Aims: Doxorubicin (Dox) is an effective chemotherapeutic agent, but its clinical use is limited by cardiotoxicity. Cellular senescence contributes to Dox-induced cardiac dysfunction; however, the underlying molecular mechanism mediating the effect of senescence remains poorly understood. This study aimed to identify senescence-associated factors secreted from cardiomyocytes in Dox-treated hearts and define their functional significance in Dox-induced cardiotoxicity.

Methods: Mice with cardiomyocyte-specific expression of the endoplasmic reticulum BioID secretome profiling system were used to identify Dox-induced secreted factors. Functional analyses were performed in neonatal rat ventricular myocytes (NRVMs). The effects of plasminogen activator inhibitor-1 (PAI-1) inhibition were evaluated in Dox-treated mice by assessing senescence markers, apoptotic responses, and cardiac structure and function. p21^High-tdTomato reporter mice were used to examine the fate of senescent cardiomyocytes in vivo.

Results: PAI-1 was identified as a major component of the senescence-associated secretory phenotype and was robustly upregulated in Dox-treated cardiomyocytes. In NRVMs, PAI-1 promoted senescence and maintained the senescent phenotype, in part by conferring resistance to apoptosis. Pharmacological inhibition of PAI-1 reduced senescence markers, enhanced apoptotic responses, and preserved cardiac structure and function in Dox-treated mice. Fate mapping analyses with p21^High-tdTomato mice revealed that PAI-1 inhibition decreased the number of p21^High senescent cardiomyocytes in Dox-treated hearts. Notably, PAI-1 inhibition did not attenuate Dox cytotoxicity in EO771 murine breast cancer cells.

Conclusion: PAI-1 is a key mediator of Dox-induced cardiac dysfunction. PAI-1 inhibition shifts the fate of cardiomyocytes from senescence toward apoptosis and preserves cardiac structure and function without compromising the antitumor function of Dox, highlighting PAI-1 as a potential therapeutic target for chemotherapy-associated cardiotoxicity.

The construction industry is undergoing a low-carbon and digital transformation. The application of recycled aggregates in 3D printed concrete has emerged accordingly, combining the advantages of solid waste recycling and automated manufacturing. However, the optimization of mix design and the prediction of mechanical properties for 3D printed recycled aggregate concrete (3DPRAC) face two main challenges, namely the micro defects inherent in recycled aggregates and the anisotropy caused by layered deposition. This study proposes a Gene Expression Programming (GEP)-based computational framework for the prediction of the splitting tensile strength (STS) of 3DPRAC. A dataset of 110 data points was generated, with layer height and loading direction as key printing parameters representing the anisotropic effect. GEP showed the best performance among models, with an R² of 0.914 on the testing set. Furthermore, the GEP model provides explicit mathematical equations that delineate the contributions of individual input variables and reveal the nonlinear effects of fiber content and printing parameters on STS.

Thermal Hall effect (THE) refers to the phenomenon whereby, in a magnetic field, when a longitudinal heat current flows through a material, the heat carriers are deflected, thereby generating a transverse temperature difference between the two lateral edges. The transition from electrical to thermal transport enables this effect to involve a wide range of carriers, thereby providing a unique perspective for investigating complex quantum states in condensed matter physics. THE is increasingly becoming a powerful probe of neutral excitations in materials and is used to explore multifield control phenomena in magneto-thermal-electrical coupled systems. Advances in the field of THE have significantly advanced the study of condensed matter systems under extreme conditions (low temperatures and strong magnetic fields) and have laid the groundwork for exploring novel magneto-thermal-electrical effects in quantum materials. This review systematically reviews recent theoretical and experimental progress on THE, with particular attention to the underlying heat carriers. Through an in-depth analysis of the transport mechanisms of different carriers, quantum material systems that can be used to investigate multicarrier coupled transport are identified, which will significantly facilitate the synergistic control of magneto-thermal-electrical transport in complex interacting systems. Finally, we propose a novel in situ, multiparameter integrated characterization method that enables simultaneous and precise measurement of magnetic, thermal, and electrical parameters on the same micro/nanoscale samples. This approach not only overcomes the limitations of bulk materials but also serves as a key experimental platform for revealing the mechanisms of multicarrier coupled transport in micro/nano samples.

