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While Merkel cell polyomavirus (MCPyV or MCV) is an abundant virus frequently shed from healthy skin, it is one of the most lethal tumor viruses in immunocompromised individuals, highlighting the crucial role of host immunity in controlling MCPyV oncogenic potential. Despite its prevalence, very little is known about how MCPyV interfaces with the host immune response to maintain asymptomatic persistent infection and how inadequate control of MCPyV infection triggers MCC tumorigenesis. In this study, we discovered that the MCPyV protein, known as the Alternative Large Tumor Open Reading Frame (ALTO), also referred to as middle T, effectively primes and activates the STING signaling pathway. It recruits Src kinase into the complex of STING downstream kinase TBK1 to trigger its autophosphorylation, which ultimately activates the subsequent antiviral immune response. Combining single-cell analysis with both loss- and gain-of-function studies of MCPyV infection, we demonstrated that the activity of ALTO leads to a decrease in MCPyV replication. Thus, we have identified ALTO as a crucial viral factor that modulates the STING-TBK1 pathway, creating a negative feedback loop that limits viral infection and maintains a delicate balance with the host immune system. Our study reveals a novel mechanism by which a tumorigenic virus-encoded protein can link Src function in cell proliferation to the activation of innate immune signaling, thereby controlling viral spread, and sustaining persistent infection. Our previous findings suggest that STING also functions as a tumor suppressor in MCPyV-driven oncogenesis. This research provides a foundation for investigating how disruptions in the finely tuned virus-host balance, maintained by STING, could alter the fate of MCPyV infection, potentially encouraging malignancy.
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Poliomavirus de Células de Merkel , Infecciones por Polyomavirus , Proteínas Serina-Treonina Quinasas , Infecciones Tumorales por Virus , Proteínas Serina-Treonina Quinasas/metabolismo , Infecciones por Polyomavirus/metabolismo , Infecciones por Polyomavirus/inmunología , Infecciones por Polyomavirus/virología , Humanos , Infecciones Tumorales por Virus/metabolismo , Infecciones Tumorales por Virus/inmunología , Infecciones Tumorales por Virus/virología , Carcinoma de Células de Merkel/virología , Carcinoma de Células de Merkel/metabolismo , Proteínas de la Membrana/metabolismo , Transducción de Señal , Proteínas Virales/metabolismo , Replicación Viral , Neoplasias Cutáneas/virología , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/inmunología , AnimalesRESUMEN
The foundations of today's societies are provided by manufactured capital accumulation driven by investment decisions through time. Reconceiving how the manufactured assets are harnessed in the production-consumption system is at the heart of the paradigm shifts necessary for long-term sustainability. Our research integrates 50 years of economic and environmental data to provide the global legacy environmental footprint (LEF) and unveil the historical material extractions, greenhouse gas emissions, and health impacts accrued in today's manufactured capital. We show that between 1995 and 2019, global LEF growth outpaced GDP and population growth, and the current high level of national capital stocks has been heavily relying on global supply chains in metals. The LEF shows a larger or growing gap between developed economies (DEs) and less-developed economies (LDEs) while economic returns from global asset supply chains disproportionately flow to DEs, resulting in a double burden for LDEs. Our results show that ensuring best practice in asset production while prioritizing well-being outcomes is essential in addressing global inequalities and protecting the environment. Achieving this requires a paradigm shift in sustainability science and policy, as well as in green finance decision-making, to move beyond the focus on the resource use and emissions of daily operations of the assets and instead take into account the long-term environmental footprints of capital accumulation.
