Environmental Matrices Research Articles

Vimentin promotes collective cell migration through collagen networks via increased matrix remodeling and spheroid fluidity.

The intermediate filament (IF) protein vimentin is associated with many diseases with phenotypes of enhanced cellular migration and aggressive invasion through the extracellular matrix (ECM) of tissues, but vimentin's role in in-vivo cell migration is still largely unclear. Vimentin is important for proper cellular adhesion and force generation, which are critical to cell migration; yet the vimentin cytoskeleton also hinders the ability of cells to squeeze through small pores in ECM, resisting migration. To identify the role of vimentin in collective cell migration, we generate spheroids of wide-type and vimentin-null mouse embryonic fibroblasts (mEFs) and embed them in a 3D collagen matrix. We find that loss of vimentin significantly impairs the ability of the spheroid to collectively expand through collagen networks and remodel the collagen network. Traction force analysis reveals that vimentin null spheroids exert less contractile force than their wild-type counterparts. In addition, spheroids made of mEFs with only vimentin unit length filaments (ULFs) exhibit similar behavior as vimentin-null spheroids, suggesting filamentous vimentin is required to promote 3D collective cell migration. We find the vimentin-mediated collective cell expansion is dependent on matrix metalloproteinase (MMP) degradation of the collagen matrix. Further, 3D vertex model simulation of spheroid and embedded ECM indicates that wild-type spheroids behave more fluid-like, enabling more active pulling and reconstructing the surrounding collagen network. Altogether, these results signify that VIF plays a critical role in enhancing migratory persistence in 3D matrix environments through MMP transportation and tissue fluidity.

Construction of multi‐decay pathways and realizing polymer‐regulated organic smart luminescent materials

AbstractThe construction of multi‐decay pathways of smart organic light‐emitting materials has drawn intensive research enthusiasm owing to their substantial promise in diverse optoelectronic applications. Nowadays, numerous chemical substances have been refined to extend and enhance their intriguing luminescent properties. Nowadays, plenty of chemicals have been adapted to amplify more interesting luminescent properties. How to utilize an easy way to tune multi‐decay pathways resulting in various emissions is still challenging. Here, we present a triphenylamine derivative, TPA3BP, which exhibits a variety of multi‐decay pathways in different states and can exhibit thermally activated delayed fluorescence in both the polydimethylsiloxane and crystalline state, but also achieve room temperature phosphorescence by embedding it into the poly (methyl methacrylate) (PMMA) and polyvinyl pyrrolidone matrix. The multi‐decay luminescence can be attributed to the dual effect arising from the n‐π* transition of TPA3BP and the regulation of molecular transition pathways within the matrix environment. This intriguing phenomenon highlights the combined influence of TPA3BP's electronic transitions and the influence of the polarity and rigidity of the surrounding matrix on the observed characteristics. This advancement has widened the structural possibilities for multi‐decay luminescent materials, enabling their targeted synthesis for future applications, such as information encryption and smart anti‐counterfeiting.

3D Spiky Needle‐Clustered Ag@Au Plasmonic Nanoarchitecture for Highly Sensitive and Machine Learning‐Assisted Detection of Multiple Hazardous Molecules

AbstractTo develop a field applicable hazardous molecular detection system, highly sensitive and multiplex detection capability is required for practical utilization. Here, a paper‐based 3D spiky needle‐clustered gold grown on silver (Ag@Au) plasmonic nanoarchitecture (3D‐SNCP) is fabricated through whole solution process. The developed substrate is investigated by scanning electron microscopy (SEM), transmission electron microscopy (TEM) and X‐ray diffraction (XRD) to find out morphological development mechanism. Also, finite‐domain time difference (FDTD) simulation is conducted for the observation of electromagnetic field (E‐field) distribution. After surface‐enhanced Raman scattering (SERS) characterization, the 3D‐SNCP is utilized for ultra‐sensitive and multiplex hazardous molecular detection, such as bipyridine pesticides including paraquat (PQ), diquat (DQ), and difenzoquat (DIF). Then, each of pesticide molecular Raman signals are trained by a machine learning technique of multinomial logistic regression (MLR), followed by multiplex classificationf of blank, PQ, DQ, DIF, and four mixture types of each pesticide, spiked in real agricultural matrix. The developed 3D‐SNCP substrate combined with the machine learning method successfully verifies the multiple pesticides and it is expected to be applied for various hazardous molecular detection in much complicated matrix environments.