Magnesium alloys are primarily composed of magnesium, with the additions of elements such as calcium, yttrium, and zinc. In the human physiological environment, they gradually degrade, and their degradation products can be absorbed, exhibiting excellent biocompatibility, mechanical properties comparable to bone tissue, and degradability; thus, they hold broad prospects in orthopedics. Nanotechnology involves the design and manufacture of materials, devices, and systems with unique physical, chemical, and biological properties by controlling the arrangement and interactions of atoms, molecules, or nanostructural units at the nanoscale (1-100 nm). The integration of these two technologies shows exceptional potential for orthopedic regenerative repair. Nanotechnology significantly enhances the mechanical performance, bioactivity, antibacterial properties, and controlled degradation of biodegradable magnesium alloys through various approaches, while biodegradable magnesium alloys provide an ideal biomaterial carrier for nanotechnology, enabling the better exertion of its advantages in bone tissue repair. This review summarizes the innovations arising from the fusion of magnesium alloys and nanotechnology in bone repair, aiming to advance the evolution of orthopedic medical devices, promote a shift in clinical treatment paradigms toward personalized and precise therapy, and ultimately deliver superior and more efficient therapeutic options for patients with orthopedic conditions, thereby improving human health and quality of life.

Rare-earth-doped upconversion nanocrystals (UCNCs), with unique anti-Stokes emission, have been extensively explored, while their performances are hindered by the restriction of parity-forbidden 4f-4f transitions, making their emission difficult to control and resulting in low quantum yields. Current research primarily relies on modifying dopant types and concentrations, matrix composition, particle size, core-shell structures, and surface functional groups, to tune the absorption and emission transitions of 4f electrons. While these methods can effectively adjust emission spectra, reduce defects, and enhance luminescence efficiency, they cannot fundamentally regulate the 4f electron transition process, especially with respect to studying the intrinsic luminescence kinetics of rare earth ions. Therefore, a fundamental understanding of the transition behavior of 4f electrons and the ability to intrinsically control their absorption and emission processes are crucial. By manipulating the local optical field around UCNCs, micro-nano structures offer a powerful means to control their upconversion luminescence, making them an important tool for developing efficient optoelectronic devices for display, lighting, and conversion applications. In this review, we comprehensively expound on the optical engineering for UC luminescence control through micro/nano-optical structures. By utilizing structures such as plasmonic antennas, dielectric superstructures, high Q microcavities, and programmable wavefront shapers, precise control over the interaction between light and matter is achieved at multiple spatial scales. Moreover, we systematically analyze how such structures enhance local excitation fields, amplify spontaneous emission, and direct photon extraction, thereby transcending the inherent limitations of rare-earth emitters. By bridging advances in materials chemistry with nanophotonics design principles, this approach unlocks unprecedented control over UC efficiency, spectral purity, and polarization properties.

Ferroptosis has emerged over the past decade as a compelling therapeutic avenue for cancer, prompting intense interest in strategies that selectively induce or inhibit this form of cell death. Although substantial progress has been made in identifying genes that regulate ferroptosis sensitivity and in developing small-molecule modulators, it remains unclear which molecular targets offer the greatest therapeutic potential in specific tissues and contexts. Here, we highlight fundamental differences between in vitro and in vivo ferroptosis modulation, with emphasis on the integration of different techniques, mouse models, and how the tumor microenvironment shapes two major ferroptosis surveillance pathways: glutathione peroxidase 4 and ferroptosis suppressor protein 1. We propose that integrating in vivo biological constraints and microenvironmental complexity is essential for the rational design and successful translation of ferroptosis-targeted therapies.

Structured light fields are engineered through precise control of their amplitude, phase, polarization, and spatiotemporal properties, which are extensively studied for both scientific and applied purposes, and can offer novel pathways for information processing, quantum communication, and precision measurement. Although the linear manipulation of structured light is already very mature with the help of liquid crystal devices and planar optical elements, nonlinear manipulation remains nascent, despite demonstrating unique potential for critical functionalities such as optical field information exchange. Hence, critical challenges now lie in harnessing nonlinear interactions, between light fields themselves and between light and matter, to achieve on-demand multidimensional control of target optical fields, particularly for spatial modes of light. The advancing nonlinear optics theory, guided by structured light, reveals novel physical phenomena in various nonlinear interactions, and promotes the development of novel applications based on nonlinear light field control technologies. Accordingly, this review systematically summarizes recent advances across key areas, including the nonlinear manipulation of spatial structured light fields, optical information transfer, full-dimensional manipulation theory, field modulation and nonlinear topological frontiers, and three-dimensional (3D) light field manipulation theory, thereby providing a comprehensive perspective on the current state and the emerging trends in this rapidly evolving field.

