Search Results (822)

L-type Ca²⁺ channels, particularly Ca_V1.2, play a crucial role in cardiac excitation-contraction coupling and are known to exhibit mechanosensitivity. However, the mechanisms regulating their response to mechanical stress remain poorly understood. To investigate the mechanosensitivity and nitric oxide (NO)-dependent regulation of L-type Ca²⁺ channels in rat ventricular cardiomyocytes, we used RNA sequencing to assess isoform expression and whole-cell patch-clamp recordings to measure L-type Ca²⁺ current (I_Ca,L) under controlled mechanical and pharmacological conditions. RNA sequencing revealed predominant expression of Ca_V1.2 (TPM: 0.1170 ± 0.0075) compared to Ca_V1.3 (0.0021 ± 0.0002) and Ca_V1.1 (0.0002 ± 0.0002). Local axial stretch (6–10 μm) consistently reduced I_Ca,L in proportion to stretch magnitude. The NO donor SNAP (200 μM) had variable effects on basal I_Ca,L in unstretched cells (stimulatory, inhibitory, or biphasic) but consistently restored stretch-reduced I_Ca,L to control levels. Ascorbic acid (10 μM), which reduces S-nitrosylation, increased basal I_Ca,L and partially restored the reduction caused by stretch, implicating S-nitrosylation in channel regulation. The sGC inhibitor ODQ (5 μM) decreased I_Ca,L in both stretched and unstretched cells, indicating involvement of the NO–cGMP pathway. Mechanical stress modulates L-type Ca²⁺ channels through a complex interplay between S-nitrosylation and NO–cGMP signaling, with S-nitrosylation playing a predominant role in stretch-induced effects. This mechanism may represent a key component of cardiac mechanotransduction and could be relevant for therapeutic targeting in cardiac pathologies involving mechanically induced dysfunction. Full article

Cardiovascular disease encompasses a wide group of conditions that affect the heart and blood vessels. Of these diseases, cardiomyopathies and arrhythmias specifically have been well-studied in their relationship to cardiac dyads, nanoscopic structures that connect electrical signals to muscle contraction. The proper development and positioning of dyads is essential in excitation–contraction (EC) coupling and, thus, beating of the heart. Three proteins, namely CMYA5, JPH2, and BIN1, are responsible for maintaining the dyadic cleft between the T-tubule and junctional sarcoplasmic reticulum (jSR). Various other dyadic proteins play integral roles in the primary function of the dyad—translating a propagating action potential (AP) into a myocardial contraction. Ca²⁺, a secondary messenger in this process, acts as an allosteric activator of the sarcomere, and its cytoplasmic concentration is regulated by the dyad. Loss-of-function mutations have been shown to result in cardiomyopathies and arrhythmias. Adeno-associated virus (AAV) gene therapy with dyad components can rescue dyadic dysfunction, which results in cardiomyopathies and arrhythmias. Overall, the dyad and its components serve as essential mediators of calcium homeostasis and excitation–contraction coupling in the mammalian heart and, when dysfunctional, result in significant cardiac dysfunction, arrhythmias, morbidity, and mortality. Full article

With the development of information and communication technologies, analysing new risks of moral harassment at work is becoming increasingly pertinent, especially with the expansion of teleworking and hybrid working (a mix of remote and face-to-face work per week) in the wake of the COVID-19 pandemic. In an attempt to respond to the new issues of labour regulation, this study places special emphasis on new risks of moral harassment in hybrid work and teleworking contexts, considering both the international and European framework and the legal regime in Portugal, identifying its specificities. With the rise in teleworking in the post-pandemic period, the online monitoring of workers has accentuated the difficulty in drawing the line between managerial power and harassment. Moral harassment at work is a persistent challenge and organisations must recognise, prevent and respond to inappropriate behaviour in the organisation. The results of this study—based on the results of an online survey completed by employees (with employment contracts)—show that teleworking employees recognise that they have been pressured, above all, both to respond to messages quickly and pressure to work beyond hours and suggest possible gender differences in the way harassment in hybrid work and teleworking contexts is reported. Full article