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Increased eosinophil counts are associated with cardiovascular disease and may be an independent predictor of major cardiovascular events. However, the causality and underlying mechanisms are poorly understood. GWAS have shown an association of a common LNK variant (R262W, T allele) with eosinophilia and atherothrombotic disorders. LNK(TT) reduces LNK function and Lnk-deficient mice display accelerated atherosclerosis and thrombosis. This study was undertaken to assess the role of eosinophils in arterial thrombosis in mice with hematopoietic Lnk deficiency. Hematopoietic Lnk deficiency increased circulating and activated eosinophils, JAK/STAT signaling in eosinophils and carotid arterial thrombosis with increased eosinophil abundance and extracellular trap formation (EETosis) in thrombi. Depletion of eosinophils by anti-Siglec-F antibody or by the ∆dbIGata1 mutation eliminated eosinophils in thrombi and markedly reduced thrombosis in mice with hematopoietic Lnk deficiency but not in control mice. Eosinophil depletion reduced neutrophil abundance and NETosis in thrombi without altering circulating neutrophil counts. To assess the role of Lnk specifically in eosinophils, we crossed Lnkf/f mice with eoCre mice. Lnk∆eos mice displayed isolated eosinophilia, increased eosinophil activation and accelerated arterial thrombosis associated with increased EETosis and NETosis in thrombi. DNase I infusion abolished EETs and NETs in thrombi and reversed the accelerated thrombosis. Human iPSC-derived LNK(TT) eosinophils showed increased activation and EETosis relative to isogenic LNK(CC) eosinophils, demonstrating human relevance. These studies show a direct link between eosinophilia, EETosis and atherothrombosis in hematopoietic Lnk deficiency and an essential role of eosinophil LNK in suppression of arterial thrombosis.
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Blood-brain barrier (BBB) breakdown and inflammation occurring at the BBB have a key, mainly a deleterious role in the pathophysiology of ischemic stroke. Neddylation is a ubiquitylation-like pathway that is critical in various cellular functions by conjugating neuronal precursor cell-expressed developmentally down-regulated protein 8 (NEDD8) to target proteins. However, the roles of neddylation pathway in ischemic stroke remain elusive. Here, we report that NEDD8 conjugation increased during acute phase after ischemic stroke and was present in intravascular and intraparenchymal neutrophils. Inhibition of neddylation by MLN4924, also known as pevonedistat, inactivated cullin-RING E3 ligase (CRL), and reduced brain infarction and improved functional outcomes. MLN4924 treatment induced the accumulation of the CRL substrate neurofibromatosis 1 (NF1). By using virus-mediated NF1 silencing, we show that NF1 knockdown abolished MLN4924-dependent inhibition of neutrophil trafficking. These effects were mediated through activation of endothelial P-selectin and intercellular adhesion molecule-1 (ICAM-1), and blocking antibodies against P-selectin or anti-ICAM-1 antibodies reversed NF1 silencing-induced increase in neutrophil infiltration in MLN4924-treated mice. Furthermore, we found that NF1 silencing blocked MLN4924-afforded BBB protection and neuroprotection through activation of protein kinase C δ (PKCδ), myristoylated alanine-rich C-kinase substrate (MARCKS), and myosin light chain (MLC) in cerebral microvessels after ischemic stroke, and treatment of mice with the PKCδ inhibitor rottlerin reduced this increased BBB permeability. Our study demonstrated that increased neddylation promoted neutrophil trafficking and thus exacerbated injury of the BBB and stroke outcomes. We suggest that the neddylation inhibition may be beneficial in ischemic stroke.
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Lesiones Encefálicas , Isquemia Encefálica , Ciclopentanos/farmacología , Proteína NEDD8/metabolismo , Proteínas del Tejido Nervioso , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Pirimidinas/farmacología , Ubiquitina-Proteína Ligasas , Animales , Lesiones Encefálicas/tratamiento farmacológico , Lesiones Encefálicas/enzimología , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/enzimología , Masculino , Ratones , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/metabolismo , Ubiquitina-Proteína Ligasas/antagonistas & inhibidores , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
The deposition of cholesterol-rich lipoproteins in the arterial wall triggers macrophage inflammatory responses, which promote atherosclerosis. The NLRP3 inflammasome aggravates atherosclerosis; however, cellular mechanisms connecting macrophage cholesterol accumulation to inflammasome activation are poorly understood. We investigated the mechanisms of NLRP3 inflammasome activation in cholesterol-loaded macrophages and in atherosclerosis-prone Ldlr-/- mice with defects in macrophage cholesterol efflux. We found that accumulation of cholesterol in macrophages treated with modified LDL or cholesterol crystals, or in macrophages defective in the cholesterol efflux promoting transporters ABCA1 and ABCG1, leads to activation of NLRP3 inflammasomes as a result of increased cholesterol trafficking from the plasma membrane to the ER, via Aster-B. In turn, the accumulation of cholesterol in the ER activates the inositol triphosphate-3 receptor, CaMKII/JNK, and induces NLRP3 deubiquitylation by BRCC3. An NLRP3 deubiquitylation inhibitor or deficiency of Abro1, an essential scaffolding protein in the BRCC3-containing cytosolic complex, suppressed inflammasome activation, neutrophil extracellular trap formation (NETosis), and atherosclerosis in vivo. These results identify a link between the trafficking of cholesterol to the ER, NLRP3 deubiquitylation, inflammasome activation, and atherosclerosis.
