SEARCH · Search NASA
Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Radiation-induced pulmonary fibrosis (RIPF) is a long-term side effect of thoracic radiation therapy. Hypoxia-induced vascular endothelial mesenchymal transition (EndMT) can occur during the development of RIPF. Here, we examined the direct contribution of endothelial HIF-1α (EC-HIF1α) on RIPF.
To investigate whether the vascular collapse in tumors by conventional dose rate (CONV) irradiation (IR) would also occur by the ultra-high dose rate FLASH IR.
Diffuse intrinsic pontine gliomas (DIPGs) arise in the pons and are the leading cause of death from brain tumors in children. DIPGs are routinely treated with radiation therapy, which temporarily improves neurological symptoms but generally fails to achieve local control. Because numerous clinical trials have not improved survival from DIPG over standard radiation therapy alone, there is a pressing need to evaluate new therapeutic strategies for this devastating disease. Vascular damage caused by radiation therapy can increase the permeability of tumor blood vessels and promote tumor cell death.
Estimates of fractional cover (fCover) across given land surfaces are used to assess, and often model, vegetation composition and diversity, which are crucial for understanding the health and functioning of terrestrial ecosystems. Remote sensing provides a useful means for scaling local, plot-measured fCover estimates to regional scales. Leveraging a recently synthesized and harmonized plot database, this study generated wall-to-wall maps of fCover for six Alaskan-Arctic plant functional types (PFT), including non-vascular plants, forbs, graminoids, and deciduous and evergreen shrubs, using 20-m satellite data (Sentinel-1, Sentinel-2, ArcticDEM) using a machine learning regression approach, specifically the random forest (RF) algorithm, which is well-suited for handling nonlinear relationships and high-dimensional satellite datasets. This study additionally addressed the spatio-temporal inconsistencies e.g., sampling scale, plot size, and collection year in plot measured fCover by adopting a multivariate outlier detection approach—Cook’s distance—to identify high-quality plots for model training and validation. Our approach achieves high accuracy (R 2 = 0.59–0.93, root mean squared errors = 0.02–0.10 for all PFTs) between plot-observed and satellite-derived fCover when using high-quality plot samples. The mapped fCover characterizes the spatial patterns of different PFTs across the tundra biome at a 20-m resolution, providing key information needed for improved representation of Arctic tundra vegetation in terrestrial biosphere models to better understand climate-vegetation feedback across the Arctic tundra.
Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is a mechanical system that provides rapid and short-term support for patients with cardiac failure. In many patients, pulmonary function is also impaired, resulting in poorly-oxygenated cardiac outflow competing against well-oxygenated VA-ECMO outflow, a condition known as North-South syndrome. North-South syndrome is a primary concern because of its potential to cause cerebral hypoxia, which has a critical influence on neurological complications often seen in this patient population. In order to reduce ischemic neurological complications, it is important to understand how clinical decisions regarding VA-ECMO parameters influence blood oxygenation. In our work, we studied the impacts of flow rate and cannulation site on oxygenation using a one-dimensional (1D) model to simulate blood flow. Our model was initially tested by comparing blood flow results to those observed from experimental work in VA-ECMO patients. The 1D model was combined with a two-phase flow model to simulate oxygenation. Additionally, the influence of various other clinician-tunable parameters on oxygenation in the common carotid arteries (CCAs) were tested, including, blood viscosity, cannula position within the insertion artery, heart rate, and systemic vascular resistance (SVR), as well as geometrical changes such as arterial radius and length. Our results indicated that blood oxygenation to the brain strongly depended on the cannula insertion site and the VA-ECMO flow rate with a weaker but potentially significant dependence on arterial radius. During femoral cannulation, VA-ECMO flow rates greater than ~4.9 L/min were needed to perfuse the CCAs. However, axillary and central cannulation began to perfuse the CCAs at significantly lower flow (~1 L/min). These results may help explain the incidence of cerebral hypoxia in this patient population and the common need to change cannulation strategies during treatment to address this clinical problem. While this work describes patient-averaged results, determining these relationships between VA-ECMO parameters and cerebral hypoxia is an important step towards future work to develop patient-specific models that clinicians can use to improve outcomes.
Explore the source record for details and available documents.
