RESUMEN
Hydrogels consist of three-dimensional (3D) and complicated polymer networks that determine their physical properties. Among the methods for structural analyses of hydrogels, the real-space imaging of a polymer network of hydrogels on a nanometer scale is one of the optimal methods; however, it is highly challenging. In this study, we propose a direct observation method for cationic polymer networks using transmission electron microscopy (TEM). By combining the double network strategy and the mineral staining technique, we overcame the challenges of polymer aggregation and the low electron density of the polymer. An objective cationic network was incorporated into a neutral skeleton network to suppress shrinkage during subsequent staining. Titania mineralization along the cationic polymer strands provided sufficient electron density for the objective polymer network for TEM observation. This observation method enables the visualization of local structures in real space and plays a complementary role to scattering methods for soft matter structure analysis.
RESUMEN
In this work, we have found that a prenotched double-network (DN) hydrogel, when subjected to tensile loading in a pure-shear geometry, exhibits intriguing stick-slip crack dynamics. These dynamics synchronize with the oscillation of the damage (yielding) zone at the crack tip. Through manipulation of the loading rate and the predamage level of the brittle network in DN gels, we have clarified that this phenomenon stems from the significant amount of energy dissipation required to form the damage zone at the crack tip, as well as a kinetic contrast between the rapid crack extension through the yielding zone (slip process) and the slow formation of a new yielding zone controlled by the external loading rate (stick process).
RESUMEN
Morphogenesis is one of the most marvelous natural phenomena. The morphological characteristics of biological organs develop through growth, which is often triggered by mechanical force. In this study, we propose a bioinspired strategy for hydrogel morphogenesis through force-controlled chemical reaction and growth under isothermal conditions. We adopted a double network (DN) hydrogel with sacrificial bonds. Applying mechanical force to the gel caused deformation and sacrificial bond rupture. By supplying monomers to the gel, the radicals generated by the bond rupture triggered the formation of a new network inside the deformed gel. This new network conferred plasticity to the elastic gel, allowing it to maintain its deformed shape, along with increased volume and strength. We demonstrated that sheet-shaped DN hydrogels rapidly adopted various three-dimensional shapes at ambient temperature when subjected to forces such as drawing and blowing. This mechanism enables morphogenesis of elastic hydrogels and will promote the application of these materials in biomedical fields and soft machines.
RESUMEN
In recent decades, more than 100 different mechanophores with a broad range of activation forces have been developed. For various applications of mechanophores in polymer materials, it is crucial to selectively activate the mechanophores with high efficiency, avoiding nonspecific bond scission of the material. In this study, we embedded cyclobutane-based mechanophore cross-linkers (I and II) with varied activation forces (fa) in the first network of the double network hydrogels and quantitively investigated the activation selectivity and efficiency of these mechanophores. Our findings revealed that cross-linker I, with a lower activation force relative to the bonds in the polymer main chain (fa-I/fa-chain = 0.8 nN/3.4 nN), achieved efficient activation with 100% selectivity. Conversely, an increase of the activation force of mechanophore II (fa-II/fa-chain = 2.5 nN/3.4 nN) led to a significant decrease of its activation efficiency, accompanied by a substantial number of nonspecific bond scission events. Furthermore, with the coexistence of two cross-linkers, significantly different activation forces resulted in the almost complete suppression of the higher-force one (i.e., I and III, fa-I/fa-III = 0.8 nN/3.4 nN), while similar activation forces led to simultaneous activations with moderate efficiencies (i.e., I and IV, fa-I/fa-IV = 0.8 nN/1.6 nN). These findings provide insights into the prevention of nonspecific bond rupture during mechanophore activation and enhance our understanding of the damage mechanism within polymer networks when using mechanophores as detectors. Besides, it establishes a principle for combining different mechanophores to design multiple mechanoresponsive functional materials.