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Aterosclerosis , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina , Colesterol , Retículo Endoplásmico , Proteína con Dominio Pirina 3 de la Familia NLR , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Aterosclerosis/metabolismo , Aterosclerosis/patología , Ratones , Colesterol/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Retículo Endoplásmico/metabolismo , Inflamasomas/metabolismo , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Transporte Biológico , Ratones NoqueadosRESUMEN
BACKGROUND: Ischemic stroke is often accompanied by oxidative stress and inflammatory response, both of which work synergistically to exacerbate the disruption of the blood-brain barrier and ischemic brain injury. ALK (anaplastic lymphoma kinase), a cancer-associated receptor tyrosine kinase, was found to play a role in oxidative stress and inflammation. In this study, we investigated the role of ALK inhibition in a murine model of ischemic stroke. METHODS: Focal cerebral ischemia was induced by temporary occlusion of the right middle cerebral artery in mice with a filament. The ALK inhibitor alectinib was administered following the stroke. ALOX15 (arachidonic acid 15-lipoxygenase) was overexpressed by adenovirus injection. The immunohistochemistry, Western blot, oxidative stress, inflammation, blood-brain barrier leakage, infarct volume, and functional outcomes were determined. RESULTS: We found that the expression of ALK was markedly increased in the neurovascular unit after cerebral ischemia. Treatment with the ALK inhibitor alectinib reduced the accumulation of reactive oxygen species, lipid peroxidation, and oxidative DNA, increased the vascular levels of antioxidant enzymes, inactivated the vascular NLRP3 (nucleotide-binding oligomerization domain-like receptor protein 3) inflammasome pathway, and reduced vascular inflammation (ICAM-1 [intercellular adhesion molecule-1] and MCP-1 [monocyte chemoattractant protein-1]) after ischemia. Moreover, alectinib reduced the loss of cerebrovascular integrity and blood-brain barrier damage, consequently decreasing brain infarction and neurological deficits. Furthermore, alectinib reduced stroke-evoked ALOX15 expression, whereas virus-mediated overexpression of ALOX15 abolished alectinib-dependent inhibition of oxidative stress and vascular inflammation, blood-brain barrier protection, and neuroprotection, suggesting the protective effects of alectinib for stroke may involve ALOX15. CONCLUSIONS: Our findings demonstrated that alectinib protects from stroke by regulating ischemic signaling cascades and suggest that ALK may be a novel therapeutic target for ischemic stroke.