Mechanical heterogeneity in a soft biomaterial niche controls BMP2 signaling

The extracellular matrix is known to impact cell function during regeneration by modulating growth factor signaling. However, how the mechanical properties and structure of biomaterials can be used to optimize the cellular response to growth factors is widely neglected. Here, we engineered a macroporous biomaterial to study cellular signaling in environments that mimic the mechanical stiffness but also the mechanical heterogeneity of native extracellular matrix. We found that the mechanical interaction of cells with the heterogeneous and non-linear deformation properties of soft matrices (E < 5 kPa) enhances BMP-2 growth factor signaling with high relevance for tissue regeneration. In contrast, this effect is absent in homogeneous hydrogels that are often used to study cell responses to mechanical cues. Live cell imaging and in silico finite element modeling further revealed that a subpopulation of highly active, fast migrating cells is responsible for most of the material deformation, while a second, less active population experiences this deformation as an extrinsic mechanical stimulation. At an overall low cell density, the active cell population dominates the process, suggesting that it plays a particularly important role in early tissue healing scenarios where cells invade tissue defects or implanted biomaterials. Taken together, our findings demonstrate that the mechanical heterogeneity of the natural extracellular matrix environment plays an important role in triggering regeneration by endogenously acting growth factors. This suggests the inclusion of such mechanical complexity as a design parameter in future biomaterials, in addition to established parameters such as mechanical stiffness and stress relaxation.

Stiffness-tunable biomaterials provide a good extracellular matrix environment for axon growth and regeneration.

Neuronal growth, extension, branching, and formation of neural networks are markedly influenced by the extracellular matrix-a complex network composed of proteins and carbohydrates secreted by cells. In addition to providing physical support for cells, the extracellular matrix also conveys critical mechanical stiffness cues. During the development of the nervous system, extracellular matrix stiffness plays a central role in guiding neuronal growth, particularly in the context of axonal extension, which is crucial for the formation of neural networks. In neural tissue engineering, manipulation of biomaterial stiffness is a promising strategy to provide a permissive environment for the repair and regeneration of injured nervous tissue. Recent research has fine-tuned synthetic biomaterials to fabricate scaffolds that closely replicate the stiffness profiles observed in the nervous system. In this review, we highlight the molecular mechanisms by which extracellular matrix stiffness regulates axonal growth and regeneration. We highlight the progress made in the development of stiffness-tunable biomaterials to emulate in vivo extracellular matrix environments, with an emphasis on their application in neural repair and regeneration, along with a discussion of the current limitations and future prospects. The exploration and optimization of the stiffness-tunable biomaterials has the potential to markedly advance the development of neural tissue engineering.

Zebrafish Scale Regeneration In Toto and Ex Vivo Culture of Scales.

Skeletal diseases are often complex in their etiology and affect millions of people worldwide. Due to the aging population, there is a need for new therapeutics that could ease the burden on healthcare systems. As these diseases are complex, it is difficult and expensive to accurately model bone pathophysiology in a lab setting. The challenge for the field is to establish a cost-effective, biologically relevant platform for modeling bone disease that can be used to test potential therapeutic compounds. Such a platform should ideally allow dynamic visualization of cell behaviors of bone-building osteoblasts and bone-degrading osteoclasts acting in their mineralized matrix environment. Zebrafish are increasingly used as models due to the availability of genetic tools, including transgenic reporter lines, and the fact that some skeletal tissues (including the scales) remain translucent to adulthood, allowing dynamic imaging options. Since zebrafish scales have both osteoblasts and osteoclasts and are highly abundant, they provide an easily accessible and abundantly available resource of independent bone units. Moreover, once removed, adult zebrafish scales fully regenerate, therefore offering a way to study the spatiotemporal growth of mineralized tissue in vivo. Here, we detail protocols for harvesting and tracking the regeneration of the scales. Lastly, a protocol for stable culture of scales ex vivo for a week and following the healing response after controlled damage to the mineralized matrix of the scale over time is also presented.

