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Living cells can perform incredible tasks that man-made micro/nano-sized robots have not yet been able to accomplish. One example is that white blood cells can sense and move to the site of pathogen attack within minutes. The robustness and precision of cellular functions have been perfected through billions of years of evolution. In this context, we ask the question whether cells follow a set of physical principles to sense, adapt, and migrate. Microfluidics has emerged as an enabling technology for recreating well-defined cellular environment for cell migration studies, and its ability to follow single cell dynamics allows for the results to be amenable for theoretical modeling. In this review, we focus on the development of microfluidic platforms for recreating cellular biophysical (e.g., mechanical stress) and biochemical (e.g., nutrients and cytokines) environments for cell migration studies in 3D. We summarize the basic principles that cells (including bacteria, algal, and mammalian cells) use to respond to chemical gradients learned from microfluidic systems. We also discuss about novel biological insights gained from studies of cell migration under biophysical cues and the need for further quantitative studies of cell function under well-controlled biophysical environments in the future.
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The risk for suffering immune checkpoint inhibitors (ICIs)-associated myocarditis increases in patients with pre-existing conditions and the mechanisms remain to be clarified. Spatial transcriptomics, single-cell RNA sequencing, and flow cytometry are used to decipher how anti-cytotoxic T lymphocyte antigen-4 m2a antibody (anti-CTLA-4 m2a antibody) aggravated cardiac injury in experimental autoimmune myocarditis (EAM) mice. It is found that anti-CTLA-4 m2a antibody increases cardiac fibroblast-derived C-X-C motif chemokine ligand 1 (Cxcl1), which promots neutrophil infiltration to the myocarditic zones (MZs) of EAM mice via enhanced Cxcl1-Cxcr2 chemotaxis. It is identified that the C-C motif chemokine ligand 5 (Ccl5)-neutrophil subpopulation is responsible for high activity of cytokine production, adaptive immune response, NF-κB signaling, and cellular response to interferon-gamma and that the Ccl5-neutrophil subpopulation and its-associated proinflammatory cytokines/chemokines promoted macrophage (Mφ) polarization to M1 Mφ. These altered infiltrating landscape and phenotypic switch of immune cells, and proinflammatory factors synergistically aggravated anti-CTLA-4 m2a antibody-induced cardiac injury in EAM mice. Neutralizing neutrophils, Cxcl1, and applying Cxcr2 antagonist dramatically alleviates anti-CTLA-4 m2a antibody-induced leukocyte infiltration, cardiac fibrosis, and dysfunction. It is suggested that Ccl5-neutrophil subpopulation plays a critical role in aggravating anti-CTLA-4 m2a antibody-induced cardiac injury in EAM mice. This data may provide a strategic rational for preventing/curing ICIs-associated myocarditis.
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Salinity stress has a great impact on crop growth and productivity and is one of the major factors responsible for crop yield losses. The K-homologous (KH) family proteins play vital roles in regulating plant development and responding to abiotic stress in plants. However, the systematic characterization of the KH family in rice is still lacking. In this study, we performed genome-wide identification and functional analysis of KH family genes and identified a total of 31 KH genes in rice. According to the homologs of KH genes in Arabidopsis thaliana, we constructed a phylogenetic tree with 61 KH genes containing 31 KH genes in Oryza sativa and 30 KH genes in Arabidopsis thaliana and separated them into three major groups. In silico tissue expression analysis showed that the OsKH genes are constitutively expressed. The qRT-PCR results revealed that eight OsKH genes responded strongly to salt stresses, and OsKH12 exhibited the strongest decrease in expression level, which was selected for further study. We generated the Oskh12-knockout mutant via the CRISPR/Cas9 genome-editing method. Further stress treatment and biochemical assays confirmed that Oskh12 mutant was more salt-sensitive than Nip and the expression of several key salt-tolerant genes in Oskh12 was significantly reduced. Taken together, our results shed light on the understanding of the KH family and provide a theoretical basis for future abiotic stress studies in rice.