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Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Animales , Ratones , Quinasa de Linfoma Anaplásico/metabolismo , Barrera Hematoencefálica/metabolismo , Isquemia Encefálica/patología , Infarto de la Arteria Cerebral Media/patología , Inflamación/patología , Accidente Cerebrovascular Isquémico/complicaciones , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
Merkel cell polyomavirus (MCPyV) has been associated with approximately 80% of Merkel cell carcinoma (MCC), an aggressive and increasingly incident skin cancer. The link between host innate immunity, viral load control, and carcinogenesis has been established but poorly characterized. We previously established the importance of the STING and NF-κB pathways in the host innate immune response to viral infection. In this study, we further discovered that MCPyV infection of human dermal fibroblasts (HDFs) induces the expression of type I and III interferons (IFNs), which in turn stimulate robust expression of IFN-stimulated genes (ISGs). Blocking type I IFN downstream signaling using an IFN-ß antibody, JAK inhibitors, and CRISPR knockout of the receptor dramatically repressed MCPyV infection-induced ISG expression but did not significantly restore viral replication activities. These findings suggest that IFN-mediated induction of ISGs in response to MCPyV infection is not crucial to viral control. Instead, we found that type I IFN exerts a more direct effect on MCPyV infection postentry by repressing early viral transcription. We further demonstrated that growth factors normally upregulated in wounded or UV-irradiated human skin can significantly stimulate MCPyV gene expression and replication. Together, these data suggest that in healthy individuals, host antiviral responses, such as IFN production induced by viral activity, may restrict viral propagation to reduce MCPyV burden. Meanwhile, growth factors induced by skin abrasion or UV irradiation may stimulate infected dermal fibroblasts to promote MCPyV propagation. A delicate balance of these mutually antagonizing factors provides a mechanism to support persistent MCPyV infection. IMPORTANCE Merkel cell carcinoma is an aggressive skin cancer that is particularly lethal to immunocompromised individuals. Though rare, MCC incidence has increased significantly in recent years. There are no lasting and effective treatments for metastatic disease, highlighting the need for additional treatment and prevention strategies. By investigating how the host innate immune system interfaces with Merkel cell polyomavirus, the etiological agent of most of these cancers, our studies identified key factors necessary for viral control, as well as conditions that support viral propagation. These studies provide new insights for understanding how the virus balances the effects of the host immune defenses and of growth factor stimulation to achieve persistent infection. Since virus-positive MCC requires the expression of viral oncogenes to survive, our observation that type I IFN can repress viral oncogene transcription indicates that these cytokines could be explored as a viable therapeutic option for treating patients with virus-positive MCC.
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Carcinoma de Células de Merkel , Interferones , Infecciones por Polyomavirus , Transducción de Señal , Infecciones Tumorales por Virus , Poliomavirus de Células de Merkel/inmunología , Interferones/fisiología , Transducción de Señal/inmunología , Infecciones por Polyomavirus/inmunología , Infecciones Tumorales por Virus/inmunología , Carcinoma de Células de Merkel/inmunología , Inmunidad Innata/inmunología , Interacciones Microbiota-Huesped/inmunología , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Expresión Génica/inmunología , Replicación Viral/genéticaRESUMEN
In two-dimensional (2D) hyperbolic materials, energy is directed into their deep subwavelength polaritonic modes through four narrow beams. Hyperbolic whispering-gallery mode nanocavity-confined phonon polaritons (PhPs) display a strongly enhanced light-matter interaction in the infrared regime. Particularly, the unidirectional phonon-polarization excitation in nanocavities has a potential application value in an on-chip integrated optical circuit design, efficient optical sensors, and enhanced spectral technology. Here, we explore the hyperbolic whispering-gallery mode PhPs on the cross section of a hexagonal BN nanotube (BNNT) and demonstrate that efficient unidirectional excitation can be achieved using a circularly polarized electric dipole, combining with optical spin-orbit coupling. Our results demonstrated that the undirectionality of the hyperbolic polariton propagation in a nanocavity can be conveniently achieved, independent of the structure symmetry of the nanocavity, providing potential applications in nanoscale light propagation, on-chip optical devices, and communication.
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OBJECTIVE: The aim of this study was to establish a simple and sensitive high-performance liquid chromatography method for therapeutic drug monitoring of venetoclax (VEN) and optimize regimens. METHODS: The analysis required the extraction of a 50â µl plasma sample and the precipitation of proteins using acetonitrile extraction. The chromatographic method employed a mobile phase of acetonitrile: 0.5% KH2PO4 (pH 3.5) (60/40, v/v) on a Diamond C18 (4.6â mmâ ×â 250â mm, 5â µm) column at a flow rate of 1.0â ml/min. The quantitative method was validated based on standards described in 'Bioanalytical Method Validation: Guidance for Industry' published by the US Food and Drug Administration (FDA). RESULTS: The calibration curve was linear (R2â =â 0.9998) over the range of 75-4800â ng/ml, with limits of quantification of 25â ng/ml. The coefficients of intraday and interday validation, specificity, recovery, and stability all met the criteria of FDA guidance. The method was successfully applied to analyze VEN concentrations in 30 cases of acute myeloid leukemia patients. The peak concentration (Cmax) was 1881.19â ±â 756.61â ng/ml, while the trough concentration (Cmin) was 1212.69â ±â 767.92â ng/ml in acute myeloid leukemia patients. CONCLUSION: Our study establishes a simple, precise, and sensitive high-performance liquid chromatography method for monitoring VEN and confirms its applicability for therapeutic drug monitoring of VEN in hematological cancers.
