupting chemical (EDC). Although the peripheral metabolic effects of CPF are relatively well characterized, its potential impact on central energy balance remains to be investigated. Here, we examined, both in vitro in murine hypothalamic cells and in vivo in murine hypothalami, whether CPF modulates the orexigenic mediators Neuropeptide Y (Npy) and Agouti-related peptide (Agrp). We further explored the molecular mechanisms underlying this regulation. Methods: For in vitro studies, murine mHypoE-N46 hypothalamic cells were treated with CPF (1 pM) under acute (4 h) and chronic (6-day) exposure conditions. For in vivo studies, hypothalamic tissue from CD-1 mice chronically exposed to CPF (10 mg/kg/day), from conception to 6 months of age while maintained on a standard diet, were analyzed. Gene and protein expression levels, as well as neuropeptide secretion, were assessed by qPCR, Western blotting, and ELISA, respectively. Selective pharmacological antagonists of ERβ and ERα were employed to determine receptor-specific effects. Results: Both acute and chronic CPF exposure significantly increased Npy and Agrp mRNA expression and secretion in mHypoE-N46 cells. Chronic CPF treatment selectively upregulated ERβ at the mRNA and protein levels, whereas ERα was unaffected. Pharmacological inhibition confirmed ERβ as the main mediator of CPF action. Consistently, in vivo hypothalamic samples from CPF-exposed mice displayed increased Npy and Agrp expression and an elevated ERβ/ERα ratio, mirroring the in vitro findings. Also, CPF exposure increased leptin receptor (Lepr) expression both in vitro and in vivo. Conclusion: Our findings indicate that CPF acts as a central endocrine disruptor by shifting estrogen receptor signaling toward ERβ dominance, thereby promoting orexigenic neuropeptide expression. Together with the increased Lepr expression, this mechanism may contribute to hypothalamic dysfunction and metabolic imbalance. The evolutionary conservation of hypothalamic circuits suggests that similar mechanisms may operate across species and impact metabolic health
El juego en equipo
No full textLos grupos son una característica de todos los contextos sociales, y cada individuo de una organización es miembro de uno o más grupos.El equipo se define como un grupo de personas que colaboran en la realización de una actividad, ya sea laboral o deportiva. Formar parte de un equipo, en cualquier actividad y situación, significa entrar a formar parte de un grupo cohesionado en el que las personas interactúan y se influyen mutuamente
Encirclement of an exceptional point and eigenvalue switch in non-Hermitian coupled spintronic nano-oscillators
No full textExceptional points (EPs) are known for their unique topological behaviors, including eigenvalue and eigenvector switching and high sensitivity to parameter changes. While EPs are usually studied in parity-time (PT) symmetric systems, we investigate the presence of EPs in the more general case of purely non-Hermitian systems. Using coupled spintronic auto-oscillators with uncompensated gain/loss, we explore the parameter space of the coupled system by fine-tuning the spin-transfer torque effect and its relative phase. Using this approach, we reveal and investigate the generalized presence of EPs. These tuning mechanisms provide direct control over the coupling nature, from conservative to dissipative. Moreover, we demonstrate the topological nature of the EP by dynamical encircling it in the phase-current parameter space, resulting in a switch of the eigenvalues. Our study introduces a new and versatile approach for exploring non-Hermitian physics in spintronic systems at room temperature
The Diet-Multiple Sclerosis Connection: Oxidative Stress and Emerging Mechanisms
No full textMultiple sclerosis (MS) is an autoimmune neuroinflammatory disease resulting in myelin degeneration and progressive disability. Oxidative stress plays a crucial role in MS pathogenesis and progression. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulator of the antioxidant mechanisms and its upregulation is associated with beneficial effects in MS. Among the environmental factors influencing MS onset and progression, diet represents a promising non-pharmacological strategy to modulate Nrf2, potentially improving MS outcomes. Indeed, several natural compounds present in Mediterranean, ketogenic and Paleolithic diets can enhance Nrf2 activity, and exert beneficial effects in preclinical models of MS. In this review, we summarize the key role of oxidative stress in MS and highlight how dietary regimens and Nrf2-modulating natural compounds might have therapeutic potential for MS patients. Additionally, we discuss emerging and still poorly explored mechanisms beyond classical Nrf2 activation, including epigenetic regulation and the stability of DNA/RNA secondary structures known as G-quadruplexes, which are involved in gene expression regulation and may represent novel nutrition-based therapeutic targets. However, while Nrf2 modulation by diet is supported by preclinical and limited clinical evidence, targeting G-quadruplexes as a strategy to counteract oxidative stress in MS remains largely speculative and requires further investigation. Notably, epigenetic mechanisms and G-quadruplexes may represent innovative targets of Nrf2-boosting dietary natural compounds for the development of supplemental therapeutic strategies for MS