This study addresses the interoperability of building information modeling (BIM) across different systems and platforms. Because the semantics of the industry foundation classes (IFC) standard are large and complex, traditional full semantic conversion methods are general-purpose, but they often lead to data expansion, which reduces system responsiveness and usability. In addition, the strong dependence of BIM models on specialized software further limits flexibility in practical use. Our novel framework combines a streamlined ontology with IFC, significantly improving memory efficiency and operational effectiveness compared to existing systems. Additionally, we integrate large language models for enhanced natural language processing in BIM data interactions. This harmonization of technologies not only simplifies system extension but also makes BIM data services more user-friendly and adaptable to various industry needs. By streamlining BIM data management and enriching data services, our approach broadens BIM’s applicability and improves data integration and extraction, establishing a more interactive and user-centric paradigm.

The nucleolus, the largest membraneless organelle in the cell, is a biomolecular condensate that houses ribosomal DNA (rDNA), facilitates ribosomal subunit assembly, and serves as a dynamic reservoir for numerous unrelated proteins. Aging across eukaryotic species is accompanied by nucleolar expansion, raising the question of whether it is a correlate of aging or a driver of cellular aging. Recent studies suggest that nucleolar expansion may drive aging and this may result from age-associated changes in the biophysical properties of the nucleolus. Emerging evidence points to age-driven biophysical changes in the nucleolar condensate, including shifts in size, dynamics, and viscoelasticity, which may occur gradually or through transitions from a liquid-like state to denser gel-like, and in some contexts amyloid-like, assemblies. These transitions remodel two core condensate properties: compartmentalization and partitioning, with consequences for ribosome biogenesis and rDNA stability. Here, we review recent literature on age-driven changes in nucleolar condensation and discuss how these changes may influence nucleolar function and longevity.

Medical catheters constitute indispensable components of contemporary healthcare, yet they are confronted with persistent limitations in biocompatibility and functionality, such as thrombosis, infection, and tissue injury, which adversely affect patient safety and therapeutic outcomes. Surface coating technology has consequently arisen as a critical approach to reengineer the catheter-biological interface, thereby augmenting functional performance while preserving the intrinsic properties of the bulk materials. This review systematically outlines recent advances in coating technologies for medical catheters. It begins by analyzing mainstream coating methods, such as layer-by-layer self-assembly, surface grafting, and biomimetic adhesion, followed by the introduction of coatings with anticoagulant, antibacterial, lubricant, and multifunctional properties. The effectiveness and challenges of these coatings in clinical applications, such as cardiovascular intervention, long-term indwelling urinary catheters, and respiratory management are critically examined. Finally, the review discusses current translational bottlenecks and future trends toward intelligent, durable, and cost-effective coating solutions, providing a comprehensive reference for developing next-generation high-performance medical catheters.

Background: Knowledge graphs (KGs) and Semantic web technologies (SWT) are increasingly explored in facilities management (FM) to address persistent problems of interoperability, fragmented data, and limited automation across operational systems.

Background: Knowledge graphs (KGs) and Semantic web technologies (SWT) are increasingly explored in facilities management (FM) to address persistent problems of interoperability, fragmented data, and limited automation across operational systems.

Methods: A scoping review was conducted in accordance with PRISMA-ScR 2020 to map KG applications in FM and identify emerging research directions. Web of Science and Scopus were queried for English-language, peer-reviewed studies applying ontologies, SWT, linked data, or KGs at building-level FM. Studies focused on non-FM contexts, earlier lifecycle phases without operation and maintenance relevance, or artificial intelligence and machine learning approaches without explicit SWT/KG integration were excluded. Following de-duplication and qualitative screening, 48 studies were thematically analysed.