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Diabetic foot ulcers (DFUs), a prevalent complication of diabetes mellitus, may result in an amputation. Natural and renewable hydrogels are desirable materials for DFU dressings due to their outstanding biosafety and degradability. However, most hydrogels are usually only used for wound repair and cannot be employed to monitor motion because of their inherent poor mechanical properties and electrical conductivity. Given that proper wound stretching is beneficial for wound healing, the development of natural hydrogel patches integrated with wound repair properties and motion monitoring was expected to achieve efficient and accurate wound healing. Here, we designed a dual-network (chitosan and sodium alginate) hydrogel embedded with lignin-Ag and quercetin-melanin nanoparticles to achieve efficient wound healing and motion monitoring. The double network formed by the covalent bond and electrostatic interaction confers the hydrogel with superior mechanical properties. Instead of the usual chemical reagents, genipin extracted from Gardenia was used as a cross-linking agent for the hydrogel and consequently improved its biosafety. Furthermore, the incorporation of lignin-Ag nanoparticles greatly enhanced the mechanical strength, antibacterial efficacy, and conductivity of the hydrogel. The electrical conductivity of hydrogels gives them the capability of motion monitoring. The motion sensing mechanism is that stretching of the hydrogel induced by motion changes the conductivity of the hydrogel, thus converting the motion into an electrical signal. Meanwhile, quercetin-melanin nanoparticles confer exceptional adhesion, antioxidant, and anti-inflammatory properties to the hydrogels. The system ultimately achieved excellent wound repair and motion monitoring performance and was expected to be used for stretch-assisted safe and accurate wound repair in the future.
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Quitosano , Conductividad Eléctrica , Hidrogeles , Cicatrización de Heridas , Hidrogeles/química , Cicatrización de Heridas/efectos de los fármacos , Quitosano/química , Animales , Quercetina/química , Quercetina/farmacología , Melaninas/química , Plata/química , Pie Diabético/terapia , Pie Diabético/tratamiento farmacológico , Ratones , Alginatos/química , Nanopartículas del Metal/química , Humanos , Antibacterianos/química , Antibacterianos/farmacología , IridoidesRESUMEN
United Nations Sustainable Development Goal 6 tackles the long-neglected economic dimension of water utilization by monitoring nations' water use efficiency (WUE). However, it is imperative to emphasize the need for consistent spatial-temporal subnational WUE estimates, rather than relying solely on recent national trends, which can obscure crucial water use concerns and improvement opportunities. Here, a time series analysis of national, state, and sectoral (e.g., industrial, service, and agriculture) WUE from 1980 to 2015 was developed by compiling the most comprehensive and disaggregated water and economic data from 3243 US counties and 50 US states. The US total WUE increased by 181% from 16.2 (1985) to 45.6 USD/m3 (2015), driven by service sector WUE enhancements. The increased industry and service WUEs in most states were more strongly correlated with decreased per capita water withdrawal than with economic growth. Simultaneously, reductions in agriculture WUE were observed in 18 states potentially because of the complicated interaction of diverse factors specific to local communities. Expanding WUE gaps between affluent and less affluent states, and persisting WUE gaps between water-abundant andwater-scarce states highlight the need to advance policies to support under-resourced communities in effective water planning and water pricing for advancing equitable development.