RESUMEN
Stress-adaptive mechanisms enabling cancer cells to survive under glucose deprivation remain elusive. N6-methyladenosine (m6A) modification plays important roles in determining cancer cell fate and cellular stress response to nutrient deficiency. However, whether m6A modification functions in the regulation of cancer cell survival under glucose deprivation is unknown. Here, we found that glucose deprivation reduced m6A modification levels. Increasing m6A modification resulted in increased hepatoma cell necrosis under glucose deprivation, whereas decreasing m6A modification had an opposite effect. Integrated m6A-seq and RNA-seq revealed potential targets of m6A modification under glucose deprivation, including the transcription factor FOSL1; further, glucose deprivation upregulated FOSL1 by inhibiting FOSL1 mRNA decay in an m6A-YTHDF2-dependent manner through reducing m6A modification in its exon1 and 5'-UTR regions. Functionally, FOSL1 protected hepatoma cells against glucose deprivation-induced necrosis in vitro and in vivo. Mechanistically, FOSL1 transcriptionally repressed ATF3 by binding to its promoter. Meanwhile, ATF3 and MAFF interacted via their leucine zipper domains to form a heterodimer, which competed with NRF2 for binding to antioxidant response elements in the promoters of NRF2 target genes, thereby inhibiting their transcription. Consequently, FOSL1 reduced the formation of the ATF3-MAFF heterodimer, thereby enhancing NRF2 transcriptional activity and the antioxidant capacity of glucose-deprived-hepatoma cells. Thus, FOSL1 alleviated the necrosis-inducing effect of glucose deprivation-induced reactive oxygen species accumulation. Collectively, our study uncovers the protective role of m6A-FOSL1-ATF3 axis in hepatoma cell necrosis under glucose deprivation, and may provide new targets for cancer therapy.
Asunto(s)
Carcinoma Hepatocelular , Glucosa , Neoplasias Hepáticas , Necrosis , Proteínas Proto-Oncogénicas c-fos , ARN Mensajero , Proteínas Proto-Oncogénicas c-fos/metabolismo , Proteínas Proto-Oncogénicas c-fos/genética , Glucosa/metabolismo , Glucosa/deficiencia , Humanos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/genética , Animales , Ratones , ARN Mensajero/metabolismo , ARN Mensajero/genética , Línea Celular Tumoral , Factor de Transcripción Activador 3/metabolismo , Factor de Transcripción Activador 3/genética , Adenosina/análogos & derivados , Adenosina/metabolismo , Ratones DesnudosRESUMEN
This research utilized single-cell RNA sequencing to map the immune cell landscape in sepsis, revealing 28 distinct cell clusters and categorizing them into nine major types. Delving into the monocyte/macrophage subclusters, 12 unique subclusters are identified and pathway enrichment analyses are conducted using KEGG and GO, discovering enriched pathways such as oxidative phosphorylation and antigen processing. Further GSVA and AUCell assessments show varied activation of interferon pathways, especially in subclusters 4 and 11. The clinical correlation analysis reveals genes significantly linked to survival outcomes. Additionally, cellular differentiation in these subclusters is explored. Building on these insights, the differential gene expression within these subclusters is specifically scrutinized, which reveal MYOF as a key gene with elevated expression levels in the survivor group. This finding is further supported by in-depth pathway enrichment analysis and the examination of cellular differentiation trajectories, where MYOF's role became evident in the context of immune response regulation and sepsis progression. Validating the role of the MYOF gene in sepsis, a dose-dependent response to LPS in THP-1 cells and C57 mice is observed. Finally, inter-cellular communications are analyzed, particularly focusing on the MYOF+Mono/Macro subcluster, which indicates a pivotal role in immune regulation and potential therapeutic targeting.
