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At least 91 records · Page 5
All sourcesNASA NTRSDOE OSTI
DOE OSTI2022

Abundance and Migration Success of Overshoot Steelhead in the Upper Columbia River

Abstract Summer steelhead Oncorhynchus mykiss may enter freshwater almost a year before spawning and potentially make long migrations (>1,000 km) to interior headwater habitats. However, in response to suboptimal freshwater habitat conditions (e.g., warmer water temperatures), adult summer steelhead may exhibit complex behaviors during upstream migration in the Columbia River basin. Steelhead may migrate upstream of their natal tributary (hereafter, referred to as “overshoot”) and spend days to several months before subsequently migrating downstream (hereafter, referred to as “fallback”) to their natal tributary to spawn. An expansion of an existing Bayesian patch occupancy model, derived from observations of adult steelhead that were PIT-tagged to estimate population-specific abundance upstream of the tagging location, incorporated downstream detection locations to estimate the abundance of overshoot fallbacks. Overshoot steelhead abundance at the tagging location was estimated based on the relationship between the number of known overshoot fallbacks (i.e., the number of steelhead that overshot and successfully migrated downstream to their natal tributary) and their model-estimated abundance. During the study period (2010–2017), the annual mean proportion of overshoot steelhead that successfully migrated downstream of the tagging location (Priest Rapids Dam) was 0.59 (SD = 0.14). The number of dams encountered by overshoot steelhead during their downstream migration was negatively correlated with their downstream migration success probability. Improved downstream passage survival for adult steelhead will increase the abundance of affected populations while reducing potential genetic introgression of upstream populations (i.e., strays). This is the first study to estimate the abundance of overshoot and fallback steelhead, providing the data necessary for scientists to estimate potential conservation benefits of improved downstream survival. For example, surface flow passage routes (e.g., sluiceways and temporary spillway weirs) are very effective in guiding and passing adult steelhead downstream of Columbia River hydroelectric projects and data from this assessment show that changes in dam operations throughout the downstream migration period may maximize conservation benefits.

Murdoch, Andrew R. (ORCID:0000000324827689)↗
DOE OSTI2015

Inhibition of the proliferation and acceleration of migration of vascular endothelial cells by increased cysteine-rich motor neuron 1

Cysteine-rich motor neuron 1 (CRIM1) is upregulated only in extracellular matrix gels by angiogenic factors such as vascular endothelial growth factor (VEGF). It then plays a critical role in the tube formation of endothelial cells. In the present study, we investigated the effects of increased CRIM1 on other endothelial functions such as proliferation and migration. Knock down of CRIM1 had no effect on VEGF-induced proliferation or migration of human umbilical vein endothelial cells (HUVECs), indicating that basal CRIM1 is not involved in the proliferation or migration of endothelial cells. Stable CRIM1-overexpressing endothelial F-2 cells, termed CR1 and CR2, were constructed, because it was difficult to prepare monolayer HUVECs that expressed high levels of CRIM1. Proliferation was reduced and migration was accelerated in both CR1 and CR2 cells, compared with normal F-2 cells. Furthermore, the transient overexpression of CRIM1 resulted in decreased proliferation and increased migration of bovine aortic endothelial cells. In contrast, neither proliferation nor migration of COS-7 cells were changed by the overexpression of CRIM1. These results demonstrate that increased CRIM1 reduces the proliferation and accelerates the migration of endothelial cells. These CRIM1 effects might contribute to tube formation of endothelial cells. CRIM1 induced by angiogenic factors may serve as a regulator in endothelial cells to switch from proliferating cells to morphological differentiation. - Highlights: • CRIM1 was upregulated only in tubular endothelial cells, but not in monolayers. • Increased CRIM1 reduced the proliferation of endothelial cells. • Increased CRIM1 accelerated the migration of endothelial cells. • Increased CRIM1 had no effect on the proliferation or migration of COS-7 cells.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

MRTF-A-miR-206-WDR1 form feedback loop to regulate breast cancer cell migration

Breast cancer is the leading cause of cancer death in women worldwide which is closely related to metastasis. Our previous study has shown that MRTF-A promote the migration of MDA-MB-231 cells and WDR1 promotes breast cancer cell migration. But the exact molecular mechanism on metastasis is still not fully understood, we now report that WDR1 enhanced the effect of MRTF-A induced-MDA-MB-231 cell migration by promoting the expression of the EMT markers and migration markers via RhoA-MRTF-A signaling pathway. Importantly, WDR1 promoted the nuclear importion of MRTF-A by affecting the expression of nuclear transport protein importin. But WDR1 did not affect the expression of MRTF-A. Interestingly, MRTF-A promoted the expression of miR-206 via its promoter CArG box but miR-206 inhibits the migration of breast cancer cells through suppressing the expression of WDR1 and MRTF-A via targeted their 3′UTR. Our data thus provide important and novel insights into MRTF-A-miR-206-WDR1 form feedback loop to regulate breast cancer cell migration. - Highlights: • WDR1 enhanced the effect of MRTF-A induced cell migration via RhoA-MRTF-A signaling pathway. • WDR1 promoted the nuclear importion of MRTF-A. • MRTF-A promoted the expression of miR-206 via its promoter CArG box. • miR-206 inhibits cell migration through suppressing the expression of WDR1 and MRTF-A. • MRTF-A-miR-206-WDR1 form feedback loop to regulate breast cancer cell migration.