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Regulación de la Expresión Génica de las Plantas , Familia de Multigenes , Oryza , Filogenia , Proteínas de Plantas , Estrés Salino , Oryza/genética , Oryza/metabolismo , Oryza/efectos de los fármacos , Oryza/crecimiento & desarrollo , Estrés Salino/genética , Regulación de la Expresión Génica de las Plantas/efectos de los fármacos , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Tolerancia a la Sal/genética , Arabidopsis/genética , Estrés Fisiológico/genéticaRESUMEN
As cells migrate through biological tissues, they must frequently squeeze through micron-sized constrictions in the form of interstitial pores between extracellular matrix fibers and/or other cells. Although it is now well recognized that such confined migration is limited by the nucleus, which is the largest and stiffest organelle, it remains incompletely understood how cells apply sufficient force to move their nucleus through small constrictions. Here, we report a mechanism by which contraction of the cell rear cortex pushes the nucleus forward to mediate nuclear transit through constrictions. Laser ablation of the rear cortex reveals that pushing forces behind the nucleus are the result of increased intracellular pressure in the rear compartment of the cell. The pushing forces behind the nucleus depend on accumulation of actomyosin in the rear cortex and require Rho kinase (ROCK) activity. Collectively, our results suggest a mechanism by which cells generate elevated intracellular pressure in the posterior compartment to facilitate nuclear transit through three-dimensional (3D) constrictions. This mechanism might supplement or even substitute for other mechanisms supporting nuclear transit, ensuring robust cell migrations in confined 3D environments.
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Movimiento Celular , Núcleo Celular , Núcleo Celular/metabolismo , Movimiento Celular/fisiología , Humanos , Actomiosina/metabolismo , Quinasas Asociadas a rho/metabolismo , Animales , Presión , RatonesRESUMEN
BACKGROUND: With rising breast augmentations worldwide, there is an increasing clinical need for an early and accurate detection of implant complications. PURPOSE: To compare the quality of chemical shift encoding-based (CSE) water-fat-silicone separation compared to double inversion recovery (DIR) silicone-only imaging in breast magnetic resonance imaging (MRI). MATERIAL AND METHODS: This retrospective, single-center study included women with silicone implants subjected to 3-T MRI between January 2021 and March 2022. MRI included (i) two-dimensional silicone-only T2-weighted turbo spin echo DIR acquisition and (ii) three-dimensional CSE imaging based on multi-echo gradient-echo sequence enabling water-, fat-, and silicone-image separation. Images were evaluated and compared by three independent radiologists using a clinically established rating including differentiability of the silicone implant, visibility and contouring of the adjacent fibrous capsule, and accuracy of intralesional folds in a ranking of 1-5. The apparent contrast-to-noise (aCNR) was calculated. RESULTS: In 71 women, the average quality of water-fat-silicone images from CSE imaging was assessed as "good" (assessment 4 ± 0.9). In 68 (96%) patients, CSE imaging achieved a concise delineation of the silicone implant and precise visualization of the fibrous capsule that was not distinguishable in DIR imaging. Implant ruptures were more easily detected in CSE imaging. The aCNR was higher in CSE compared to DIR imaging (18.43 ± 9.8 vs. 14.73 ± 2.5; P = 0.002). CONCLUSION: Intrinsically co-registered water-fat-silicone-separated CSE-based images enable a reliable assessment of silicone implants. The simultaneously improved differentiability of the implant and fibrous capsule may provide clinicians with a valuable tool for an accurate evaluation of implant integrity and early detection of potential complications.
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Implantes de Mama , Imagen por Resonancia Magnética , Siliconas , Humanos , Femenino , Estudios Retrospectivos , Imagen por Resonancia Magnética/métodos , Adulto , Persona de Mediana Edad , Mama/diagnóstico por imagen , Agua , Tejido Adiposo/diagnóstico por imagen , Geles de Silicona , AncianoRESUMEN
Endosperm, the major storage organ in cereal grains, determines the grain yield and quality. Mitochondria provide the energy for dry matter accumulation, in the endosperm development. Although mitochondrial single-stranded DNA-binding proteins (mtSSBs) play a canonical role in the maintenance of single-stranded mitochondrial DNA, their molecular functions in RNA processing and endosperm development remain obscure. Here, we report a defective rice endosperm mutant, floury endosperm26 (flo26), which develops abnormal starch grains in the endosperm. Map-based cloning and complementation experiments showed that FLO26 allele encodes a mitochondrial single-stranded DNA-binding protein, named as mtSSB1.1. Loss of function of mtSSB1.1 affects the transcriptional level of many mitochondrially-encoded genes and RNA splicing of nad1, a core component of respiratory chain complex I in mitochondria. As a result, dysfunctional mature nad1 led to dramatically decreased complex I activity, thereby reducing ATP production. Our results reveal that mtSSB1.1 plays an important role in the maintenance of mitochondrial function and endosperm development by stabilizing the splicing of mitochondrial RNA in rice.