Prescribing inlet boundary conditions for computational fluid dynamics (CFD) simulations of internal flow in complex geometries such as anatomical vascular models is challenging. In the absence of patient-specific inlet velocity data, a common approach for long blood vessels is to assume that the inlet flow is fully developed. In vessels of irregular cross section, however, prescribing fully developed conditions is complicated due to the lack of a general closed-form analytical solution. In this study, we develop a simple Poisson equation method for prescribing fully developed inlet conditions for the flow of either Newtonian or non-Newtonian fluids in CFD models of arbitrary cross-section. We first derive the generalized Poisson equation for fully developed flow of a non-Newtonian fluid and we then develop and verify a methodology for numerically computing the solution on any planar boundary domain. In addition, we develop a simple extension of the method for prescribing a non-orthogonal inlet velocity that represents fully developed flow from an upstream tube that is connected to the CFD inlet at a non-orthogonal angle. This may be used to investigate a common source of uncertainty in CFD simulations of internal flow that is due to a lack of information concerning the exact streamwise flow direction at the inlets. Comparison to several Newtonian and non-Newtonian benchmark verification solutions shows the method to be extremely accurate. As a practical demonstration case, we use the method to prescribe fully developed conditions on multiple non-circular inlets for the non-Newtonian flow of blood in a patient-specific model of the inferior vena cava (IVC). Finally, we further demonstrate the utility of the method by performing a sensitivity study using the patient-specific IVC model, wherein we investigate the influence of inlet velocity flow direction on the non-Newtonian IVC hemodynamics. Given its simplicity and computational efficiency, the method is shown to be far superior to alternative approaches for prescribing fully developed inlet conditions in such complicated geometries. In conclusion, to facilitate the adoption of our Poisson equation method, we have distributed our OpenFOAM source code and the associated test cases from this study as open-source software.
Xylan is the second most abundant polysaccharide in plant biomass. It is a crucial component of cell wall structure as well as a significant factor contributing to biomass recalcitrance. Xylan consists of a linear chain of β-1,4-linked xylosyl residues that are often substituted with glycosyl side chains, such as glucuronosyl/methylglucuronosyl and arabinofuranosyl residues, and acetylated at O-2 and/or O-3. Xylan from gymnosperms and dicots contains a unique reducing end tetrasaccharide sequence that is not detected in xylan from grasses, bryophytes and seedless vascular plants. Grass xylan is heavily decorated at O-3 with arabinofuranosyl residues that are frequently esterified with hydroxycinnamates. Further, genetic and biochemical studies have uncovered a number of genes involved in xylan backbone elongation and acetylation, xylan glycosyl substitutions and their modifications, and the synthesis of the unique xylan reducing end tetrasaccharide sequence, but some outstanding issues on the biosynthesis of xylan still remain unanswered. Here, we provide a brief overview of xylan structure and focus on discussion of the current understanding and open questions on xylan biosynthesis. Further elucidation of the biochemical mechanisms underlying xylan biosynthesis will not only shed new insights into cell wall biology but also provide molecular tools for genetic modification of biomass composition tailored for diverse end uses.
A suite of biomarkers, including amino acids, pigments, and lignin phenols coupled with high resolution mass spectrometry were used to evaluate differences in the sources and fate of organic matter (OM) in Everglades treatment wetlands as a model for OM cycling in shallow water wetlands. Five components of the system (water column particulate organic matter, vertical traps, flocculent material, periphyton, and surface soil) were assessed for OM transformations down-profile (i.e. water column to soil) and between treatment cells dominated by emergent aquatic vegetation (EAV) and submerged aquatic vegetation (SAV), with comparisons to reference sites that resemble historic Everglades conditions. We found that OM cycling is fundamentally different between EAV and SAV wetlands, and that SAV wetlands have some shared characteristics with similar habitats in the Everglades. Other than locations densely populated by Typha spp., water column particulate organic C was derived from microbial/cryptomonad sources, rather than macroscopic sources (vascular plants and algal mats). Bacterial amino acid biomarkers were positively correlated with amino acid degradation indices and organic P (Po), respectively suggesting that microbial abundance is associated with "fresher" OM, and that further investigation into relationships between microbial biomass and Po is warranted. Overall, this multi-biomarker approach can evaluate the relative "freshness" of OM pools, identify sources of OM, and highlight the importance of water column processes in shallow water wetlands.