Results: Four dominant application areas were identified: (1) ontology-driven semantic interoperability (n = 36), (2) systems integration across FM data sources (n = 24), (3) data and information retrieval from graph-based stores (n = 14), and (4) automated compliance and validation through knowledge-based reasoning (n = 6). Most studies employed modular, domain-specific ontologies deployed on graph databases to link static building information modelling and asset data with near real-time streams. Emerging directions include the use of KGs as semantic integration layers in digital twin (DT) architectures, and KG-grounded retrieval-augmented generation to enhance trustworthy and explainable access to FM information.

Conclusion: This review consolidates dispersed research on KG applications in FM and outlines a structured research agenda spanning modular ontology development, integration with DT and compliance workflows, as well as longer-term opportunities for scalable and auditable generative AI applications. Findings reflect peer-reviewed journal literature and may under-represent emerging industry practice.

Reproductive aging progressively impairs fertility and contributes to broader systemic decline. Stress granules (SGs), transient membraneless ribonucleoprotein assemblies formed during cellular stress, have recently emerged as important regulators of gonadal homeostasis. Their function is highly context dependent: properly resolved SGs promote cellular adaptation and survival, whereas persistent SGs disrupt proteostasis and trigger cell death pathways. In the testis, transient SGs protect germ cells under stress; however, persistent SG accumulation activates necroptosis through the ZBP1-RIPK3 axis, a pathway implicated in human non-obstructive azoospermia and testicular aging. In the ovary, defective autophagic clearance leads to pathological SG persistence in granulosa cells, while several SG-associated proteins are indispensable for normal oogenesis. Together, these findings indicate that dysregulated SG dynamics, particularly impaired clearance, represent a convergent mechanism linking cellular stress responses to reproductive decline. Despite these advances, critical gaps remain. The cell-type-specific regulation of SG assembly and disassembly within the gonad is not fully defined, and the molecular mechanisms by which persistent SGs drive tissue-level aging require clarification. Addressing these questions will refine our understanding of reproductive aging and its mechanistic connection to proteostatic imbalance.

Aims: EffecTri aims to develop a comprehensive, multi-class prediction framework to accurately identify bacterial effector proteins secreted by Type III, IV, and VI secretion systems. Current methodologies often employ binary classifications, overlooking the complexity and interactions among multiple effector classes.

Methods: EffecTri integrates deep contextual embeddings from Evolutionary Scale Modeling and handcrafted descriptors, including Amino Acid Composition and Dipeptide Composition. The performance of the model was rigorously evaluated through comparative descriptor analyses and optimized feature combinations, complemented by Uniform Manifold Approximation and Projection visualization for interpretability.

Results: EffecTri outperformed traditional machine learning methods, achieving a weighted F1-score of 0.850 on an independent test dataset. The fusion of Evolutionary Scale Modeling embeddings with handcrafted descriptors demonstrated superior predictive performance, clearly distinguishing effector classes in UMAP visualizations.

Conclusion: EffecTri represents a robust, interpretable, and accurate computational tool, enhancing the multi-class identification of bacterial secretory effectors and contributing valuable insights into bacterial pathogenic mechanisms.

Cytoplasmic chromatin fragments (CCFs) are structures formed by nuclear chromatin leaked into the cytoplasm in response to cellular senescence, stress, or tumorigenesis, primarily due to genomic instability and nuclear envelope rupture. These cytoplasmic DNA fragments are recognized by cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS) and activate the cGAS–STING pathway, which promotes activation of IRF3 and NF-κB, and induces expression of type I interferons and pro-inflammatory cytokines, thereby driving the senescence-associated secretory phenotype (SASP). CCFs are not only a hallmark of cellular senescence but also a critical signaling hub that links DNA damage to chronic inflammation via SASP factors like IL-6 and IL-8, reinforcing senescence through autocrine and paracrine loops. In cancer, CCFs play distinct roles at different stages: in early-stage tumors, they induce cell cycle arrest and enhance immune surveillance, thereby suppressing tumor initiation; whereas in advanced tumors, persistent CCFs chronically activate the cGAS–STING–NF-κB signaling axis, promoting epithelial–mesenchymal transition, angiogenesis, metastasis, and immune evasion. Notably, CCFs formation is heterogeneous and regulated by key factors such as p53, 53BP1, and Lamin B1. Therefore, targeting the CCFs–cGAS–STING pathway and its upstream regulators, including mitochondrial function, autophagy, and epigenetic modifications, offers a promising strategy to alleviate aging-related diseases and improve cancer therapy by suppressing SASP and blocking tumor progression. This review summarizes the mechanisms of CCFs biogenesis, their complex roles in aging and cancer, and emerging therapeutic approaches aimed at this axis, offering insights for both basic research and clinical translation.