The C-kinase-activated protein phosphatase-1 (PP1) inhibitor of 17 kDa (CPI-17) is a specific inhibitor of the PP1 catalytic subunit (PP1c) and the myosin phosphatase (MP) holoenzyme. CPI-17 requires the phosphorylation of Thr38 in the peptide segment ³⁵ARV(P)TVKYDRREL⁴⁶ for inhibitory activity. CPI-17 regulates myosin phosphorylation in smooth muscle contraction and the tumorigenic transformation of several cell lines via the inhibition of MP. A phosphospecific antibody (anti-CPI-17^pThr38) against the phosphorylation peptide was used to determine the phosphorylation levels in cells. We found that phospho-CPI-17 and its closely related proteins are not present in HeLa and MCF7 cells after inducing phosphorylation by inhibiting phosphatases with calyculin A. In contrast, cross-reactions of proteins in the 40–220 kDa range with anti-CPI-17^pThr38 were apparent. Searching the protein database for similarities to the CPI-17 phosphorylation sequence revealed several proteins with 42–75% sequence identities. The LIMK2-1 isoform emerged as a possible PP1 inhibitor. Experiments with Flag-LIMK2-1 overexpressed in tsA201 cells proved that LIMK2-1 interacts with PP1c isoforms and is phosphorylated predominantly by protein kinase C. Phosphorylated LIMK2-1 inhibits PP1c and the MP holoenzyme with similar potencies (IC50 ~28–47 nM). In conclusion, our results suggest that LIMK2-1 is a novel phosphorylation-dependent inhibitor of PP1c and MP and may function as a CPI-17-like phosphatase inhibitor in cells where CPI-17 is present but not phosphorylated upon phosphatase inhibition. Full article

Prolactin (PRL) is a hormone primarily associated with lactation, but it plays various roles in both men and women. PRL belongs to the family of peptide hormones, including placental lactogen and growth hormone. Interestingly, PRL is a pleiotropic hormone affecting several physiological and pathological conditions, including fertility. Moreover, several pathophysiological roles have been associated with this hormone, including those of the immune system, autoimmune disorders, asthma, and ageing. Additionally, PRL receptors are ubiquitously expressed in tissues, including the mammary gland, gonads, liver, kidney, adrenal gland, brain, heart, lungs, pituitary gland, uterus, skeletal muscle, skin blood cells, and immune system. Therefore, in the present paper, we cover the potential role that PRL may play in asthma by promoting inflammation and modulating immune responses. The detection of its receptor in lung tissue suggests a direct role in airway smooth muscle contractility through activation of signaling pathways such as JAK2-STAT5, MAPK/ERK1/2, and PI3K/Akt, as well as influencing ionic currents that regulate cell contraction, proliferation, and survival. In this sense, this review aims to explore the potential involvement of PRL in asthma pathophysiology by examining its interactions with intracellular signaling pathways and its possible impact on airway smooth muscle contractility and immune modulation. Full article

To address the challenges posed by the instability of renewable energy output and load fluctuations on grid operations and to support the low-carbon sustainable development of the energy system, this paper integrates artificial intelligence technology to establish an economic stability dispatch framework for distributed resource aggregators. A phased multi-contract collaborative scheduling model oriented toward sustainable development is proposed. Through intelligent algorithms, the model dynamically optimises decisions across the day-ahead and intraday phases: During the day-ahead scheduling phase, intelligent algorithms predict load demand and energy output, and combine with elastic performance-based response contracts to construct a user-side electricity consumption behaviour intelligent control model. Under the premise of ensuring user comfort, the model generates a 24 h scheduling plan with the objectives of minimising operational costs and efficiently integrating renewable energy. In the intraday scheduling phase, a rolling optimisation mechanism is used to activate energy storage capacity contracts and dynamic frequency stability contracts in real time based on day-ahead prediction deviations. This efficiently coordinates the intelligent frequency regulation strategies of energy storage devices and electric vehicle aggregators to quickly mitigate power fluctuations and achieve coordinated control of primary and secondary frequency regulation. Case study results indicate that the intelligent optimisation-driven multi-contract scheduling model significantly improves system operational efficiency and stability, reduces system operational costs by 30.49%, and decreases power purchase fluctuations by 12.41%, providing a feasible path for constructing a low-carbon, resilient grid under high renewable energy penetration. Full article