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Endospermo , Oryza , Proteínas de Plantas , Empalme del ARN , Oryza/genética , Oryza/metabolismo , Oryza/crecimiento & desarrollo , Endospermo/genética , Endospermo/metabolismo , Endospermo/crecimiento & desarrollo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Genes Mitocondriales , Mitocondrias/metabolismo , Mitocondrias/genética , Regulación de la Expresión Génica de las PlantasRESUMEN
BACKGROUND/OBJECTIVES: Weight loss outcomes vary individually. Magnetic resonance imaging (MRI)-based evaluation of adipose tissue (AT) might help to identify AT characteristics that predict AT loss. This study aimed to assess the impact of an 8-week low-calorie diet (LCD) on different AT depots and to identify predictors of short-term AT loss using MRI in adults with obesity. METHODS: Eighty-one adults with obesity (mean BMI 34.08 ± 2.75 kg/m², mean age 46.3 ± 10.97 years, 49 females) prospectively underwent baseline MRI (liver dome to femoral head) and anthropometric measurements (BMI, waist-to-hip-ratio, body fat), followed by a post-LCD-examination. Visceral and subcutaneous AT (VAT and SAT) volumes and AT fat fraction were extracted from the MRI data. Apparent lipid volumes based on MRI were calculated as approximation for the lipid contained in the AT. SAT and VAT volumes were subdivided into equidistant thirds along the craniocaudal axis and normalized by length of the segmentation. T-tests compared baseline and follow-up measurements and sex differences. Effect sizes on subdivided AT volumes were compared. Spearman Rank correlation explored associations between baseline parameters and AT loss. Multiple regression analysis identified baseline predictors for AT loss. RESULTS: Following the LCD, participants exhibited significant weight loss (11.61 ± 3.07 kg, p < 0.01) and reductions in all MRI-based AT parameters (p < 0.01). Absolute SAT loss exceeded VAT loss, while relative apparent lipid loss was higher in VAT (both p < 0.01). The lower abdominopelvic third showed the most significant SAT and VAT reduction. The predictor of most AT and apparent lipid losses was the normalized baseline SAT volume in the lower abdominopelvic third, with smaller volumes favoring greater AT loss (p < 0.01 for SAT and VAT loss and SAT apparent lipid volume loss). CONCLUSIONS: The LCD primarily reduces lower abdominopelvic SAT and VAT. Furthermore, lower abdominopelvic SAT volume was detected as a potential predictor for short-term AT loss in persons with obesity.
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Sex-specific abdominal organ volume and proton density fat fraction (PDFF) in people with obesity during a weight loss intervention was assessed with automated multiorgan segmentation of quantitative water-fat MRI. An nnU-Net architecture was employed for automatic segmentation of abdominal organs, including visceral and subcutaneous adipose tissue, liver, and psoas and erector spinae muscle, based on quantitative chemical shift-encoded MRI and using ground truth labels generated from participants of the Lifestyle Intervention (LION) study. Each organ's volume and fat content were examined in 127 participants (73 female and 54 male participants; body mass index, 30-39.9 kg/m2) and in 81 (54 female and 32 male participants) of these participants after an 8-week formula-based low-calorie diet. Dice scores ranging from 0.91 to 0.97 were achieved for the automatic segmentation. PDFF was found to be lower in visceral adipose tissue compared with subcutaneous adipose tissue in both male and female participants. Before intervention, female participants exhibited higher PDFF in subcutaneous adipose tissue (90.6% vs 89.7%; P < .001) and lower PDFF in liver (8.6% vs 13.3%; P < .001) and visceral adipose tissue (76.4% vs 81.3%; P < .001) compared with male participants. This relation persisted after intervention. As a response to caloric restriction, male participants lost significantly more visceral adipose tissue volume (1.76 L vs 0.91 L; P < .001) and showed a higher decrease in subcutaneous adipose tissue PDFF (2.7% vs 1.5%; P < .001) than female participants. Automated body composition analysis on quantitative water-fat MRI data provides new insights for understanding sex-specific metabolic response to caloric restriction and weight loss in people with obesity. Keywords: Obesity, Chemical Shift-encoded MRI, Abdominal Fat Volume, Proton Density Fat Fraction, nnU-Net ClinicalTrials.gov registration no. NCT04023942 Supplemental material is available for this article. Published under a CC BY 4.0 license.
