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Notch signaling is a conserved pathway crucial for nervous system development. Disruptions in this pathway are linked to neurodevelopmental disorders, neurodegenerative diseases, and brain tumors. Hairy/E(spl) (HES) genes, major downstream targets of Notch, are commonly used as markers for Notch activation. However, these genes can be activated, inhibited, or function independently of Notch signaling, and their response to Notch disruption varies across tissues and developmental stages. MIB1/Mib1 is an E3 ubiquitin ligase that enables Notch receptor activation by processing ligands like Delta and Serrate. We investigated Notch signaling disruption using the zebrafish Mib1 mutant line, mib1ta52b, focusing on changes in the expression of Hairy/E(spl) (her) genes. Our findings reveal significant variability in her gene expression across different neural cell types, regions, and developmental stages following Notch disruption. This variability questions the reliability of Hairy/E(spl) genes as universal markers for Notch activation, as their response is highly context-dependent. This study highlights the complex and context-specific nature of Notch signaling regulation. It underscores the need for a nuanced approach when using Hairy/E(spl) genes as markers for Notch activity. Additionally, it provides new insights into Mib1's role in Notch signaling, contributing to a better understanding of its involvement in Notch signaling-related disorders. [ABSTRACT FROM AUTHOR]

Extracellular matrix (ECM) has emerged as a dynamic tissue component, providing not only structural support, but also functionally participating in a wide range of signaling events during development, injury, and disease remodeling. Investigation of dynamic changes in cardiac ECM proteome is challenging due to the relative insolubility of ECM proteins, which results from their macromolecular nature, extensive post-translational modification (PTM), and tendency to form protein complexes. Finally, the relative abundance of cellular and mitochondrial proteins in cardiac tissue further complicates cardiac ECM proteomic approaches. Recent developments of various techniques to enrich and analyze ECM proteins are playing a major role in overcoming these challenges. Application of cardiac ECM proteomics in disease tissues can further provide spatial and temporal information relevant to disease diagnosis, prognosis, treatment, and engineering of therapeutic candidates for cardiac repair and regeneration.

Network-wide traffic measurement is of interest to network operators to uncover global network behavior for the management tasks of traffic accounting, debugging or troubleshooting, security, and traffic engineering. Increasingly, sophisticated network measurement tasks such as anomaly detection and security forensic analysis are requiring in-depth fine-grained flow-level measurements. However, performing in-depth per-flow measurements (e.g., detailed payload analysis) is often an expensive process. Given the fast-changing Internet traffic landscape and large traffic volume, a single monitor is not capable of accomplishing the measurement tasks for all applications of interest due to its resource constraint. Moreover, uncovering global network behavior requires network-wide traffic measurements at multiple monitors across the network since traffic measured at any single monitor only provides a partial view and may not be sufficient or accurate. These factors call for coordinated measurements among multiple distributed monitors. In this paper, we present a centralized optimization framework, LEISURE (Load- EqualIzed mea SUREment), for load-balancing network measurement workloads across distributed monitors. Specifically, we consider various load-balancing problems under different objectives and study their extensions to support both fixed and flexible monitor deployment scenarios. We formulate the latter flexible monitor deployment case as an MILP (Mixed Integer Linear Programming) problem and propose several heuristic algorithms to approximate the optimal solution and reduce the computation complexity. We evaluate LEISURE via detailed simulations on Abilene and GEANT network traces to show that LEISURE can achieve much better load-balanced performance (e.g., 4.75 × smaller peak workload and 70 × smaller variance in workloads) across all coordinated monitors in comparison to a naive solution (uniform assignment) to accomplish network-wide traffic measurement tasks under the fixed monitor deployment scenario. We also show that under the flexible monitor deployment setting, our heuristic solutions can achieve almost the same load-balancing performance as the optimal solution while reducing the computation times by a factor up to 22.5 × in Abilene and 800 × in GEANT.