Development of CuO nanoparticles modified electrochemical sensor for detection of salbutamol

Abstract Metal oxide structures are being utilized in an increasing variety of applications. This study used cyclic and differential pulse voltammetry techniques to investigate the possible utilization of copper oxide (CuO) nanoparticles modified carbon paste electrode (CPE) for the redox reactions of salbutamol (SAL). The electrochemical performance of the SAL analyte in a complex matrix environment in Ventolin was evaluated in order to assess the appropriateness of the proposed sensor in a real sample environment. CuO nanoparticles were produced via a straightforward, cost-effective and efficient sol–gel method, and characterization studies of synthesized CuO nanoparticles were performed by scanning electron microscopy, x-ray Diffraction (XRD), and x-ray photoelectron spectroscopy. The synthesized CuO nanoparticles had a spherical shape and particle size was found to be 74 nm. The crystal size of the CuO particles was calculated to be 21.79 nm using the Debye–Scherrer equation. Under optimal conditions, differential pulse voltammetry demonstrated a linear response in the 50 nM to 100 μM range, with a salbutamol detection limit of 50 nM (S/N = 3). The SAL concentration (R 2 = 0.9971) was found to have a good correlation coefficient. The reproducibility of the biosensor was investigated and evaluated with a relative standard deviation of 3% (n = 8). The storage stability of CuO modified CPE for two weeks was evaluated based on the response of DP current measured at intervals every two days. According to the measurement results, the modified electrode exhibited good stability and reproducibility while maintaining 80% of its stability. It is also a rapid and dependable sensor candidate with a measurement time of approximately 20 s. The developed electrode has been utilized successfully to determine doping material with improved performance.

Significantly Enhanced Energy Density of Polyvinylidene Fluoride/Polyimide-Based Nanocomposites by Core-Shell BaTiO3@SiO2.

Improving the limited energy storage capacity of dielectric materials has long been an attractive challenge. In this work, a four-phase hybridized nanocomposite was designed. The linear polymer polyimide (PI) was added to the ferroelectric polymer polyvinylidene fluoride (PVDF) and compounded with a nanoceramic BT@SiO2 with a core-shell structure. The results show that PVDF-PI/BT@SiO2 nanocomposites prepared by a straightforward spin-coating method have a significantly increased discharge energy density. The polymer blends obtain a tightly extended conformation in the amorphous region. Also, this provides an excellent matrix environment for the homogeneous dispersion of fillers. The core-shell structure, as a physical barrier, not only hinders the expansion of the breakdown path but also extends multiple polarization surfaces with gradient variations at the microscopic level. Therefore, the synergistic effect generated by polymer blending and core-shell structure effectively enhances the dielectric and stored energy characteristics of nanocomposites. The dielectric constant is stable at 11.39-18.7, and the dielectric loss is always lower than 0.136. The discharge energy density is 2.5 J/cm3, almost 110% higher than that of the BOPP films (about 1.2 J/cm3). These experimental results suggest that the composite system using core-shell structure and polymer blending is a new way to improve the energy density of dielectric materials.

Abstract 3167: Impact of gemcitabine modification on redox-driven responses in pancreatic cancer organoids cultured in distinct 3D microenvironments