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Grasa Abdominal , Imagen por Resonancia Magnética , Humanos , Masculino , Femenino , Imagen por Resonancia Magnética/métodos , Grasa Abdominal/diagnóstico por imagen , Persona de Mediana Edad , Adulto , Factores Sexuales , Obesidad/diagnóstico por imagen , Obesidad/dietoterapia , Protones , Restricción CalóricaRESUMEN
Natural killer (NK) cell-based immunotherapy holds promise for cancer treatment; however, its efficacy remains limited, necessitating the development of alternative strategies. Here, we report that venetoclax, an FDA-approved BCL-2 inhibitor, directly activates NK cells, enhancing their cytotoxicity against acute myeloid leukemia (AML) both in vitro and in vivo, likely independent of BCL-2 inhibition. Through comprehensive approaches, including bulk and single-cell RNA sequencing, avidity measurement, and functional assays, we demonstrate that venetoclax increases the avidity of NK cells to AML cells and promotes lytic granule polarization during immunological synapse (IS) formation. Notably, we identify a distinct CD161lowCD218b+ NK cell subpopulation that exhibits remarkable sensitivity to venetoclax treatment. Furthermore, venetoclax promotes mitochondrial respiration and ATP synthesis via the NF-κB pathway, thereby facilitating IS formation in NK cells. Collectively, our findings establish venetoclax as a multifaceted immunometabolic modulator of NK cell function and provide a promising strategy for augmenting NK cell-based cancer immunotherapy.
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Compuestos Bicíclicos Heterocíclicos con Puentes , Inmunoterapia Adoptiva , Células Asesinas Naturales , Leucemia Mieloide Aguda , Sulfonamidas , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/efectos de los fármacos , Humanos , Sulfonamidas/farmacología , Animales , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/patología , Ratones , Inmunoterapia Adoptiva/métodos , Línea Celular Tumoral , FN-kappa B/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Ratones Endogámicos NODRESUMEN
Uncontrolled growth of tumor cells in confined spaces leads to the accumulation of compressive stress within the tumor. Although the effects of tension within 3D extracellular matrices (ECMs) on tumor growth and invasion are well established, the role of compression in tumor mechanics and invasion is largely unexplored. In this study, we modified a Transwell assay such that it provides constant compressive loads to spheroids embedded within a collagen matrix. We used microscopic imaging to follow the single cell dynamics of the cells within the spheroids, as well as invasion into the 3D ECMs. Our experimental results showed that malignant breast tumor (MDA-MB-231) and non-tumorigenic epithelial (MCF10A) spheroids responded differently to a constant compression. Cells within the malignant spheroids became more motile within the spheroids and invaded more into the ECM under compression; whereas cells within non-tumorigenic MCF10A spheroids became less motile within the spheroids and did not display apparent detachment from the spheroids under compression. These findings suggest that compression may play differential roles in healthy and pathogenic epithelial tissues and highlight the importance of tumor mechanics and invasion.
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Neoplasias , Esferoides Celulares , Humanos , Colágeno , Matriz Extracelular , Línea Celular TumoralRESUMEN
A mechanistic understanding of algal growth is essential for maintaining a sustainable environment in an era of climate change and population expansion. It is known that algal growth is tightly controlled by complex interactive physical and chemical conditions. Many mathematical models have been proposed to describe the relation of algal growth and environmental parameters, but experimental verification has been difficult due to the lack of tools to measure cell growth under precise physical and chemical conditions. As such, current models depend on the specific testing systems, and the fitted growth kinetic constants vary widely for the same organisms in the existing literature. Here, we present a microfluidic platform where both light intensity and nutrient gradients can be well controlled for algal cell growth studies. In particular, light shading is avoided, a common problem in macroscale assays. Our results revealed that light and nitrogen colimit the growth of algal cells, with each contributing a Monod growth kinetic term in a multiplicative model. We argue that the microfluidic platform can lead towards a general culture system independent algal growth model with systematic screening of many environmental parameters. Our work advances technology for algal cell growth studies and provides essential information for future bioreactor designs and ecological predictions.