Transcription–replication conflicts (TRCs) are an increasingly recognized driver of genome instability in human cells. We recently identified the CUL3 adaptor KCTD10 as a sensor of co-directional TRCs, recruiting CUL3 to ubiquitinate transcriptional machinery and clear the path for replication forks. Here, we discuss the implications of this conflict-resolution pathway for human cancer. By integrating our mechanistic findings with large-scale functional genomics datasets, we identify oncogenic conditions that potentially create TRC-rich environments and render cells selectively dependent on KCTD10. These contexts reveal new mechanistic insights and potential therapeutic opportunities across a range of human cancers.

This study addresses the challenges of solidifying high-moisture, high-alkalinity inorganic softening sludge (ISS) by utilizing alkali-activated slag-based cementitious materials. The research investigated strength evolution via unconfined compressive strength tests, while X-ray diffraction and scanning electron microscopy were employed to analyze phase composition and microstructural changes. Furthermore, response surface methodology was utilized to optimize mix proportions and explore interaction mechanisms. Results indicate that granulated blast furnace slag is the primary strength contributor, whereas fly ash and sodium silicate exhibit nonlinear effects. Microscopic analysis reveals that changes in raw material ratios influence strength development by regulating the formation of products such as calcium aluminosilicate hydrate (C-A-S-H) and sodium aluminosilicate hydrate (N-A-S-H). Optimization results from response surface methodology show that, when sodium hydroxide dosage is fixed at 2.5%, the optimal dosages for granulated blast furnace slag, fly ash, and sodium silicate are 30.65%, 29.98%, and 6.96%, respectively, achieving a 7-day unconfined compressive strength of 5.38 MPa. Furthermore, significant interactions exist between granulated blast furnace slag and fly ash, as well as between fly ash and sodium silicate. This study provides a theoretical basis for the resource utilization of ISS in road base materials.

With global warming, urban workers engaged in physically demanding occupations are increasingly exposed to severe heat stress. While the physical health risks are well recognized, less is known about how heat stress affects cognitive function at the neurophysiological level, an understanding critical for protecting worker well-being. This study conducted a controlled laboratory experiment to examine cognitive and neural responses to heat stress in middle-aged heat-exposed manual workers. Twenty participants (mid-40s) completed six representative cognitive tasks under four wet-bulb globe temperature (WBGT) conditions (23, 26, 28.5, and 31 °C). Electroencephalogram (EEG) recordings were used to monitor brain activity and assess changes in relative band power across δ, θ, α, and β frequency bands. The results revealed that performance in the executive- memory dimension peaked under moderate heat (forming an inverted-U pattern), while performance in the sensorimotor reactivity dimension remained stable or improved with rising WBGT. Neurophysiologically, rising heat stress led to increased δ band power but decreased α, θ, and β band powers. These EEG band power changes showed a nonlinear relationship with cognitive performance across both dimensions, with the left frontal cortex demonstrating higher sensitivity. Furthermore, topographical coupling maps indicated that executive-memory demanding tasks activated a more widespread cortical region than sensorimotor-reactivity demanding tasks. These findings show that graded heat stress alters brain dynamics and cognitive performance in a cognitive load-dependent manner, offering insights for designing adaptive work environments and real-time cognitive performance monitoring devices for heat- exposed workers.