Kidney Ankyrin Repeat-containing Proteins (KANKs) comprise a family of four evolutionary conserved proteins (KANK1 to 4) that localize to the belt of mature focal adhesions (FAs) where they regulate integrin-mediated adhesion, actomyosin contractility, and link FAs to the cortical microtubule stabilization complex (CMSC). The human KANK proteins were first identified in kidney and have been associated with kidney cancer and nephrotic syndrome. Here, we report the distributions and subcellular localizations of the four Kank mRNAs and proteins in mouse tissues. We found that the KANK family members display distinct and rarely overlapping expression patterns. Whereas KANK1 is expressed at the basal side of epithelial cells of all tissues tested, KANK2 expression is mainly observed at the plasma membrane and/or cytoplasm of mesenchymal cells and KANK3 exclusively in vascular and lymphatic endothelial cells. KANK4 shows the least widespread expression pattern and when present, overlaps with KANK2 in contractile cells, such as smooth muscle cells and pericytes. Our findings show that KANKs are widely expressed in a cell type-specific manner, which suggests that they have cell- and tissue-specific functions.
Highlights: • Serum PAI-2 is decreased in patients with pulmonary arterial hypertension. • Serum PAI-2 is associated with disease severity in pulmonary arterial hypertension. • Exogenous PAI-2 attenuates monocrotaline induced pulmonary hypertension in rats. • PAI-2 inhibits pulmonary arterial smooth muscle proliferation via PI3K/Akt and ERK. The proliferation of pulmonary arterial smooth muscle cells (PASMCs) and subsequent pulmonary vascular remodeling leads to pulmonary arterial hypertension (PAH). Understanding the underlying mechanisms and identifying molecules that can suppress PASMCs proliferation is critical for developing effective pharmacological treatment. We previously showed that plasminogen activator inhibitor-2 (PAI-2) inhibited human PASMC (hPASMCs) proliferation in vitro. However, its inhibitory effect on PAH remains to be determined, and the mechanism remains to be illustrated.
Ovarian metastases exfoliate from the primary tumor and it is thought that aggregation supports their survival in the peritoneal cavity during dissemination but the underlying mechanisms are not clearly identified. We have previously shown that ovarian cancer cells acquire an increasingly glycolytic and metabolic flexible phenotype during progression. In the present study, we investigated how hypoxia, aggregation, and the incorporation of the obese stromal vascular fraction (SVF) affect cellular metabolism and the response to common anti-cancer and anti-diabetic drugs. Our results show a reduction of glucose uptake, lactate secretion, cellular respiration and ATP synthesis in response to hypoxia and aggregation, suggesting that the observed reduced proliferation of cells aggregated into spheroids is the result of a down-regulation of respiration. Recruitment of SVF to spheroids increased the spheroids invasive capacity but reduced respiration only in the most aggressive cells. Further, aggregation and hypoxia reduced the response to the metabolic drugs AICAR and metformin, and the chemotherapeutic agents cisplatin and paclitaxel. Our results suggest that the adaptation of cellular metabolism may contribute to enhanced survival under non-permissive conditions, and that these metabolic alterations may provide targets for future interventions that aim to enhance the survival of women with metastatic ovarian cancer.
Highlights: F0B7 • LMPs possess strong angiogenesis-inhibiting properties. F0B7 • LMPs suppress Müller cell-derived angiogenic/chemoattractant factors. F0B7 • LMPs attenuate pathological retinal NV and the infiltration of macrophages in vivo. F0B7 • LMPs downregulate ERK1/2 and HIF-1α both in vitro and in vivo. Retinopathy of prematurity (ROP) is the primary cause of visual impairment and vision loss in premature infants, which results from the formation of aberrant retinal neovascularization (NV). An emerging body of evidence has shown that Müller cells are the predominant source of vascular endothelial growth factor (VEGF), which also serves as a chemoattractant for monocyte/macrophage lineage. The recruitment of macrophages is increased during retinal NV, and they exert a pro-angiogenic role in ROP. We have shown that lymphocytic microparticles (microvesicles; LMPs) derived from apoptotic human T lymphocytes possess strong angiogenesis-inhibiting properties. Here, we investigated the effect of LMPs on the chemotactic capacity of Müller cells in vitro using rat Müller cell rMC-1 and mouse macrophage RAW 264.7. In addition, the impact of LMPs was determined in vivo using a mouse model of oxygen-induced ischemic retinopathy (OIR). The results revealed that LMPs were internalized by rMC-1 and reduced their cell proliferation dose-dependently without inducing cell apoptosis. LMPs inhibited the chemotactic capacity of rMC-1 on RAW 264.7 via reducing the expression of VEGF. Moreover, LMPs attenuated pathological retinal NV and the infiltration of macrophages in vivo. LMPs downregulated ERK1/2 and HIF-1α both in vitro and in vivo. These findings expand our understanding of the effects of LMPs, providing evidence of LMPs as a promising therapeutic approach for the treatment of retinal NV diseases.