Asunto(s)
Macrófagos , Monocitos , Sepsis , Análisis de la Célula Individual , Humanos , Sepsis/inmunología , Sepsis/genética , Sepsis/metabolismo , Monocitos/inmunología , Monocitos/metabolismo , Ratones , Análisis de la Célula Individual/métodos , Macrófagos/inmunología , Macrófagos/metabolismo , Animales , Pronóstico , Ratones Endogámicos C57BL , Masculino , Células THP-1 , FemeninoRESUMEN
Precisely measuring pressure in microfluidic flows is essential for flow control, fluid characterization, and monitoring, but faces specific challenges such as achieving sufficient resolution, non-invasiveness, or ease of use. Here, we demonstrate a fully integrated multiplexed optofluidic pressure sensor, entirely decoupled from the flow path, that enables local pressure measurements along any microfluidic channel without altering its flow geometry. The sensor itself relies on the compression of a soft mechano-actuated hydrogel, changing color in response to a pressure change. The hydrogel is separated from the fluid circulating in the channel by a thin membrane, allowing for the unrestricted use of different types of fluids. Imaging the gel through the transparent PDMS with a color camera provides a direct, easy, and contact-free determination of the fluid pressure at the sensing location for pressures as small as 20mbar with a resolution of around 10mbar. The sensitivity and accessible pressure range can be tuned via the mechanical properties of the sensing unit. The photonic gel can also be used to acquire 2D pressure or deformation maps, taking advantage of the fast response time and fine spatial resolution.
RESUMEN
Double-network (DN) hydrogels are tough soft materials, and the high fracture resistance can be attributed to the formation of a large damage zone (internal fracture of the brittle first network) around the crack tip. In this work, we studied the effect of predamage in the brittle network on the fracture energy Γc of DN hydrogels. The prestretch of the first network was induced by prestretching the DN gels to prestretch ratio λpre. Depending on the λpre in relative to the yielding stretch ratio λy, above which the brittle first network starts to break into discontinuous fragments inside DN gels, two regimes were observed: Γc decreases monotonically with λpre in the regime of λpre < λy, mainly due to the decreasing contribution from the bulk internal damage, while Γc increases with λpre in the regime of λpre > λy. The latter can be understood by the release of the hidden length of the stretchable network strands by the rupture of the brittle network, whereby the broken fragments of the brittle network could serve as sliding cross-links to further delocalize the stress-concentration near the crack tip and prevent chain scissions.
RESUMEN
Azobenzene has been widely explored as a photoresponsive element in materials science. Although some studies have investigated the force-induced isomerization of azobenzene, the effect of force on the rupture of azobenzene has not been explored. Here we show that the light-induced structural change of azobenzene can also alter its rupture forces, making it an ideal light-responsive mechanophore. Using single-molecule force spectroscopy and ultrasonication, we found that cis and trans para-azobenzene isomers possess contrasting mechanical properties. Dynamic force spectroscopy experiments and quantum-chemical calculations in which azobenzene regioisomers were pulled from different directions revealed that the distinct rupture forces of the two isomers are due to the pulling direction rather than the energetic difference between the two isomers. These mechanical features of azobenzene can be used to rationally control the macroscopic fracture behaviours of polymer networks by photoillumination. The use of light-induced conformational changes to alter the mechanical response of mechanophores provides an attractive way to engineer polymer networks of light-regulatable mechanical properties.
RESUMEN
Soft materials with mechanical adaptability have substantial potential for various applications in tissue engineering. Gaining a deep understanding of the structural evolution and adaptation dynamics of soft materials subjected to cyclic stretching gives insight into developing mechanically adaptive materials. Here, we investigate the effect of hierarchy structure on the mechanical adaptation of self-healing hydrogels under cyclic stretching training. A polyampholyte hydrogel, composed of hierarchical structures including ionic bonds, transient and permanent polymer networks, and bicontinuous hard/soft-phase networks, is adopted as a model. Conditions for effective training, mild overtraining, and fatal overtraining are demonstrated in soft materials. We further reveal that mesoscale hard/soft-phase networks dominate the long-term memory effect of training and play a crucial role in the asymmetric dynamics of compliance changes and the symmetric dynamics of hydrogel shape evolution. Our findings provide insights into the design of hierarchical structures for adaptive soft materials.