Parathyroid hormone (PTH) has been studied to determine its broader role in musculoskeletal health, particularly its effects on skeletal muscle. Bone and muscle are inextricably linked via mechanical loading and biochemical signaling, with both processes playing important roles in muscular metabolism and function. Furthermore, the nervous system must maintain muscle mass and function, as neuromuscular transmission controls muscle contraction, protein synthesis, and energy metabolism. As a systemic endocrine regulator, PTH influences the physiology of skeletal muscle—both directly and through interactions with bone and the nervous system, modulating myokines, osteokines, and neuromuscular activity. The intricate relationships between PTH, muscle, bone, and nerves continue to be investigated due to their implications for aging, metabolic pathologies, and musculoskeletal disorders. Full article

Background: Previously, we found that the pathological changes in the corpus spongiosum (CS) in hypospadias were mainly localized within smooth muscle tissue, presenting as a transformation from the contraction phenotype to synthesis. The role of low-intensity pulsed ultrasound (LIPUS) in regulating smooth muscle cells (SMCs) and angiogenesis has been confirmed. Objectives: To demonstrate the feasibility of regulating the phenotypic transformation of corpus spongiosum smooth muscle cells (CSSMCs) in hypospadias using LIPUS and to explore the potential mechanisms. Materials and Methods: The CSSMCs were extracted from CS in patients with proximal hypospadias. In vitro experiments were conducted to explore the appropriate LIPUS irradiation intensity and duration which could promote the phenotypic transformation of CSSMCs. A total of 71 patients with severe hypospadias were randomly divided into a control group and a LIPUS group to verify the in vivo transition effect of LIPUS. Consequently, the potential mechanisms by which LIPUS regulates the phenotypic transformation of CSSMCs were explored in vitro. Results: In vitro experiments showed that LIPUS with an intensity of 100 mW/cm² and a duration of 10 min could significantly increase the expression of contraction markers in CSSMCs and decrease the expression of synthesis markers. Moreover, LIPUS stimulation could alter the phenotype of CSSMCs in patients with proximal hypospadias. RNA sequencing results revealed that peroxisome proliferator-activated receptor gamma (PPAR-γ) significantly increased after LIPUS stimulation. Overexpression of PPAR-γ significantly increased the expression of contraction markers in CSSMCs, and the knockdown of PPAR-γ blocked this effect. Conclusions: LIPUS can regulate the transition of CSSMCs from a synthetic to a contractile phenotype in hypospadias. The PPAR-γ-mediated signaling pathway is a possible mechanism involved in this process. Full article

(1) Background: The insect male accessory gland (MAG) produces seminal fluid components crucial for male reproduction, analogous to the mammalian prostate. While some insect MAGs exhibit binucleate epithelial cells for luminal volume plasticity, the diversity of cellular arrangements and their functional implications across insects remain largely unknown. (2) Methods: We investigated the cellular architecture of MAG epithelia in various shore bug species (infraorder Leptopodomorpha, Hemiptera) and their mechanisms of multinucleation and potential MAG volume regulation. (3) Results: The MAG epithelia of shore bugs comprise a small number of large, plastic syncytial cells with varying nuclear numbers. We hypothesize that these syncytia facilitate effective MAG volume expansion post-eclosion. Uniquely, MAG shrinkage involves the localized contraction of limited muscle fibers, unlike the systematic contraction of circular muscles in most other insects. We further describe sequential cell fusion during the nymphal stage as the mechanism of multinucleation. (4) Conclusions: The unique syncytial organization of Leptopodomorpha MAG epithelia represents an evolutionary divergence from typical binucleate or mononucleate structures in other insects; it is likely that this enables distinct mechanisms for reproductive fluid storage and evacuation. This study highlights the evolutionary diversity of male reproductive organ morphology and function within insects. Full article