Glycemic control is a strong predictor of long-term cardiovascular risk in patients with diabetes mellitus, and poor glycemic control influences long-term risk of cardiovascular disease even decades after optimal medical management. This phenomenon, termed glycemic memory, has been proposed to occur due to stable programs of cardiac and endothelial cell gene expression. This transcriptional remodeling has been shown to occur in the vascular endothelium through a yet undefined mechanism of cellular reprogramming.
Highlights: • CAM supports the growth and differentiation of embryonic stem cells into teratomas. • In teratomas, parenchymal Embryonic stem cell-derived endothelial cells form chimeric vessels with stromal endothelial cells. • CAM allows the simultaneously characterization of vasculogenesis and angiogenesis processes. Tumor neovascularization may occur via both angiogenic and vasculogenic events. In order to investigate the vessel formation during tumor growth, we developed a novel experimental model that takes into account the differentiative and tumorigenic properties of Embryonic Stem cells (ESCs). Leukemia Inhibitory Factor-deprived murine ESCs were grafted on the top of the chick embryo chorionallantoic membrane (CAM) in ovo. Cell grafts progressively grew, forming a vascularized mass within 10 days. At this stage, the grafts are formed by cells with differentiative features representative of all three germ layers, thus originating teratomas, a germinal cell tumor. In addition, ESC supports neovascular events by recruiting host capillaries from surrounding tissue that infiltrates the tumor mass. Moreover, immunofluorescence studies demonstrate that perfused active blood vessels within the tumor are of both avian and murine origin because of the simultaneous occurrence of angiogenic and vasculogenic events. In conclusion, the chick embryo ESC/CAM-derived teratoma model may represent a useful approach to investigate both vasculogenic and angiogenic events during tumor growth and for the study of natural and synthetic modulators of the two processes.
Highlights: • MiR-205-5p was commonly downregulated in GC tissues from TCGA database and our hospital, and these events were associated with a worse TNM stagedistant metastasis and poor survival. • MiR-205-5p and CD31 expressions were negatively inter-related within GC tissues from TCGA database and our hospital. • GC cell lines expressed lower level of miR-205-5p significantly as compared with the normal gastric cell line. • MiR-205-5p upregulation significantly impaired proliferation and colony formation of GC cells and neovascularization induced by GC cells in vitro and in vivo. • The angiogenesis and ERK-signaling were depressed by VEGFA and FGF1 downregulation induced by miR-205-5p overexpression. The miR-205-5p inhibitor promoted malignant phenotypes by enhancing VEGFA and FGF1 expressions, as well as the activation of ERK-signaling. Anti-angiogenic therapy represents one of the most promising treatment modalities for human cancers. However, the response to antiangiogenic therapy in gastric cancer (GC) remains dismal. To help identify new strategies for antiangiogenic therapy in GC, we evaluated miR-205–5p expression in GC tissues from TCGA database and our hospital, and its functions in angiogenesis were explored in vitro and in vivo. We investigated miR-205–5p expression and microvessel densities (MVDs) in GC tissues and liver metastases from patients. The function and mechanisms of miR-205–5p were examined in human cell lines and in xenograft mouse models. Associations between miR-205–5p expression and clinical characteristics were analyzed using either Pearson's χ{sup 2} test or Fisher's exact test. Differences in overall survival (OS) distributions were evaluated using the log-rank test. Differences in measurement data were compared using Student's t-test and one-way ANOVA. We found that miR-205–5p expression was downregulated in GC tissues and was negatively correlated with CD31 expression in both TCGA and our clinical samples. GC cell lines expressed low levels of miR-205–5p, and miR-205–5p upregulation significantly impaired the proliferation and angiogenesis of GC cells. Moreover, vascular endothelial growth factor A (VEGFA) and fibroblast growth factor 1 (FGF1) expression and activation of extracellular-related kinase (ERK) signaling were suppressed by miR-205–5p. MiR-205–5p inhibition promoted malignant phenotypes by enhancing VEGFA and FGF1 expression, as well as the activation of ERK signaling. Angiogenesis and ERK signaling were decreased in response to VEGFA and FGF1 downregulation induced by miR-205–5p overexpression. The dual-luciferase reporter assay showed that VEGFA and FGF1 were direct targets of miR-205–5p. Xenograft mouse models revealed that miR-205–5p suppressed tumor growth by inhibiting neovascularization. Altogether, these results demonstrate that miR-205–5p suppresses angiogenesis in GC by attenuating the expression of VEGFA and FGF1, indicating that upregulation of miR-205–5p may represent as an antiangiogenic therapy for GC.