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Abastecimiento de Agua , Estados Unidos , Agricultura/economía , Agua , Desarrollo SostenibleRESUMEN
The severe water scarcity in China poses significant economic risks to its agriculture, energy, and manufacturing sectors, which can have a cascading effect through the supply chains. Current research has assessed water scarcity losses for global countries and Chinese provinces by using the water scarcity risk (WSR) method. However, this method involves subjective functions and parameter settings, and it fails to capture the adaptive behaviors of economies to water scarcity, compromising the reliability of quantified water scarcity loss. There is a pressing need for a new method to assess losses related to water scarcity. Here, we develop an agent-based complex network model to estimate the inter-regional and intersectoral impacts of water scarcity on both cities and basins. Subsequently, we evaluate the supply chain-wide economic benefits of four different water conservation measures as stipulated by the 14th Five-Year Plan for the Construction of a Water-Saving Society. These measures include increasing the utilization rate of recycled water in water-scarce cities, reducing the national water consumption per industrial value-added, and implementing agricultural and residential water conservation measures. Results show that direct losses constitute only 9% of the total losses from water scarcity. Approximately 37% of the losses can be attributed to interregional impacts. Among the water-scarce cities, Qingdao, Lanzhou, Jinan, and Zhengzhou pose a significant threat to China's supply chains. Agricultural water conservation yields the highest amount of water savings and economic benefits, while residential water conservation provides the highest economic benefit per unit of water saved. The results provide insights into managing water scarcity, promoting cross-regional cooperation, and mitigating economic impacts.
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Conservación de los Recursos Hídricos , Abastecimiento de Agua , Reproducibilidad de los Resultados , Inseguridad Hídrica , China , Agricultura , AguaRESUMEN
The Belt and Road Initiative (BRI) stands as the most ambitious infrastructure project in history, marked by its scale of investment, extensive geographical reach across continents and countries, and a diverse array of projects from roads to digital networks. While the BRI's environmental sustainability has raised concerns, the impacts of construction materials used in these projects have been overlooked, especially in developing countries. Here, we map and account for the materials embodied in the BRI by integrating, for the first time, official governmental project reports, geographical information, and material flow analysis. We pinpoint and analyze the BRI material stocks in each individual project by material types, countries, regions, and sectors. Between 2008 and 2023, 328 million tons of construction materials have accumulated in 540 BRI projects around the world, mostly in Asia and Africa. Aggregates (sand and gravel) constitute the largest share (82%), followed by cement, steel, and other materials. Most of the materials are used in transportation infrastructure. Our work further highlights some limitations in terms of data quality for such sustainability assessments. By shedding light on the significant impact of BRI projects on raw material usage across the globe, this study sets the stage for further investigations into environmental impacts of BRI and material stock-flow-nexus from perspective of an initiative.
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The challenging clinical outcomes associated with advanced cervical cancer underscore the need for a novel therapeutic approach. Monensin, a polyether antibiotic, has recently emerged as a promising candidate with anti-cancer properties. In line with these ongoing efforts, our study presents compelling evidence of monensin's potent efficacy in cervical cancer. Monensin exerts a pronounced inhibitory impact on proliferation and anchorage-independent growth. Additionally, monensin significantly inhibited cervical cancer growth in vivo without causing any discernible toxicity in mice. Mechanism studies show that monensin's anti-cervical cancer activity can be attributed to its capacity to inhibit the Wnt/ß-catenin pathway, rather than inducing oxidative stress. Monensin effectively reduces both the levels and activity of ß-catenin, and we identify Akt, rather than CK1, as the key player involved in monensin-mediated Wnt/ß-catenin inhibition. Rescue studies using Wnt activator and ß-catenin-overexpressing cells confirmed that ß-catenin inhibition is the mechanism of monensin's action. As expected, cervical cancer cells exhibiting heightened Wnt/ß-catenin activity display increased sensitivity to monensin treatment. In conclusion, our findings provide pre-clinical evidence that supports further exploration of monensin's potential for repurposing in cervical cancer therapy, particularly for patients exhibiting aberrant Wnt/ß-catenin activation.
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Soft ionic elastomers that are self-healable, fatigue-free, and environment-tolerant are ideal structural and sensing materials for artificial prosthetics, soft electronics, and robotics to survive unpredictable service conditions. However, most synthetic strategies failed to unite rapid healing, fatigue resistance, and environmental robustness, limited by their singular compositional/structural designs. Here, we present a soft, tough, fatigue-resistant, and self-healable ionic elastomer (STFSI elastomer), which fuses skin-like binary assembly and Bouligand helicoidal structure into a composite of thermoplastic polyurethane (TPU) fibers and a supramolecular ionic biopolymer. The interlocked binary assembly enables skin-like softness, high stretchability, and strain-adaptive stiffening through a matrix-to-scaffold stress transfer. The Bouligand structure contributes to superhigh fracture toughness (101.6 kJ m-2) and fatigue resistance (4937 J m-2) via mechanical toughening by interlayer slipping and twisted crack propagation path. Besides, the STFSI elastomer is self-healable through a "bridging" method and environment-tolerant (-20 ËC ~ 60 ËC, strong acid/alkali, saltwater). To demonstrate the versatile structural and sensing applications, we showcase a safety cushion with efficient damping and suppressed rebounding, and a robotic sensor with excellent fatigue crack tolerance and instant sensation recovery upon cutting-off damage. Our presented synthetic strategy is generalizable to other fiber-reinforced tough polymers for applications involving demanding mechanical/environmental conditions.