RationaleBoth β-adrenergic receptor (β-AR) and Gq-coupled receptor (GqR) agonist-driven signaling play key roles in the events, leading up to and during cardiac dysfunction. How these stimuli interact at the level of protein kinase D (PKD), a nodal point in cardiac hypertrophic signaling, remains unclear.ObjectiveTo assess the spatiotemporal dynamics of PKD activation in response to β-AR signaling alone and on coactivation with GqR-agonists. This will test our hypothesis that compartmentalized PKD signaling reconciles disparate findings of PKA facilitation and inhibition of PKD activation.Methods and resultsWe report on the spatial and temporal profiles of PKD activation using green fluorescent protein-tagged PKD (wildtype or mutant S427E) and targeted fluorescence resonance energy transfer-based biosensors (D-kinase activity reporters) in adult cardiomyocytes. We find that β-AR/PKA signaling drives local nuclear activation of PKD, without preceding sarcolemmal translocation. We also discover pronounced interference of β-AR/cAMP/PKA signaling on GqR-induced translocation and activation of PKD throughout the cardiomyocyte. We attribute these effects to direct, PKA-dependent phosphorylation of PKD-S427. We also show that phosphomimetic substitution of S427 likewise impedes GqR-induced PKD translocation and activation. In neonatal myocytes, S427E inhibits GqR-evoked cell growth and expression of hypertrophic markers. Finally, we show altered S427 phosphorylation in transverse aortic constriction-induced hypertrophy.Conclusionsβ-AR signaling triggers local nuclear signaling and inhibits GqR-mediated PKD activation by preventing its intracellular translocation. PKA-dependent phosphorylation of PKD-S427 fine-tunes the PKD responsiveness to GqR-agonists, serving as a key integration point for β-adrenergic and Gq-coupled stimuli.

Background: Ankle-brachial index (ABI) is a simple method for diagnosing peripheral artery disease (PAD) but has limited reliability in patients with diabetes mellitus (DM) because of medial artery calcification. Our study aims to investigate whether the toe brachial index (TBI) or the cardio-ankle vascular index (CAVI) has a better detection over the ABI for diagnosing PAD in diabetic kidney disease (DKD). Materials and Methods: A cohort of 368 patients (mean age 68.59 ± 13.14 years, 190 males and 178 females) with type 2 DM underwent ABI, TBI, and CAVI measurements at our outpatient clinic. Results: Of all enrolled patients, the TBI is significant in evaluating PAD, especially in patients whose chronic kidney disease (CKD) stage 3a with adjusted odds ratio (AOR) = 6.50, 95% confidence interval (CI) 1.63–25.97, p = 0.0080, stage 3b AOR = 7.47, 95% CI 1.52–36.81, p = 0.0135, and stage 4–5 AOR = 20.13, 95% CI 1.34–94.24, p = 0.0116. CAVI is also significant in CKD stage 1 with AOR = 0.16, 95% CI 0.03–0.77, p = 0.0223, stage 2 with AOR = 0.18, 95% CI 0.04–0.74, p = 0.0180, and stage 3a AOR = 0.31, 95% CI 0.10–0.93, p = 0.0375. Conclusion: TBI has a better yield of detection of PAD compared to ABI among Taiwanese patients with DKD. CAVI may play a role in the early stage of DKD. [ABSTRACT FROM AUTHOR]

In this study, ZnO/V2O5 hybrid nanocomposites were fabricated for UV light/H2 gas dual sensing device. V2O5 were sputtered on hydrothermally grown ZnO nanorods (NRs) for various times, and multiple material characterizations were performed on the nanostructures. Results indicate that the increase of defects and lattice strain may enhance the UV light photo-sensing capability, while the wrapping of V2O5 on ZnO NRs may block the gas molecule transport and degrade the hydrogen gas sensitivity. Addition of V2O5 was distinct from the stuttering of WO3 and IGZO on ZnO NRs. ZnO/V2O5 NRs are promising for future compact light/gas modulation devices. [ABSTRACT FROM AUTHOR]