The inherent limitations of ordinary cement mortar—characterized by its high brittleness and low flexibility—result in a diminished load-bearing capacity, predisposing concrete pavements to cracking. A novel approach has been proposed to enhance material performance by incorporating emulsified asphalt and latex into ordinary cement mortar, aiming to improve the flexibility and durability of concrete pavements effectively. To further validate the feasibility of this proposed approach, a series of comprehensive experimental investigations were conducted, with corresponding conclusions detailed herein. As outlined below, the flexibility properties of the modified cement mortar were systematically evaluated at curing durations of 3, 7, and 28 days. The ratio of flexural to compressive strength can be increased by up to 38.9% at 8% emulsified asphalt content at the age of 28 days, and by up to 50% at 8% latex content. The mechanism of emulsified asphalt and latex-modified cement mortar was systematically investigated using a suite of analytical techniques: X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, thermogravimetric analysis (TG-DTG), X-ray photoelectron spectroscopy (XPS), and scanning electron microscopy (SEM). Through comprehensive analyses of microscopic morphology, hydration products, and elemental distribution, the enhancement in cement mortar toughness can be attributed to two primary mechanisms. First, Ca²⁺ ions combine with the carbonyl groups of emulsified asphalt to form a flexible film structure during cement hydration, thereby reducing the formation of brittle hydrates. Second, active functional groups in latex form a three-dimensional network, regulating internal expansion-contraction tension in the modified mortar and extending its service life. Full article

Redox regulation is crucial for the cardiac action potential, coordinating the sodium-driven depolarization, calcium-mediated plateau formation, and potassium-dependent repolarization processes required for proper heart function. Under physiological conditions, low-level reactive oxygen species (ROS), generated by mitochondria and membrane oxidases, adjust ion channel function and support excitation–contraction coupling. However, when ROS accumulate, they modify a variety of important channel proteins in cardiomyocytes, which commonly results in reducing potassium currents, enhancing sodium and calcium influx, and enhancing intracellular calcium release. These redox-driven alterations disrupt the cardiac rhythm, promote after-depolarizations, impair contractile force, and accelerate the development of heart diseases. Experimental models demonstrate that oxidizing agents reduce repolarizing currents, whereas reducing systems restore normal channel activity. Similarly, oxidative modifications of calcium-handling proteins amplify sarcoplasmic reticulum release and diastolic calcium leak. Understanding the precise redox-dependent modifications of cardiac ion channels would guide new possibilities for targeted therapies aimed at restoring electrophysiological homeostasis under oxidative stress, potentially alleviating myocardial infarction and cardiovascular dysfunction. Full article

The rapid integration of AI into IoT systems has outpaced the ability to explain and audit automated decisions, resulting in a serious transparency gap. We address this challenge by proposing a blockchain-based framework to create immutable audit trails of AI-driven IoT decisions. In our approach, each AI inference comprising key inputs, model ID, and output is logged to a permissioned blockchain ledger, ensuring that every decision is traceable and auditable. IoT devices and edge gateways submit cryptographically signed decision records via smart contracts, resulting in an immutable, timestamped log that is tamper-resistant. This decentralized approach guarantees non-repudiation and data integrity while balancing transparency with privacy (e.g., hashing personal data on-chain) to meet data protection norms. Our design aligns with emerging regulations, such as the EU AI Act’s logging mandate and GDPR’s transparency requirements. We demonstrate the framework’s applicability in two domains: healthcare IoT (logging diagnostic AI alerts for accountability) and industrial IoT (tracking autonomous control actions), showing its generalizability to high-stakes environments. Our contributions include the following: (1) a novel architecture for AI decision provenance in IoT, (2) a blockchain-based design to securely record AI decision-making processes, and (3) a simulation informed performance assessment based on projected metrics (throughput, latency, and storage) to assess the approach’s feasibility. By providing a reliable immutable audit trail for AI in IoT, our framework enhances transparency and trust in autonomous systems and offers a much-needed mechanism for auditable AI under increasing regulatory scrutiny. Full article