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Endocrine-therapy-resistant estrogen receptor-positive (ER+) breast cancer cells often exhibit an augmented capacity to maintain endoplasmic reticulum (EnR) homeostasis under adverse conditions. Oncoprotein hepatitis B X-interacting protein (HBXIP) is a known transcriptional coactivator that promotes cancer development. However, it is unclear whether HBXIP participates in maintaining EnR homeostasis and promoting drug resistance in ER+ breast cancer. Here, we report that tamoxifen-resistant (TmaR) breast cancer cells exhibit increased expression of HBXIP, which acts as an inactivator of the unfolded protein response (UPR) to diminish tamoxifen-induced EnR stress. We show that HBXIP deficiency promotes EnR-associated degradation, enhances UPR-element reporter activity and cellular oxidative stress, and ultimately attenuates the growth of TmaR cells in vitro and in vivo. Mechanistically, we demonstrate that HBXIP acts as a chaperone of UPR transducer inositol-requiring enzyme 1a and diminishes production of reactive oxygen species (ROS) in TamR breast cancer cells. Upon loss of HBXIP expression, tamoxifen treatment hyperactivates IRE1α and its downstream proapoptotic pathways and simultaneously induces accumulation of intracellular ROS. This elevated ROS programmatically activates the other two branches of the UPR, mediated by PKR-like ER kinase and activating transcription factor 6α. Clinical investigations and Kaplan-Meier plotter analysis revealed that HBXIP is highly expressed in TamR breast cancer tissues. Furthermore, reinforced HBXIP expression is associated with a high recurrence and poor relapse-free survival rates in tamoxifen monotherapy ER+ breast cancer patients. These findings indicate that HBXIP is a regulator of EnR homeostasis and a potential target for TamR breast cancer therapy.
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Proteínas Adaptadoras Transductoras de Señales , Neoplasias de la Mama , Tamoxifeno , Respuesta de Proteína Desplegada , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Resistencia a Antineoplásicos , Retículo Endoplásmico , Endorribonucleasas/metabolismo , Femenino , Humanos , Recurrencia Local de Neoplasia , Proteínas Serina-Treonina Quinasas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Receptores de Estrógenos/metabolismo , Tamoxifeno/farmacologíaRESUMEN
Intracerebral hemorrhage associated with thrombolytic therapy with tissue plasminogen activator (tPA) in acute ischemic stroke continues to present a major clinical problem. Here, we report that infusion of tPA resulted in a significant increase in markers of neutrophil extracellular traps (NETs) in the ischemic cortex and plasma of mice subjected to photothrombotic middle cerebral artery occlusion. Peptidylarginine deiminase 4 (PAD4), a critical enzyme for NET formation, is also significantly upregulated in the ischemic brains of tPA-treated mice. Blood-brain barrier (BBB) disruption after ischemic challenge in an in vitro model of BBB was exacerbated after exposure to NETs. Importantly, disruption of NETs by DNase I or inhibition of NET production by PAD4 deficiency restored tPA-induced loss of BBB integrity and consequently decreased tPA-associated brain hemorrhage after ischemic stroke. Furthermore, either DNase I or PAD4 deficiency reversed tPA-mediated upregulation of the DNA sensor cyclic GMP-AMP (cGAMP) synthase (cGAS). Administration of cGAMP after stroke abolished DNase I-mediated downregulation of the STING pathway and type 1 interferon production and blocked the antihemorrhagic effect of DNase I in tPA-treated mice. We also show that tPA-associated brain hemorrhage after ischemic stroke was significantly reduced in cGas-/- mice. Collectively, these findings demonstrate that NETs significantly contribute to tPA-induced BBB breakdown in the ischemic brain and suggest that targeting NETs or cGAS may ameliorate thrombolytic therapy for ischemic stroke by reducing tPA-associated hemorrhage.