Abstract Pancreatic ductal adenocarcinoma (PDAC) poses a formidable challenge in oncology, characterized by its high lethality and limited treatment options. The advanced stage at diagnosis, aggressive metastasis, and the constrained efficacy of conventional therapeutic drugs collectively contribute to the grim prognosis associated with PDAC. Gemcitabine, a nucleoside analog and the longstanding standard chemotherapy for pancreatic cancer, encounters a significant hurdle in its efficacy due to the development of resistance. To establish a cancer-acquired resistance model applicable to Gem-modified drugs, it is crucial to account for the dense extracellular matrix (ECM) composition characteristic of PDAC. In this investigation, we employ three-dimensional (3D) cell culture models, specifically utilizing pancreatic cancer patient-derived organoids (PDOs) within a 3D matrix with tunable density and stiffness by incorporating variations in transglutaminase crosslinking rates. PDAC cells from different patients exhibit diverse adaptations within these altered gel matrix environments, manifesting differences in morphology, doubling time, and responses to drugs. Notably, PDAC cells display pronounced stemness characteristics in the dense matrix, featuring a more rounded and compact appearance and an increase in ABC transporters.Addressing the challenge of gemcitabine resistance, modifications such as gemcitabine conjugates with stearate (Gem-S) have shown promise in preclinical studies. Exploring the effects of both Gem and Gem-S in a viscoelastic-specific ECM model derived from PDAC patient-derived organoids, distinct responses based on matrix stiffness come to light. The physical properties of the matrix exert a significant influence on cellular function, thereby impacting the effectiveness of therapeutic agents. Intriguingly, within a stiffer environment, Gem-S demonstrates higher sensitivity compared to Gem, suggesting the potential application of Gem-S in the dense pathological PDAC environment. Further investigation reveals that Gem-S treatment induces a noteworthy increase in reactive oxygen species (ROS) and HIF-1 expression compared to Gem. Surprisingly, the role of multidrug transporters in Gem-S sensitivity is limited, while the downregulation of NRF (Nrf2) after Gem-S treatment hints at distinct mechanisms underlying the development of drug resistance. This study provides valuable insights into the intricate interplay between gemcitabine resistance and the PDAC microenvironment. Understanding the matrix-specific responses opens avenues for tailored therapeutic interventions, offering the potential for improved outcomes in PDAC patients. Citation Format: Bo Han, Shuqing Zhao, Edward Agyare, Xueyou Zhu, Jose Trevino, Sherise Rogers, Enrique Velazquez, Jason Brant, Payam Eliahoo, Jonathan Barajas, Ba Xuan Hoang. Impact of gemcitabine modification on redox-driven responses in pancreatic cancer organoids cultured in distinct 3D microenvironments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3167.

Abstract 6770: Acquired temozolomide resistance instructs patterns of glioblastoma cell motility and proteome expression within gelatin hydrogels

Abstract Acquired drug resistance in glioblastoma (GBM) presents a major clinical challenge and is one of the key factors contributing to the abysmal prognosis with less than 15 months median overall survival. The aggressive chemotherapy with the frontline therapeutic, temozolomide (TMZ), ultimately fails to kill residual, highly invasive tumor cells after surgical resection and radiotherapy. Here, we present a robust three-dimensional (3D) in vitro hydrogel model of acquired temozolomide (TMZ) resistance using isogenically-matched glioblastoma (GBM) cell lines. We demonstrate distinct drug response patterns between TMZ-sensitive and TMZ-resistant GBM cells, emphasizing our model's promise for future pre-clinical investigations aimed at developing novel therapies targeting drug-resistant GBM. Importantly, our model detects apoptosis-related protein changes in response to TMZ, validating its ability to study drug-induced molecular changes. Furthermore, our study delves into the migratory potential of GBM cells within the 3D extracellular matrix environment. Additionally, we uncover significant alterations in cytokine expression associated with matrix remodeling and angiogenesis, providing new avenues for therapeutic investigation. Although our findings are derived from a specific set of isogenically-matched cell lines, this model highlights the potential to explore personalized treatment strategies. Ongoing research in our lab is dedicated to gaining a more profound understanding of matrix remodeling and the migratory potential of TMZ-resistant GBM cells. Moreover, our future work will aim to expand our study to include a wider range of cell lines and patient-derived xenografts within our advanced microphysiological systems that include key elements of GBM tumor microenvironment such as perivascular niche. This endeavor seeks to establish connections between observed therapeutic behaviors and clinical outcomes, ultimately contributing to the development of more effective treatments for GBM patients. Citation Format: Viktoriia Kriuchkovskaia, Ela Eames, Rebecca Riggins, Brendan Harley. Acquired temozolomide resistance instructs patterns of glioblastoma cell motility and proteome expression within gelatin hydrogels [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6770.

Effects of lipids on the rate-limiting steps in the dark-to-light transition of Photosystem II core complex of Thermostichus vulcanus.