Wittgenstein, Turing, and the Intelligence of Games
No full textOne of Wittgenstein’s most quoted passages from his Remarks on the Philosophy of Psychology concerns Turing’s “machines” and says verbatim: “These machines are humans who calculate. And one might express what he [Turing] says also in the form of games.” This passage not only captures the kernel of Turing’s conceptual argument for the adequacy of his definition of “computability”, as presented in his article On Computable Numbers (1936), but also helps clarify Turing’s idea of “mechanical intelligence.” Indeed, the notion of game provides an ideal means to focus on similarities and differences between Turing and Wittgenstein’s views of mechanical procedures, mathematical understanding, and thinking activity. The live encounter between Ludwig Wittgenstein and Alan Turing took place in Cambridge in 1939, when Wittgenstein’s Lectures on the Foundations of Mathematics were regularly attended by Turing. Interestingly, during the conversations between the two, Turing seems to play the role of the Wittgenstein of the Tractatus, to allow the present Wittgenstein to reassess what he deplores as mistaken or misleading in his early work. As for Turing himself, his reflection on thinking machines from the late 1940s demonstrates the significance of his dialogue with Wittgenstein
Numerical and experimental analysis of a 200 N class GOX-ABS hybrid rocket engine
No full textHybrid rocket engines offer a promising alternative to liquid and solid rockets, and the use of 3D-printable fuels enables great flexibility in grain design, allowing engine performance to be tailored to mission requirements. Among such fuels, acrylonitrile butadiene styrene (ABS) stands out as one of the most promising options due to its favorable mechanical properties and combustion performance. In this context, predictive numerical simulations can serve as a key tool during the design phase, allowing for a significant reduction in development time and costs. Accurate prediction of ABS combustion behavior is essential to fully exploit its potential for cost-effective and flexible hybrid rocket design. Nonetheless, significant uncertainties remain in modeling its behavior as a rocket fuel. In this work, a firing test of a 200 N-class hybrid rocket using gaseous oxygen and ABS is conducted, followed by an extensive numerical simulation campaign. A computational approach based on axisymmetric Reynolds-averaged Navier-Stokes (RANS) simulations is employed, incorporating sub-models for turbulence, chemistry, gas-surface interaction, and radiation. A reconstruction of the firing test is carried out, yielding errors of 2 % and 5 % on the average regression rate and chamber pressure, respectively. Considering the uncertainties in fuel properties, parametric simulations are conducted to evaluate the effect of the pyrolysis law and heat of vaporization on the computed regression rate. These analyses highlight the importance of a detailed understanding of the main gas-surface interaction parameters in accurately predicting the fuel burning behavior
Enhancement of Polyethylene Terephthalate Rheological Properties via Chain Extension and Branching: A Design of Experiment Approach
No full textUpgrading recycled polyethylene terephthalate (PET) for high-value applications requires enhanced viscoelastic properties that are difficult to achieve with single chain extenders. This study investigates the synergistic effect of pyromellitic dianhydride (PMDA, tetrafunctional) and 1,3-phenylene-bis-2-oxazoline (PBO, bifunctional) on virgin and recycled PET using the Design of Experiment methodology. Real-time rheological monitoring, combined with a heuristic kinetic analysis, enabled the identification of the reaction mechanisms and their evolution over time. Subsequently, the linear viscoelasticity analysis of the reacted samples revealed that the dual-additive system led to an increase of two orders of magnitude in zero-shear viscosity (compared to one order for PMDA alone) and three orders of magnitude in relaxation times, reaching approximately 20 s. Critical differences between virgin and recycled PET responses are identified, with recycled material showing enhanced properties at high additive concentrations due to higher carboxyl end-group content. These findings provide a systematic approach for upgrading postconsumer PET to meet industrial performance requirements for foaming and blow molding applications