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Luz , Nitrógeno , Nitrógeno/metabolismo , Microalgas/crecimiento & desarrollo , Microalgas/metabolismo , Cinética , Modelos BiológicosRESUMEN
Tumor spheroids are in vitro three-dimensional, cellular collectives consisting of cancerous cells. Embedding these spheroids in an in vitro fibrous environment, such as a collagen network, to mimic the extracellular matrix (ECM) provides an essential platform to quantitatively investigate the biophysical mechanisms leading to tumor invasion of the ECM. To understand the mechanical interplay between tumor spheroids and the ECM, we computationally construct and study a three-dimensional vertex model for a tumor spheroid that is mechanically coupled to a cross-linked network of fibers. In such a vertex model, cells are represented as deformable polyhedrons that share faces. Some fraction of the boundary faces of the tumor spheroid contain linker springs connecting the center of the boundary face to the nearest node in the fiber network. As these linker springs actively contract, the fiber network remodels. By toggling between fluid-like and solid-like spheroids via changing the dimensionless cell shape index, we find that the spheroid rheology affects the remodeling of the fiber network. More precisely, fluid-like spheroids displace the fiber network more on average near the vicinity of the spheroid than solid-like spheroids. We also find more densification of the fiber network near the spheroid for the fluid-like spheroids. These spheroid rheology-dependent effects are the result of cellular motility due to active cellular rearrangements that emerge over time in the fluid-like spheroids to generate spheroid shape fluctuations. Our results uncover intricate morphological-mechanical interplay between an embedded spheroid and its surrounding fiber network with both spheroid contractile strength and spheroid shape fluctuations playing important roles in the pre-invasion stages of tumor invasion.
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Cell migration is critical for tissue development and regeneration but requires extracellular environments that are conducive to motion. Cells may actively generate migratory routes in vivo by degrading or remodeling their environments or instead utilize existing extracellular matrix microstructures or microtracks as innate pathways for migration. While hydrogels in general are valuable tools for probing the extracellular regulators of 3-dimensional migration, few recapitulate these natural migration paths. Here, we develop a biopolymer-based bicontinuous hydrogel system that comprises a covalent hydrogel of enzymatically crosslinked gelatin and a physical hydrogel of guest and host moieties bonded to hyaluronic acid. Bicontinuous hydrogels form through controlled solution immiscibility, and their continuous subdomains and high micro-interfacial surface area enable rapid 3D migration, particularly when compared to homogeneous hydrogels. Migratory behavior is mesenchymal in nature and regulated by biochemical and biophysical signals from the hydrogel, which is shown across various cell types and physiologically relevant contexts (e.g., cell spheroids, ex vivo tissues, in vivo tissues). Our findings introduce a design that leverages important local interfaces to guide rapid cell migration.
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Matriz Extracelular , Hidrogeles , Hidrogeles/química , Movimiento Celular , Matriz Extracelular/metabolismo , Esferoides Celulares , Biopolímeros/metabolismoRESUMEN
Therapeutic resistance and metastasis largely contribute to mortality from breast cancer and therefore understanding the underlying mechanisms of such remains an urgent challenge. By cross-analysis of TCGA and GEO databases, LINC00460 was identified as an oncogenic long non-coding RNA, highly expressed in Doxorubicin resistant breast cancer. LINC00460 was further demonstrated to promote stem cell-like and epithelial-mesenchymal transition (EMT) characteristics in breast cancer cells. LINC00460 interacts with FUS protein with consequent enhanced stabilization, which further promotes MYC mRNA maturation. LINC00460 expression was transcriptionally enhanced by c-MYC protein, forming a positive feedback loop to promote metastasis and Doxorubicin resistance. LINC00460 depletion in Doxorubicin-resistant breast cancer cells restored sensitivity to Doxorubicin and increased the efficacy of c-MYC inhibitor therapy. Collectively, these findings implicate LINC00460 as a promising prognostic biomarker and potential therapeutic target to overcome Doxorubicin resistance in breast cancer.