In our earlier works, we have shown that the rate-limiting steps, associated with the dark-to-light transition of Photosystem II (PSII), reflecting the photochemical activity and structural dynamics of the reaction center complex, depend largely on the lipidic environment of the protein matrix. Using chlorophyll-a fluorescence transients (ChlF) elicited by single-turnover saturating flashes, it was shown that the half-waiting time (Δτ 1/2) between consecutive excitations, at which 50% of the fluorescence increment was reached, was considerably larger in isolated PSII complexes of Thermostichus (T.) vulcanus than in the native thylakoid membrane (TM). Further, it was shown that the addition of a TM lipid extract shortened Δτ 1/2 of isolated PSII, indicating that at least a fraction of the 'missing' lipid molecules, replaced by detergent molecules, caused the elongation of Δτ 1/2. Here, we performed systematic experiments to obtain information on the nature of TM lipids that are capable of decreasing Δτ 1/2. Our data show that while all lipid species shorten Δτ 1/2, the negatively charged lipid phosphatidylglycerol appears to be the most efficient species - suggesting its prominent role in determining the structural dynamics of PSII reaction center.

Effect of cryogenic aging and test-environment on the tribological and mechanical properties of PEEK composites

This study investigated mechanical and tribological properties of polyetheretherketone (PEEK) and PEEK composites, before and after aging in liquid nitrogen for 5 months. Tribological tests conducted at 25 °C and at − 100 °C in air and in high vacuum (10−5 Pa) environment revealed the effect of matrix modification, fillers, environment, temperature, and cryogenic aging on their performances. Cryogenic aging of the polymers resulted in cryogenic embrittlement and decrease of the fracture toughness by around 10% and increase of wear rate by at least 20%. Very low coefficient of friction (0.02) was achieved in cryogenic vacuum environment for carbon fiber, graphite, and PTFE reinforced PEEK. The results indicate the significant impact of aging, temperature and environment on PEEK and its composites.

Modulation of Stiffness-Dependent Macrophage Inflammatory Responses by Collagen Deposition.

Macrophages are innate immune cells that interact with complex extracellular matrix environments, which have varied stiffness, composition, and structure, and such interactions can lead to the modulation of cellular activity. Collagen is often used in the culture of immune cells, but the effects of substrate functionalization conditions are not typically considered. Here, we show that the solvent system used to attach collagen onto a hydrogel surface affects its surface distribution and organization, and this can modulate the responses of macrophages subsequently cultured on these surfaces in terms of their inflammatory activation and expression of adhesion and mechanosensitive molecules. Collagen was solubilized in either acetic acid (Col-AA) or N-(2-hydroxyethyl)piperazine-N'-ethanesulfonic acid (HEPES) (Col-HEP) solutions and conjugated onto soft and stiff polyacrylamide (PA) hydrogel surfaces. Bone marrow-derived macrophages cultured under standard conditions (pH 7.4) on the Col-HEP-derived surfaces exhibited stiffness-dependent inflammatory activation; in contrast, the macrophages cultured on Col-AA-derived surfaces expressed high levels of inflammatory cytokines and genes, irrespective of the hydrogel stiffness. Among the collagen receptors that were examined, leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) was the most highly expressed, and knockdown of the Lair-1 gene enhanced the secretion of inflammatory cytokines. We found that the collagen distribution was more homogeneous on Col-AA surfaces but formed aggregates on Col-HEP surfaces. The macrophages cultured on Col-AA PA hydrogels were more evenly spread, expressed higher levels of vinculin, and exerted higher traction forces compared to those of cells on Col-HEP. These macrophages on Col-AA also had higher nuclear-to-cytoplasmic ratios of yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), key molecules that control inflammation and sense substrate stiffness. Our results highlight that seemingly slight variations in substrate deposition for immunobiology studies can alter critical immune responses, and this is important to elucidate in the broader context of immunomodulatory biomaterial design.

Biofabrication of biomimetic undulating microtopography at the dermal-epidermal junction and its effects on the growth and differentiation of epidermal cells.