RESUMEN
We report a thermoresponsive anisotropic photonic hydrogel: poly(dodecyl glyceryl itaconate)/polyacrylamide-poly(N-isopropylacrylamide) hydrogel (PDGI/PAAm-PNIPAM hydrogel). Hydrogels with uniaxially aligned lamellar bilayers possess bright structural color and swelling anisotropy, while PNIPAM-based hydrogels exhibit distinct thermoresponsive properties around a lower critical solution temperature (LCST). Hybridization of thermoresponsive PNIPAM with the lamellar hydrogel can give the anisotropic photonic hydrogel various fascinating thermoresponsive properties, such as structural color/turbid transition, thermoresponsive structural color, and anisotropic deswelling/reswelling behavior by temperature stimuli. The temperature-induced changes in turbidity, structural color, and anisotropic swelling of the gel around the LCST can be tuned by controlling the incorporated PNIPAM density. PNIPAM can be regioselectively incorporated into the specific region of the lamellar hydrogels by photomasking during UV polymerization. The PDGI/PAAm-PNIPAM hydrogel can find diverse promising applications such as smart windows and smart displays.
RESUMEN
Mirror radius analysis of fractured surfaces is a powerful fractographic method for determining the cause of failure in linear elastic hard materials because it does not require prior loading information. However, mirror analysis for soft materials is lacking. In this study, we established a general mirror radius law for nonlinear elastic soft materials using highly deformable brittle hydrogels. The fracture stress and mirror radius follow a -1 power law, which differs from the -0.5 power law for linear elastic hard materials. The constant in the power law is related to the fracture energy of the material. This discovery provides insights into fracture mechanisms and leads the way for applying fractography to soft materials.
RESUMEN
Background and aims: Whether ultra-processed food consumption is associated with cancer prognosis remains unknown. We aimed to test whether prediagnosis ultra-processed food consumption is positively associated with all-cause and cancer-specific mortality in patients with colorectal, lung, prostate, or breast cancer. Methods: This study included 1,100 colorectal cancer patients, 1750 lung cancer patients, 4,336 prostate cancer patients, and 2,443 breast cancer patients. Ultra-processed foods were assessed using the NOVA classification before the diagnosis of the first cancer. Multivariable Cox regression was used to calculate hazard ratio (HR) and 95% confidence interval (CI) for all-cause and cancer-specific mortality. Results: High ultra-processed food consumption before cancer diagnosis was significantly associated with an increased risk of all-cause mortality in lung (HRquartile 4 vs. 1: 1.18; 95% CI: 0.98, 1.40; Ptrend = 0.021) and prostate (HRquartile 4 vs. 1: 1.18; 95% CI: 1.00, 1.39; Ptrend = 0.017) cancer patients in a nonlinear dose-response manner (all Pnonlinearity < 0.05), whereas no significant results were found for other associations of interest. Subgroup analyses additionally revealed a significantly positive association with colorectal cancer-specific mortality among colorectal cancer patients in stages I and II but not among those in stages III and IV (Pinteraction = 0.006), and with prostate cancer-specific mortality among prostate cancer patients with body mass index <25 but not among those with body mass index ≥25 (Pinteraction = 0.001). Conclusion: Our study suggests that reducing ultra-processed food consumption before cancer diagnosis may improve the overall survival of patients with lung or prostate cancer, and the cancer-specific survival of certain subgroups of patients with colorectal or prostate cancer.