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Reprogramming of energy metabolism exerts pivotal functions in cancer progression and immune surveillance. Identification of the mechanisms mediating metabolic changes in cancer may lead to improved strategies to suppress tumor growth and stimulate antitumor immunity. Here, it was observed that the secretomes of hypoxic breast cancer cells and breast cancer stem cells (BCSC) induced reprogramming of metabolic pathways, particularly glycolysis, in normoxic breast cancer cells. Screening of the BCSC secretome identified MIF as a pivotal factor potentiating glycolysis. Mechanistically, MIF increased c-MYC-mediated transcriptional upregulation of the glycolytic enzyme aldolase C by activating WNT/ß-catenin signaling. Targeting MIF attenuated glycolysis and impaired xenograft growth and metastasis. MIF depletion in breast cancer cells also augmented intratumoral cytolytic CD8+ T cells and proinflammatory macrophages while decreasing regulatory T cells and tumor-associated neutrophils in the tumor microenvironment. Consequently, targeting MIF improved the therapeutic efficacy of immune checkpoint blockade in triple-negative breast cancer. Collectively, this study proposes MIF as an attractive therapeutic target to circumvent metabolic reprogramming and immunosuppression in breast cancer. SIGNIFICANCE: MIF secreted by breast cancer stem cells induces metabolic reprogramming in bulk tumor cells and engenders an immunosuppressive microenvironment, identifying MIF targeting as a strategy to improve immunotherapy efficacy in breast cancer.
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Neoplasias de la Mama , Factores Inhibidores de la Migración de Macrófagos , Humanos , Femenino , Neoplasias de la Mama/patología , Reprogramación Metabólica , Evasión Inmune , Glucólisis , Células Madre Neoplásicas/patología , Microambiente Tumoral , Factores Inhibidores de la Migración de Macrófagos/genética , Factores Inhibidores de la Migración de Macrófagos/metabolismo , Oxidorreductasas Intramoleculares/metabolismoRESUMEN
Cell traction force plays a critical role in directing cellular functions, such as proliferation, migration, and differentiation. Current understanding of cell traction force is largely derived from 2D measurements where cells are plated on 2D substrates. However, 2D measurements do not recapitulate a vital aspect of living systems; that is, cells actively remodel their surrounding extracellular matrix (ECM), and the remodeled ECM, in return, can have a profound impact on cell phenotype and traction force generation. This reciprocal adaptivity of living systems is encoded in the material properties of biological gels. In this review, we summarize recent progress in measuring cell traction force for cells embedded within 3D biological gels, with an emphasis on cell-ECM cross talk. We also provide perspectives on tools and techniques that could be adapted to measure cell traction force in complex biochemical and biophysical environments.
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Matriz Extracelular , Esferoides Celulares , Humanos , Matriz Extracelular/metabolismo , Esferoides Celulares/citología , Animales , Movimiento Celular , Geles/química , Adhesión Celular , Microscopía de Fuerza Atómica/métodos , Análisis de la Célula Individual/métodos , Hidrogeles/químicaRESUMEN
ZMIZ1 acts as an oncogene in hepatocellular carcinoma (HCC). circZMIZ1 (hsa_circ_0018964) derives from ZMIZ1; its underlying mechanism in HCC has not been reported. Peripheral blood and peripheral blood mononuclear cells (PBMCs) were obtained from HCC patients and healthy volunteers. CD8+ T cells were sorted from PBMCs of HCC patients. Applying flow cytometry, cell apoptosis and the proportion of KCNJ2/CD8+ T cells were examined. The cytotoxicity of CD8+ T cells against HCC cells was evaluated. The interaction among circZMIZ1, miR-15a-5p, and KCNJ2 was investigated by dual luciferase assay, RNA immunoprecipitation, and RNA pull-down assay. An orthotopic mouse model of HCC was constructed by intrahepatic injection of H22 cells. Upregulation of circZMIZ1 and KCNJ2 and downregulation of miR-15a-5p were observed in peripheral blood and PBMCs of HCC patients. The proportion of KCNJ2/CD8+ T cells was also increased in HCC patients. circZMIZ1 knockdown restrained apoptosis of CD8+ T cells and elevated cytotoxicity of CD8+ T cells. Mechanically speaking, circZMIZ1 elevated KCNJ2 expression by sponging miR-15a-5p. miR-15a-5p inhibitor reversed circZMIZ1 silencing-mediated inhibition of apoptosis and promotion of cytotoxicity in CD8+ T cells. In vivo, orthotopic mice of HCC exhibited increased expression of circZMIZ1 and KCNJ2, elevated proportion of KCNJ2/CD8+ T cells, and decreased expression of miR-15a-5p. This work demonstrated that circZMIZ1 inhibited the anti-tumor activity of CD8+ T cells in HCC by regulating the miR-15a-5p/KCNJ2 axis. This provides a theoretical basis for the development of effective circZMIZ1 in tumor immunotherapy.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroARNs , Animales , Humanos , Ratones , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Linfocitos T CD8-positivos/patología , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Leucocitos Mononucleares/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , MicroARNs/genéticaRESUMEN