Highlights: • Targeted therapy can be a useful therapeutic method along with traditional methods for breast cancer treatment. • Decreasing Akt/Nf-Kβ signaling pathway is crucial target in order to decreasing angiogenesis in TNBC. • The recombinant antibody can have inhibitory effects on production IL6,8, MMP2, and MMP9. Tumor progression and metastasis, especially in invasive cancers (such as triple-negative breast cancer [TNBC]), depend on angiogenesis, in which vascular epithelial growth factor (VEGF)/vascular epithelial growth factor receptor [1] has a decisive role, followed by the metastatic spread of cancer cells. Although some studies have shown that anti-VEGFR2/VEGF monoclonal antibodies demonstrated favorable results in the clinic, this approach is not efficient, and further investigations are needed to improve the quality of cancer treatment. Besides, the increased expression of epithelial cell adhesion molecule (EpCAM) in various cancers, for instance, invasive breast cancer, contributes to angiogenesis, facilitating the migration of tumor cells to other parts of the body. Thus, the main goal of our study was to target either VEGFR2 or EpCAM as pivotal players in the progression of angiogenesis in breast cancer. Regarding cancer therapy, the production of bispecific antibodies is easier and more cost-effective compared to monoclonal antibodies, targeting more than one antigen or receptor; for this reason, we produced a recombinant antibody to target cells expressing EpCAM and VEGFR2 via a bispecific antibody to decrease the proliferation and metastasis of tumor cells. Following the cloning and expression of our desired anti-VEGFR2/EPCAM sequence in E. coli, the accuracy of the expression was confirmed by Western blot analysis, and its binding activities to VEGFR2 and EPCAM on MDA-MB-231 and MCF-7 cell lines were respectively indicated by flow cytometry. Then, its anti-proliferative potential was indicated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and apoptosis assay to evaluate inhibitory effects of the antibody on tumor cells. Subsequently, the data indicated that migration, invasion, and angiogenesis were inhibited in breast cancer cell lines via the bispecific antibody. Furthermore, cytokine analysis indicated that the bispecific antibody could moderate interleukin 8 (IL-8) and IL-6 as key mediators in angiogenesis progression in breast cancer. Thus, our bispecific antibody could be considered as a promising candidate tool to decrease angiogenesis in TNBC.
Inflammation is an essential factor contributing to sepsis-induced endothelial cell (EC) activation. Interleukin-35 (IL-35) is an anti-inflammatory/immunosuppressive cytokine that exerts protective effects on many inflammatory diseases. In this study, we investigated the effects of IL-35 on lipopolysaccharide (LPS)-induced EC activation and the potential underlying mechanism. Human umbilical vein endothelial cells (HUVECs) were incubated with LPS (1 μg/ml) for 24 h and then cocultured with different concentrations (0, 1, 10, or 100 ng/ml) of recombinant human IL-35 (rhIL-35) for 12 h. Flow cytometry analysis revealed that IL-35 inhibited LPS-induced HUVEC apoptosis in a dose-dependent manner. RT-qPCR and Western blot analyses showed significantly higher mRNA and protein levels of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and the inflammatory factors IL-6 and IL-8 in the LPS group than in the control group. These changes were alleviated by IL-35 treatment, suggesting that IL-35 protects ECs by downregulating inflammation. Furthermore, IL-35 induced signal transducer and activator of transcription 1 (STAT1) and STAT4 activation and promoted their interaction. Blocking STAT1 or STAT4 expression by fludarabine (STAT1 inhibitor) treatment or siRNA-STAT4-interfering fragment transfection inhibited the protective effect of IL-35 on ECs. Moreover, we observed a similar protective effect of IL-35 treatment on ECs in a mouse sepsis model induced by intraperitoneal LPS injection. This study indicated that IL-35 exerts anti-inflammatory and antiapoptotic effects on LPS-induced EC activation by activating the STAT1 and STAT4 signaling pathways.