Sister chromatid cohesion, established during DNA replication, is essential for accurate chromosome segregation. While acetylation of the cohesin subunit SMC3 by ESCO1/2 promotes the recruitment of the cohesin stabilizer Sororin, this pathway is insufficient for full Sororin function. In a recent study, Jiang et al. identify a previously uncharacterized human microprotein, RSMC, as a Sororin cofactor required for sister chromatid cohesion. The authors show that RSMC interacts with Sororin, and this interaction is enhanced during S-phase by PARP1/2-mediated poly(ADP-ribosyl)ation (PARylation) of RSMC. PARylation of RSMC, triggered by DNA replication intermediates, acts in parallel with SMC3 acetylation to ensure the timely and efficient recruitment of Sororin to chromatin. Consequently, inhibition of PARP activity reduces chromatin-bound Sororin and causes cohesion defects, which can be rescued by overexpressing wild-type RSMC or Sororin, but not by PARylation- or interaction-deficient mutants. Furthermore, RSMC stimulates the anti-Wapl activity of Sororin in vitro, promoting stable cohesin binding. Taken together, the work of Jiang et al. describes a dual, replication-coupled regulatory mechanism wherein S-phase PARylation of the microprotein RSMC cooperates with SMC3 acetylation to fully enable Sororin’s function in establishing sister chromatid cohesion. This mechanism is important for maintaining genomic stability, and its dysregulation may contribute to chromosome segregation errors observed in cancer.

Glaucoma is an ocular disease and a leading cause of irreversible blindness, driven by progressive retinal ganglion cell (RGC) loss. While elevated intraocular pressure (IOP) is a major risk factor, RGC degeneration often persists despite effective IOP-lowering therapy. This persistence suggests the involvement of pressure-independent pathogenic mechanisms. Growing evidence implicates ferroptosis – an iron-dependent, oxidative form of regulated cell death –as a critical contributor to RGC loss in glaucoma. It is characterized by iron accumulation, lipid peroxidation, antioxidant (glutathione) depletion, and mitochondrial dysfunction in degenerating RGCs. Dysregulated iron metabolism and nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy promote iron overload. Simultaneously, impairment of the glutathione-GPX4 axis compromises lipid peroxide detoxification, which converges with oxidative stress and glutamate excitotoxicity, to drive a self-amplifying cycle of RGC ferroptotic death. Preclinical studies show that ferroptosis inhibitors, iron chelators, NRF2 activators, MAPK inhibitors, hydrogen sulfide donors, and natural antioxidants protect RGCs and preserve retinal function. These findings highlight ferroptosis as a promising therapeutic target. Targeting ferroptotic pathways, either alone or in combination with IOP-lowering strategies, may improve long-term visual outcomes. Future research should focus on optimizing therapeutic combinations, assessing safety, and facilitating clinical translation.

While digitalization is fundamentally reshaping circular construction, the specific evolutionary trajectory from static building information modeling (BIM) toward dynamic Digital Twins (DT) remains unclear. To unpack this complexity, a PRISMA-guided systematic review and scientometric mapping of 271 publications (2019-2025) was performed using VOSviewer and CiteSpace. The analysis identifies a four-phase pathway: (i) strategic foundations focused on circular frameworks and material reuse; (ii) design integration emphasizing tool implementation and BIM workflows; (iii) dynamic integration toward digital twins enabling lifecycle data continuity; and (iv) systemic management and lifecycle assessment for real-time control and compliance. Critical turning points in this journey are marked by burst terms such as “framework” (2021), “integration” (2022), and the current emphasis on “management” (2023-2025). Crucially, the review synthesizes conflicting paradigms to identify three fundamental gaps hindering the BIM-to-DT shift: the ontological schism in data sufficiency, the agency gap between digital shadows and twins, and the logistical gap in stochastic reverse flows. To bridge these divides, a three-layer architecture is proposed in which BIM serves as the static product backbone, process information modelling as the essential logic bridge, and DT as the operational decision core. This constructs a time-indexed evolution model that quantifies the shift from process optimization to systemic value creation and provides an adoption roadmap prioritizing interoperability to support policy instruments.

Despite rapid progress in health monitoring, many smart wearable devices still function primarily as passive sensing-and-logging platforms. Their performance is constrained by fixed hardware configurations and cloud-centric analytics pipelines. As a result, they often fail to deliver real-time responses to user intent and rarely support closed-loop physical intervention. This perspective argues that enabling embodied intelligence in wearables requires three paradigm shifts. First, wearables should transition from closed, integrated hardware to open, modular computing architectures that can accommodate evolving on-device artificial intelligence (AI) demands. Second, cloud-dependent inference should be replaced, where appropriate, by ultra-low-latency edge intelligence to support millisecond-scale prediction and control. Third, devices should evolve from passive information feedback to active physical intervention supported by human-in-the-loop optimization. Together, these shifts may reshape the human–machine relationship by moving wearables from external tools toward digital partners that operate under explicit user intent and safety constraints.