RESUMEN
Although hepatocellular carcinoma (HCC) is rather frequent, little is known about the molecular pathways underlying its development, progression, and prognosis. In the current study, we comprehensively analyzed the deferentially expressed metabolism-related genes (MRGs) in HCC based on TCGA datasets attempting to discover the potentially prognostic genes in HCC. The up-regulated MRGs were further subjected to analyze their prognostic values and protein expressions. Twenty-seven genes were identified because their high expressions were significant in OS, PFS, DFS, DSS, and HCC tumor samples. They were then used for GO, KEGG, methylation, genetics changes, immune infiltration analyses. Moreover, we established a prognostic model in HCC using univariate assays and LASSO regression based on these MRGs. Additionally, we also found that SLC38A1, an amino acid metabolism closely related transporter, was a potential prognostic gene in HCC, and its function in HCC was further studied using experiments. We found that the knockdown of SLC38A1 notably suppressed the growth and migration of HCC cells. Further studies revealed that SLC38A1 modulated the development of HCC cells by regulating PI3K/AKT/mTOR signaling via glutamine mediated energy metabolism. In conclusion, this study identified the potentially prognostic MRGs in HCC and uncovered that SLC38A1 regulated HCC development and progression by regulating PI3K/AKT/mTOR signaling via glutamine mediated energy metabolism, which might provide a novel marker and potential therapeutic target in HCC.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Glutamina/metabolismo , Neoplasias Hepáticas/patología , Proliferación Celular/genética , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Metabolismo Energético , Línea Celular Tumoral , Sistema de Transporte de Aminoácidos A/metabolismoRESUMEN
Double-network (DN) gels are unique mechanochemical materials owing to their structures that can be dynamically remodelled during use. The mechanical energy applied to DN gels is efficiently transferred to the chemical bonds of the brittle network, generating mechanoradicals that initiate the polymerisation of pre-loaded monomers, thereby remodelling the materials. To attain continuous remodelling or growth in response to repetitive mechanical stimuli, a sustainable supply of chemical reagents to such dynamic materials is essential. In this study, inspired by the vascular perfusion transporting nutrients to cells, we constructed a circulatory system for a continuous supply of chemicals to channel-containing DN hydrogels (c-DN gels). The perfusion of monomer solutions through the channel and permeability of the c-DN gels not only replenishes the monomers consumed by the polymerisation but also replenishes the water loss caused by the surface evaporation of hydrogel, thereby freeing the mechanochemical process of DN gels from the constraints of the underwater environment. The facile chemical supply enabled us to modulate the mechanical enhancement of the c-DN gel and attain muscle-like strengthening under repeated mechanical training in deoxygenated air. We also studied the kinetics of polymer growth and strengthening and deciphered unique features of mechanochemical reaction in DN gels including the extremely long-living radicals and delayed mechanical strengthening.
Asunto(s)
Hidrogeles , Polímeros , Polímeros/química , PerfusiónRESUMEN
Anisotropic photonic hydrogels with alternatively stacked poly(dodecyl glyceryl itaconate) (PDGI) bilayers and polyacrylamide (PAAm) gel layers are unique soft materials with various functions. It is known that to form the lamellar phase of bilayers, a small amount of co-surfactant sodium dodecyl sulfate (SDS) should be present in the precursor monomer solutions of the gels. However, little is known about the influence of the co-surfactant on the structure of bilayers and on the mechanical properties of such photonic hydrogels. Herein, we chose several co-surfactants and studied the effect of the co-surfactants on the self-assembly behavior of the bilayers and on the mechanical properties of the resulting photonic hydrogels. A macroscopically aligned lamellar phase could be induced for all the co-surfactants. Interestingly, the mechanical response of the photonic hydrogels sensitively depends on the chemical structure of the co-surfactant, especially at large deformation. We hypothesize that doping by small amounts of co-surfactants dramatically changes the anchoring strength and density of PAAm strands onto the bilayer surface, thereby influencing the load transfer efficiency from the bilayer to the PAAm gel layer at large deformation and the rupture of the bilayer. This work provides new understanding in the molecular mechanisms of deformation and strengthening in this soft and anisotropic nanocomposite, helping to design more robust photonic hydrogels.