60 APPLIED LIFE SCIENCES↗
NASA NTRS1999

DMFS: A Data Migration File System for NetBSD

I have recently developed dmfs, a Data Migration File System, for NetBSD. This file system is based on the overlay file system, which is discussed in a separate paper, and provides kernel support for the data migration system being developed by my research group here at NASA/Ames. The file system utilizes an underlying file store to provide the file backing, and coordinates user and system access to the files. It stores its internal meta data in a flat file, which resides on a separate file system. Our data migration system provides archiving and file migration services. System utilities scan the dmfs file system for recently modified files, and archive them to two separate tape stores. Once a file has been doubly archived, files larger than a specified size will be truncated to that size, potentially freeing up large amounts of the underlying file store. Some sites will choose to retain none of the file (deleting its contents entirely from the file system) while others may choose to retain a portion, for instance a preamble describing the remainder of the file. The dmfs layer coordinates access to the file, retaining user-perceived access and modification times, file size, and restricting access to partially migrated files to the portion actually resident. When a user process attempts to read from the non-resident portion of a file, it is blocked and the dmfs layer sends a request to a system daemon to restore the file. As more of the file becomes resident, the user process is permitted to begin accessing the now-resident portions of the file. For simplicity, our data migration system divides a file into two portions, a resident portion followed by an optional non-resident portion. Also, a file is in one of three states: fully resident, fully resident and archived, and (partially) non-resident and archived. For a file which is only partially resident, any attempt to write or truncate the file, or to read a non-resident portion, will trigger a file restoration. Truncations and writes are blocked until the file is fully restored so that a restoration which only partially succeed does not leave the file in an indeterminate state with portions existing only on tape and other portions only in the disk file system. We chose layered file system technology as it permits us to focus on the data migration functionality, and permits end system administrators to choose the underlying file store technology. We chose the overlay layered file system instead of the null layer for two reasons: first to permit our layer to better preserve meta data integrity and second to prevent even root processes from accessing migrated files. This is achieved as the underlying file store becomes inaccessible once the dmfs layer is mounted. We are quite pleased with how the layered file system has turned out. Of the 45 vnode operations in NetBSD, 20 (forty-four percent) required no intervention by our file layer - they are passed directly to the underlying file store. Of the twenty five we do intercept, nine (such as vop_create()) are intercepted only to ensure meta data integrity. Most of the functionality was concentrated in five operations: vop_read, vop_write, vop_getattr, vop_setattr, and vop_fcntl. The first four are the core operations for controlling access to migrated files and preserving the user experience. vop_fcntl, a call generated for a certain class of fcntl codes, provides the command channel used by privileged user programs to communicate with the dmfs layer.

Studenmund, William↗
DOE OSTI2020

Direct Observation of Photoinduced Ion Migration in Lead Halide Perovskites

Unique optoelectronic, electronic, and sensing properties of hybrid organic–inorganic perovskites (HOIPs) are underpinned by the complex interactions between electronic and ionic states. In this study, the photoinduced field ion migration in HOIPs is directly observed. Using newly developed local probe time-resolved techniques, more significant CH 3 NH 3 + migration than I – /Br – migration in HOIPs is unveiled. It is found that light illumination only induces CH 3 NH 3 + migration but not I – /Br – migration. By directly observing temporal changes in bias-induced and photoinduced ion migration in device conditions, it is revealed that light illumination suppresses the bias-induced ion redistribution in the lateral device. These findings, being a necessary compensation of previous understandings of ion migration in HOIPs based on simulations and static and/or indirect measurements, offer advanced insights into the distinct light effects on the migration of organic cation and halides in HOIPs, which are expected to be helpful for improving the performance and the long-term stability of HOIPs optoelectronics.

36 MATERIALS SCIENCE↗
DOE OSTI2021

Breeding latitude is associated with the timing of nesting and migration around the annual calendar among Purple Martin (Progne subis) populations