Recently, water contamination caused by the misuse of antibiotics has become a growing concern. In this study, an economical chitin/calcite composite (CCA) was extracted from crab shell waste, and the effects and mechanisms of its removal of ciprofloxacin (CIP) and tetracycline (TC) from aqueous solution were investigated. The functional groups of chitin and the metal phase of calcite gave CCA the ability to remove antibiotics. Experiments on kinetics, isothermal adsorption, thermodynamics, co-removal, and reusability were conducted to systematically explore the adsorption performances of CCA toward antibiotics. The pseudo-second-order (FSO) and Langmuir models suited the data obtained from experiments best and displayed a good fit for the chemisorption and a certain homogeneity of adsorption sites. At 25 °C, the maximum adsorption capacities (Qmax) toward CIP and TC were 228.86 and 150.76 mg g-1, respectively. The adsorption mechanisms of CCA with TC and CIP are pH dependent since pH can affect the surface charge of CCA and the form in which CIP and TC are existing. The X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared (FTIR) demonstrated that the keto-O and carboxyl groups of CIP and the carbonyl, hydroxyl, and amido groups of TC could be responsible for the binding with the calcite and the functional groups of chitin through surface complexation, cation bridge and hydrogen bonding.
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Ciprofloxacina , Contaminantes Químicos del Agua , Ciprofloxacina/química , Carbonato de Calcio , Quitina , Antibacterianos/química , Tetraciclina/química , Contaminantes Químicos del Agua/análisis , Adsorción , Cinética , Concentración de Iones de Hidrógeno , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
To evaluate the effect of relieving urinary tract obstructions (RUO) on the risk of gouty arthritis in patients with postrenal obstructions and hyperuricemia. We retrospectively analyzed the clinical data of 130 patients with urinary tract obstructions at Rongcheng People's Hospital from 2018 to 2021. Patients were divided into groups A (n = 62) and B (n = 68) according to the treatment method. Patients in group A underwent conservative treatments, such as drugs, extracorporeal shock wave lithotripsy (ESWL), and hemodialysis. Patients in Group B underwent catheterization, cystostomy, nephrostomy, or double J ureteral catheterization for rapid RUO. The ages of groups A and B were 58.40 ± 17.69 and 59.63 ± 16.12 years, respectively (P = .42). Before treatment, the serum uric acid values were 572.05 ± 106.93 and 567.79 ± 97.21 µmol/L, respectively (P = .94); serum creatinine values were 226.66 ± 269.67 and 280.15 ± 200.75 µmol/L, respectively (P = .88); and urine volumes were 913.23 ± 481.92 and 886.18â ±â 552.72 mL/24 h, respectively (P = .08). No significant differences in the general data were identified between the two groups (Pâ >â .05). The effects of the two treatments on the incidence of gout in patients with hyperuricemia complicated by postrenal obstruction were compared based on changes in uric acid level, creatinine level, and urine volume within 1 week after treatment. Multivariate logistic regression analysis was used to analyze clinical factors that increased the incidence of gout after RUO. The gout incidence rates in group A before and after treatment were 8.1% (5/62) and 6.5% (4/62), respectively (Pâ >â .99). The gout incidence rates in group B before and after treatment were 4.4% (3/68) and 19.1% (10/68), respectively (P = .01). Group B had a statistically significant increase in the gout incidence rate after RUO (Pâ <â .05). Multivariate logistic regression analysis showed that having an ageâ >â 60 years, urine volume ≤400 mL/24 h, and creatinine levelâ >â 186 µmol/L before treatment were risk factors for gout in patients with hyperuricemia after RUO. Relieving urinary tract obstruction increases the risk of gouty arthritis in patients with hyperuricemia and acute postrenal obstruction. Age, urine volume, and creatinine levels before treatment are risk factors for gout in patients with hyperuricemia after RUO.