RESUMEN
Understanding the physicochemical properties of hydrogel surfaces and their molecular origins is important for their applications. In this paper, we elucidate the molecular origin of surface charges in double-network hydrogels synthesized by two-step sequential polymerization. Synthesis of hydrogels by free-radical polymerization does not fully complete the reaction, leaving a small number of unreacted monomers. When this approach is used to synthesize double network (DN) hydrogels by a two-step sequential polymerization from charged monomers for the first network and neutral monomers for the second network, the unreacted first network monomers are incorporated into the second network. Since the surface of such DN hydrogels is covered with a µm-thick layer of the neutral second network, the incorporation of a small amount of charged monomers into the second network increases the surface charge and, thereby, their repulsive/adhesive properties. Therefore, we propose a method to remove unreacted monomers and modulate the surface charge density of DN hydrogels.
RESUMEN
Mechanical behaviors of a polymer gel are coupled with its swelling behavior. It has been known that typical hydrogels display extension-induced swelling and drying-induced stiffening, called normal mechanical-swelling coupling. In this study, we experimentally found that highly extended double-network (DN) hydrogels exhibit abnormal inverse mechanical-swelling coupling such as extension-induced deswelling and drying-induced softening. We established theoretical hyperelastic and swelling models that reproduced all the complicated mechanical and swelling trends of the highly deformed DN hydrogels. From these theoretical analyses, it is considered that the inverse mechanical-swelling coupling of a DN gel is derived from the extreme nonlinear elasticity of its first network at its ultimate deformation state. These findings contribute toward the understanding of the mechanics of rubber-like materials up to their ultimate deformation and fracture limit.
RESUMEN
As a protective mechanism regulating excessive inflammation, endotoxin tolerance plays a vital role in regulating endotoxin shock. Kupffer cells are players in mediating endotoxin tolerance. Nonetheless, the regulatory mechanism regulating endotoxin tolerance is barely known. A nonclassical IKK kinase called TRAF-associated NF-κB activator (TANK)-binding kinase 1 (TBK1) can regulate inflammation. Here, we found that TBK1 is required for endotoxin tolerance in Kupffer cells. TBK1 plays a dominant role in regulating endotoxin tolerance by negatively regulating the induction of p100 processing. Deltex E3 ubiquitin ligase 4 (DTX4), a negative regulator of TBK1, can promote TBK1 K48-mediated ubiquitination and indirectly regulate endotoxin tolerance in Kupffer cells. We demonstrate that the c-Myb transcription factor could negatively regulate DTX4. Overexpression of c-Myb can be used to reduce the ubiquitination of TBK1 by reducing DTX4 transcription and to boost the anti-inflammatory effect of endotoxin tolerance. Thus, this study reveals a novel theory of TBK1-mediated endotoxin tolerance in Kupffer cells.
Asunto(s)
Proteínas Serina-Treonina Quinasas , Transducción de Señal , Humanos , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Macrófagos del Hígado/metabolismo , Tolerancia a Endotoxinas , InflamaciónRESUMEN
MC-PDGI/PAAm gels are cylindrical composite gels containing poly(dodecyl glyceryl itaconate) (PDGI) as a polymerized lipid oriented in a multilayer tubular shape within a polyacrylamide (PAAm) network. The most unique feature of the MC-PDGI/PAAm gel is its super-anisotropic swelling, wherein the diameter of the gel increases, but the length decreases with an increase in the volume of the gel. Through swelling and small-angle X-ray diffraction experiments, we investigated the effects of PDGI lipid bilayers and polymer network on the swelling of the MC-PDGI/PAAm gel, which suggests that the swelling anisotropy of the MC-PDGI/PAAm gel is dominated by the elasticity of the PDGI bilayers. Furthermore, we investigated the equation of state of the gel that roughly reproduced the experimental swelling results. These findings are crucial for realizing the controlled super-anisotropic swelling of MC-PDGI/PAAm gels and their applications as anisotropic actuation devices.