The undulating microtopography located at the junction of the dermis and epidermis of the native skin is called rete ridges (RRs), which plays an important role in enhancing keratinocyte function, improving skin structure and stability, and providing three-dimensional (3D) microenvironment for skin cells. Despite some progress in recent years, most currently designed and manufactured tissue-engineered skin models still cannot replicate the RRs, resulting in a lack of biological signals in the manufactured skin models. In this study, a composite manufacturing method including electrospinning, 3D printing, and functional coating was developed to produce the epidermal models with RRs. Polycaprolactone (PCL) nanofibers were firstly electrospun to mimic the extracellular matrix environment and be responsible for cell attachment. PCL microfibers were then printed onto top of the PCL nanofibers layer by 3D printing to quickly prepare undulating microtopography and finally the entire structures were dip-coated with gelatin hydrogel to form a functional coating layer. The morphology, chemical composition, and structural properties of the fabricated models were studied. The results proved that the multi-process composite fabricated models were suitable for skin tissue engineering. Live and dead staining, cell counting kit-8 (CCK-8) as well as histology (haematoxylin and eosin (HE) methodology) and immunofluorescence (primary and secondary antibodies combination assay) were used to investigate the viability, metabolic activity, and differentiation of skin cells forin vitroculturing.In vitroresults showed that each model had high cell viability, good proliferation, and the expression of differentiation marker. It was worth noting that the sizes of the RRs affected the cell growth status of the epidermal models. In addition, the unique undulation characteristics of the epidermal-dermal junction can be reproduced in the developed epidermal models. Overall, thesein vitrohuman epidermal models can provide valuable reference for skin transplantation, screening and safety evaluation of drugs and cosmetics.

Nonspecific membrane-matrix interactions influence diffusivity of lipid vesicles in hydrogels

The diffusion of extracellular vesicles and liposomes in vivo is affected by different tissue environmental conditions and is of great interest in the development of liposome-based therapeutics and drug-delivery systems. Here, we use a bottom-up biomimetic approach to better isolate and study steric and electrostatic interactions and their influence on the diffusivity of synthetic large unilamellar vesicles in hydrogel environments. Single-particle tracking of these extracellular vesicle-like particles in agarose hydrogels as an extracellular matrix model shows that membrane deformability and surface charge affect the hydrogel pore spaces that vesicles have access to, which determines overall diffusivity. Moreover, we show that passivation of vesicles with PEGylated lipids, as often used in drug-delivery systems, enhances diffusivity, but that this effect cannot be fully explained with electrostatic interactions alone. Finally, we compare our experimental findings with existing computational and theoretical work in the field to help explain the nonspecific interactions between diffusing particles and gel matrix environments.

A Microfluidic-Fabricated Rod Sprayer for Nanoelectrospray Mass Spectrometry.

The nanoelectrosprayer is a key device in the hyphenation of nanoLC-ESI-MS, and its development plays a crucial role in pushing forward the mining depth of biological discovery and industrialization of omics science. In this work, a new type of nanoelectrospray emitter, a rod sprayer, was developed based on microfluidic manufacture. Due to its porous silica structure, the rod sprayer in effect worked as a multinozzle sprayer, which is composed of a bunch of micrometer sized spray channels. Without the need for sophisticated microfabrication equipment, a superclean environment, or a complicated assembling process, such sprayer rods can be facilely fabricated in a mass production style: 3,600 rods with excellent monodispersity have been fabricated in 1 h, and rod sprayers thus made have demonstrated excellent intraday, interday, and interbatch reproducibilities: RSD = 1.9, 4.9, and 6.1%, respectively. The rod sprayer can generate stable electrospray in a wide voltage range from 2.6 to 3.2 kV and flow rates from 50 to 1000 nL/min, covering typical flow rates of subnanoLC, nanoLC, to microLC, and work steadily even under complex matrix environments (e.g., Hank's balanced salt solution containing sodium, magnesium, and calcium ions) without clogging. Meanwhile, the rod sprayers exhibited 200-1800% ionization efficiency enhancement in comparison with commonly used tapered tip emitters, for small molecule drugs, peptides, and proteins, respectively, and provided a broadened linear dynamic range of 4 orders of magnitude. The excellent characteristics of the rod sprayer, together with its small size and mass production capacity, should provide a high quality, high durability, high consistency, and disposable use-supported nanoelectrospray solution for MS-based bioanalyses.

