We consider semi-coherent binary systems that are subject to simultaneous failures of its components. These are systems whose components can be either working or failed; the system can also be working or failed depending on the state of the components; and repairing a component cannot cause the system to fail. We consider that one or more components can fail simultaneously, allowing us to model external shocks and disasters. For this, we use the Lévy-frailty Marshall–Olkin (LFMO) multivariate distribution to model the failure times of the components. We aim to answer in which states of the system we should repair the components. This is a challenging question, as the number of repair policies grows super-exponentially in the number of components. To tackle this, we propose a simple family of repair policies, which we call r-out-of-n repair policies, where one repairs all failed components when the system fails or when there are r or more failed components. Our main contribution is that we derive exact and simple expressions for key performance-evaluation quantities of the system operating under our proposed repair policies. That is, we give explicit expressions for the mean time-to-failure of the system, mean time-to-repair, probability of system-failure before repair, and component- and system-repair rate. We also give expressions for the expected cost and long-term average cost, when there are components’ and system repair cost. The only relevant parameters involved in the derived expressions are the structural signature of the system, and the Laplace exponent associated to the LFMO distribution.
The thioredoxin system, comprising thioredoxin (Trx) and thioredoxin reductase (TrxR), is a central regulator of cellular redox homeostasis and plays essential roles in normal brain physiology and redox signaling. In glioblastoma (GBM), this system undergoes profound pathological rewiring, creating a redox dependency that represents a potential therapeutic vulnerability. The overexpression of Trx and TrxR in GBM promotes tumor proliferation, invasion, angiogenesis, and resistance to chemotherapy and radiotherapy, while the endogenous Trx inhibitor, thioredoxin-interacting protein (TXNIP), is frequently downregulated. This imbalance drives redox adaptation and sustains tumor survival under metabolic and therapeutic stress. Pharmacological modulation of the Trx system using synthetic inhibitors, such as auranofin, platinum-based compounds, and PX-12, as well as selected natural compounds including curcumin analogs and flavonoids, has shown efficacy in preclinical GBM models by inducing oxidative stress and enhancing sensitivity to standard therapies. Emerging evidence also suggests that Trx system targeting may modulate the tumor immune microenvironment, providing a rationale for combination strategies with immunomodulatory approaches. Overall, targeting the Trx system represents a promising precision oncology strategy for GBM. Future efforts should focus on the development of brain-penetrant inhibitors, rational combination therapies, and predictive biomarkers to facilitate clinical translation. Given the essential role of the Trx system in normal brain homeostasis, therapeutic targeting requires careful consideration of safety, therapeutic index, and tumor-selective vulnerabilities. This narrative review discusses current evidence on the physiological functions of the Trx system in the brain, its dysregulation in GBM, and its relevance as a precision therapeutic target.
Carbonic anhydrase isoforms I and II (hCA-I and hCA-II) are metalloenzymes involved in essential physiological processes and represent relevant therapeutic targets for disorders such as glaucoma and osteoporosis. Chalcones have emerged as promising scaffolds for carbonic anhydrase inhibition; however, their structure-activity relationships, particularly for non-sulfonamide derivatives, remain insufficiently explored from a computational point of view. In this study, a dataset of 118 chalcone derivatives has been analyzed by using a three-dimensional quantitative structure-activity relationship (3D-QSAR) modeling, which comprises Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis (CoMSIA). The developed models exhibited strong internal consistency and predictive capability for both isoforms. For hCA-I, steric, electrostatic, hydrophobic, and hydrogen bond acceptor fields has been identified as key contributors to inhibitory activity, whereas for hCA-II, hydrogen bond donor features played a more prominent role. Molecular docking and molecular dynamics simulations have been employed as complementary approaches to analyze ligand-protein interactions and binding stability. In addition, quantum chemical descriptors, derived from density functional theory, that have been integrated with the 3D-QSAR analysis, reveal a consistent correspondence between contour map features and the distribution of frontier molecular orbitals and molecular electrostatic potential. Furthermore, ADME-based pharmacokinetic properties of the proposed compounds have been evaluated to assess their potential drug-likeness. Based on the integrated computational analysis, six new chalcone derivatives, with predicted inhibitory activity in the nanomolar range, are proposed. Overall, this study provides a consistent physicochemical framework for understanding the inhibitory activity of chalcone derivatives and highlights key molecular features that may guide the modulation of activity across hCA-I and hCA-II isoforms.
Lepton number violating meson decays, such as M-1(-) -> M-2(+) l(1)(-)l(2)(-), provide constraints on d = 9 Delta L = 2 operators. Renormalization group equation (RGE)-improved bounds on the Wilson coefficients of these operators have been presented in the literature, taking into account perturbative quantum chromodynamics (QCD) one-loop corrections and the corresponding operator mixing. Here, we present for the first time the contribution of connected diagrams to the hadronic matrix elements < M2 vertical bar Oh vertical bar M-1 >. These diagrams, usually overlooked under the assumption that < M2 vertical bar Oh|M-1 > similar to < M-2 vertical bar J(q3q4)vertical bar 0 > x < 0 vertical bar J(q1q2)vertical bar M-1 > >> < M-2 vertical bar J(q3q2) x J(q1q4 vertical bar)M(1 >), can give indeed a significant contribution to the matrix element. Including these connected diagrams is but the first step toward a full nonperturbative computation of the long-range QCD effects in these operators, that should be performed using lattice field theory techniques. However, connected diagrams represent the leading order in the 1/N-c expansion of the QCD nonperturbative effects and thus our work can be understood as a realistic, first approximation to a complete calculation of the long-range part of the matrix elements.
We investigate a cosmological model based on matter creation in a single-component universe, its late time behavior and observational constraints derived from observational data. Furthermore, we explore the equivalence between this framework and interacting dark sector models, which establishes a connection between the matter creation rate and cosmological interactions. We first focus on the case of a constant equation of state parameter, where both known and novel interaction terms naturally emerge from matter creation, numerous of them exhibiting a sign-changeable behavior. The analysis is then extended to a time-dependent equation of state by using dynamical systems techniques.