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Trampas Extracelulares/metabolismo , Hemorragias Intracraneales/complicaciones , Hemorragias Intracraneales/patología , Nucleotidiltransferasas/metabolismo , Accidente Cerebrovascular/complicaciones , Animales , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/patología , Desoxirribonucleasa I/metabolismo , Humanos , Interferón Tipo I/metabolismo , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Masculino , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , Infiltración Neutrófila , Arginina Deiminasa Proteína-Tipo 4/deficiencia , Arginina Deiminasa Proteína-Tipo 4/metabolismo , Transducción de Señal , Activador de Tejido Plasminógeno , Regulación hacia ArribaRESUMEN
Cuboid, a basic geometric structure, has been widely applied in architecture and mathematics. In chemistry, the introduction of cuboid structures always provides a specific structural shape, enhances the stability of the structure and improves the performance of materials. Herein, a simple strategy exploiting self-discrimination to construct a cuboid-stacking crystal material is proposed, in which a chiral macrocycle (TBBP) based on Tröger's base (TB) and benzophenone (BP) was synthesized as the building element of the cuboid. The cuboid is designed to be transformable compared with cuboid structures in previous work. For this reason, it is considered that the cuboid-stacking structure can be transformed through external stimulation. Iodine vapor is selected as the external stimulus to transform the cuboid-stacking structure due to the favorable interaction between iodine and the cuboid. The changes in the stacking mode of TBBP is studied by single-crystal X-ray diffraction (SCXRD) and powder X-ray diffraction (PXRD). To our surprise, this Tröger's base-based cuboid shows strong iodine adsorption capacity up to 3.43â g g-1 and exhibits potential as a crystal material for iodine adsorption.
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Gases , Yodo , Adsorción , Cristalografía por Rayos X , Difracción de Rayos XRESUMEN
Machinery and equipment, integral as technology-specific capital goods, play a dual role in climate change: it acts as both a mitigator and an exacerbator due to its carbon-intensive life cycle. Despite their importance, current climate mitigation analyses often overlook these items, leaving a gap in comprehensive analyses of their material stock and environmental impacts. To address this, our research integrates input-output analysis (IOA) with dynamic material flow analysis (d-MFA) to assess the carbon and material footprints of machinery. It finds that in 2019, machinery production required 30% of global metal production and 8% of global carbon emissions. Between 2000 and 2019, the metal footprint of the stock of machinery grew twice as fast as the economy. To illustrate the global implications and scale, we spotlight key countries. China's rise in machinery material stock is noteworthy, surpassing the United States in 2008 in total amount and achieving half of the US per capita level by 2019. Our study also contrasts economic depreciationâa value-centric metricâwith the tangible lifespan of machinery, revealing how much the physical size of the capital stock exceeds its book values. As physical machinery stocks saturate, new machinery can increasingly be built from metals recycled from retired machinery.
Asunto(s)
Huella de Carbono , Tecnología , Cambio Climático , Carbono , ChinaRESUMEN
Pulmonary hypertension (PH) is a disease which affects the cardiopulmonary system; it is defined as a mean pulmonary artery pressure (mPAP) > 20 mmHg as measured by right heart catheterization at rest, and is caused by complex and diverse mechanisms. In response to stimuli such as hypoxia and ischemia, the expression and synthesis of endothelin (ET) increase, leading to the activation of various signaling pathways downstream of it and producing effects such as the induction of abnormal vascular proliferation during the development of the disease. This paper reviews the regulation of endothelin receptors and their pathways in normal physiological processes and disease processes, and describes the mechanistic roles of ET receptor antagonists that are currently approved and used in clinical studies. Current clinical researches on ET are focused on the development of multi-target combinations and novel delivery methods to improve efficacy and patient compliance while reducing side effects. In this review, future research directions and trends of ET targets are described, including monotherapy and precision medicine.