This study addresses a critical deficiency in real estate management by examining how contractual arrangements between property owners and facility managers (FMs) can mitigate reputational damage arising from third-party liability incidents. While Spanish regulations impose comprehensive conservation and maintenance duties on property owners, current contractual frameworks inadequately protect owners from reputational risks when damages occur due to FMs’ negligence or operational failures. This conceptual study employs a systematic analysis of 16 Spanish regulations governing real estate conservation and maintenance duties, complemented by an examination of the statutory contract law and a Strengths, Weaknesses, Opportunities, and Threats (SWOT) analysis to evaluate the proposed solutions. The analysis reveals four distinct liability attribution blocks, ranging from quasi-objective owner liability to full objective installation holder liability. Current service contracts between owners and FMs provide insufficient reputational protection, as civil liability remains with the property owners regardless of the FMs’ performance. This study identifies specific contractual mechanisms—combining statutory work contracts with representative mandates and installation ownership transfers—that effectively redirect tort liability from owners to FMs. While this study focuses on Spanish regulatory frameworks as a methodologically necessary foundation for theoretical development, the conceptual framework provides transferable mechanisms for adaptation to other civil law jurisdictions. This study constitutes the first comprehensive analysis bridging legal architecture and facility management to propose novel liability transfer mechanisms within established frameworks. Full article

This study adopts an evolutionary game theory framework and focuses on the strategic interaction between brands and KOLs. It examines how the two parties interact under conditions of uncertainty and risk, especially when the KOLs’ contract fulfillment capability is low, and how they adjust strategies to achieve sustainable collaboration. Different from previous studies, this paper not only examines objective parameters such as commission rate, brand value, return cost, and reputation risk, but also introduces behavioral factors, including risk preference, loss aversion, and the psychological perception of gains and losses. By modeling the decision-making process of KOLs and brands under uncertainty and risk, the key factors affecting the evolution of cooperation strategies are identified. The simulation results show that although the cooperation strategy (such as information disclosure and truthful promotion) can achieve stability under certain conditions, the system is highly sensitive to external factors (such as environmental uncertainty) and internal psychological factors (such as risk preference and loss sensitivity). This study provides practical suggestions for brands and KOLs to promote long-term cooperation, emphasizing the importance of incentive coordination, reputation risk management, commission structure optimization, and psychological perception regulation. These findings provide practical guidance for enhancing the sustainability of brand–KOL collaborations. Full article

Stroke-induced hand dysfunction substantially impairs patients’ quality of life, creating an urgent need for portable, adaptive rehabilitation devices. This study introduces a smart rehabilitation glove actuated by shape-memory alloy (SMA) wires, leveraging their high power-to-weight ratio, controllable strain recovery, and reversible phase transformation to overcome the limitations of conventional motor-driven or pneumatic gloves. The glove incorporates SMA-based actuation units achieving 50 mm contraction (5% strain) within 7 s, enabling finger flexion to ~34° for personalized rehabilitation protocols. A mobile application provides wireless regulation of SMA actuation modes and facilitates real-time telemedicine consultations. The prototype demonstrates an ultra-lightweight, compact design enabled by SMA’s intrinsic properties, offering a promising solution for home-based post-stroke rehabilitation. This work establishes the transformative potential of SMAs in wearable biomedical technologies. Full article