Targeting RORγ inhibits the growth and metastasis of hepatocellular carcinoma

Approximately 80%-90% of hepatocellular carcinomas (HCC) occur in a premalignant environment of fibrosis and abnormal extracellular matrix (ECM), highlighting an essential role of ECM in the tumorigenesis and progress of HCC. However, the determinants of ECM in HCC are poorly defined. Here, we show that nuclear receptor RORγ is highly expressed and amplified in HCC tumors. RORγ functions as an essential activator of the matrisome program via directly driving the expression of major ECM genes in HCC cells. Elevated RORγ increases fibronectin-1 deposition, cell-matrix adhesion, and collagen production, creating a favorable microenvironment to boost liver cancer metastasis. Moreover, RORγ antagonists effectively inhibit tumor growth and metastasis in multiple HCC xenografts and immune-intact models, and they effectively sensitize HCC tumors to sorafenib therapy in mice. Notably, elevated RORγ expression is associated with ECM remodeling and metastasis in patients with HCC. Taken together, we identify RORγ as a key player of ECM remodeling in HCC and as an attractive therapeutic target for advanced HCC.

Semifactives in comparatives

This is more complicated than I realized. How are we to understand the status of realize's complement in a sentence like this? What sort of relationship must this complement bear to its matrix environment, in light of realize's status as a cognitive factive or semifactive predicate (Kiparsky &amp; Kiparsky 1970; Karttunen 1971)? Comparative constructions, I suggest, do much to illuminate the nature of semifactives and the semantic–pragmatic status of their clausal complements. Specifically, I propose that semifactives support graded awareness—knowledge of something less, but not more, than the full truth with respect to some question or issue—while requiring that their complement be informationally consistent with the matrix environment, rather than presupposed true. The picture that emerges fits naturally with pragmatic approaches to presupposition generation and projection (Beaver 2010; Simons, Beaver, Roberts &amp; Tonhauser 2017; Degen &amp; Tonhauser 2022) and depends on sensitivity to scalar polarity and orientation (Kennedy 2001).

Functionalities of pH-responsive DNA nanostructures in tumor-targeted strategies.

Nanostructures integrating pH-sensitive DNA motifs have emerged as versatile platforms for active tumor targeting, owing to their ability to undergo conformation changes in response to the common acidic environment of the tumor extracellular matrix and endocytosis pathway. This review summarizes the latest advances in the design and application of various pH-responsive DNA nanostructures for tumor-targeted strategies, including tumor recognition, cell imaging, dynamic nanocarrier construction, and controlled drug release. A comprehensive framework for pH-controlled multi-stage tumor targeting is introduced, addressing the divergences in targeting strategies for extracellular and intracellular environments. The unique attributes, practical performance and application challenges of pH-responsive DNA nanostructures are also critically discussed to provide guidance for future development in this field.

Evaluation of bioactive extract nanoparticles on pulp stem cell behavior relevant to dental care using chemical composition of gelatin-Arabian gum nano polymer.

This study aimed to investigate the impact of bioactive plant extracts on the proliferation and migration of dental pulp stem cells (DPSCs) and their potential implications for dental care, focusing on the nurse-caring aspect. TDPSCs were cultured on gelatin polymer scaffolds mimicking the extracellular matrix (ECM) environment. Bioactive plant extracts with antibacterial, anti-inflammatory, and anti-oxidant properties were incorporated into the gelatin polymer at concentrations ranging from 0.1% to 2.0%. Proliferation and migration assays were performed, considering nurse-caring practices during the experiments. Treatment with specific bioactive plant extracts significantly enhanced DPSC proliferation, showing a 2.5-fold increase compared to the control groups. The migration assay revealed a substantial increase in cell migration distance, with treated cells covering an average distance of 400-500 μm compared to 220-260 μm in the control group. Treated cells also exhibited improved viability and metabolic activity, with a 30% increase in cell viability and a 10-20% increase in metabolic activity compared to the control group. This study demonstrates that bioactive plant extracts have the potential to enhance DPSC proliferation, migration, viability, and metabolic activity. These findings support the use of these extracts in dental care, benefiting from the nurse-caring practices.