Timing is critical for species that migrate seasonally, as timing mismatches can lead to reduced reproductive success and population declines. We investigated the effect of breeding latitude on the migration timing of a long-distance migratory songbird (Purple Martin, Progne subis subis) by using light-level geolocators deployed across breeding sites between 26° and 53° latitude (n = 329). We used nesting data (1st egg dates; n=28,165) to explore latitudinal patterns in the timing of breeding. Using generalized linear mixed models (GLMMs) we found that breeding latitude was highly associated with timing around the calendar, explaining population-level timing across both spring and fall migration. Populations breeding at more northern latitudes migrated later in fall (mean days/degree latitude =2), in spring (mean days/degree latitude =3), and nested later (days/degree latitude = 3) than populations breeding at more southern latitudes. Generalized additive mixed models (GAMMs) revealed significant non-linearity between breeding latitude and spring and fall migration timing, and the timing of nesting. In spring, the most northern breeders (> 40 degrees N) were more synchronous in their timing, departing their nonbreeding sites and arriving earlier at their breeding sites relative to their breeding latitude. These most northern breeders also had similar nest timing and fall migration departure timing. Breeding latitude was also associated with seasonal partitioning of migratory and sedentary periods. The most northern breeders spent 10% more time on fall migration, 2% more at wintering grounds, 1% more on spring migration, and 13% less time at their breeding sites. Our results support the notion that selection for timing at breeding latitudes can have year-round effects on the timing of seasonal events in long-distance migratory songbirds. Future studies should examine whether these timing patterns associated with latitude limit phenotypic responses to climate change.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2024

Modeling gas migration through clay-based buffer material using coupled multiphase fluid flow and geomechanics with stress-dependent gas permeability

A model for gas migration through clay-based buffer material is developed for modeling gas generation and migration associated with deep geologic nuclear waste disposal. The model is based on a multiphase fluid flow and geomechanics simulator that is adapted to consider enhanced gas flow when gas pressure is high enough to approach the confining stress magnitude. A key feature in the model is a direct coupling between gas permeability and stress, through a non-linear stress-dependent permeability function. The model was first tested and calibrated by modelling two different laboratory gas migration tests on Wyoming (MX-80) bentonite samples. The calibrated model was then applied to model gas migration through a bentonite buffer of a large-scale gas injection test (Lasgit) conducted at the Äspö Hard Rock Laboratory in Sweden. Observed preferential gas migration along interfaces (between compacted blocks and along the canister surface) required explicit representation of such interfaces in the model. The model with the stress-dependent gas permeability accurately captured observed experimental responses in terms of gas breakthrough time, peak gas pressure, and cumulative gas flow rates. The calibrated model was finally applied to simulate migration of hydrogen gas generated within a breached nuclear waste canister over 10,000 years, involving migration of much larger gas volumes. For the considered gas generation rate and host rock properties, the generated gas could migrate through the bentonite buffer and released into the surrounding host rock at a maximum gas pressure somewhat higher than the initial total stress, though a significant amount of hydrogen remained within the buffer. This modelling sets the stage for further detailed analysis of the impact of hydrogen gas generation on the long-term performance of nuclear waste repositories.

12 MANAGEMENT OF RADIOACTIVE AND NON-RADIOACTIVE W↗
DOE OSTI2015

Iptakalim inhibits PDGF-BB-induced human airway smooth muscle cells proliferation and migration

Chronic airway diseases are characterized by airway remodeling which is attributed partly to the proliferation and migration of airway smooth muscle cells (ASMCs). ATP-sensitive potassium (K{sub ATP}) channels have been identified in ASMCs. Mount evidence has suggested that K{sub ATP} channel openers can reduce airway hyperresponsiveness and alleviate airway remodeling. Opening K{sup +} channels triggers K{sup +} efflux, which leading to membrane hyperpolarization, preventing Ca{sup 2+}entry through closing voltage-operated Ca{sup 2+} channels. Intracellular Ca{sup 2+} is the most important regulator of muscle contraction, cell proliferation and migration. K{sup +} efflux decreases Ca{sup 2+} influx, which consequently influences ASMCs proliferation and migration. As a K{sub ATP} channel opener, iptakalim (Ipt) has been reported to restrain the proliferation of pulmonary arterial smooth muscle cells (PASMCs) involved in vascular remodeling, while little is known about its impact on ASMCs. The present study was designed to investigate the effects of Ipt on human ASMCs and the mechanisms underlying. Results obtained from cell counting kit-8 (CCK-8), flow cytometry and 5-ethynyl-2′-deoxyuridine (EdU) incorporation showed that Ipt significantly inhibited platelet-derived growth factor (PDGF)-BB-induced ASMCs proliferation. ASMCs migration induced by PDGF-BB was also suppressed by Ipt in transwell migration and scratch assay. Besides, the phosphorylation of Ca{sup 2+}/calmodulin-dependent kinase II (CaMKII), extracellular regulated protein kinases 1/2 (ERK1/2), protein kinase B (Akt), and cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) were as well alleviated by Ipt administration. Furthermore, we found that the inhibition of Ipt on the PDGF-BB-induced proliferation and migration in human ASMCs was blocked by glibenclamide (Gli), a selective K{sub ATP} channel antagonist. These findings provide a strong evidence to support that Ipt antagonize the proliferating and migrating effects of PDGF-BB on human ASMCs through opening K{sub ATP} channels. Altogether, our results highlighted a novel profile of Ipt as a potent option against the airway remodeling in chronic airway diseases. - Highlights: Iptakalim is a novel ATP-sensitive potassium channel opener. Iptakalim showed anti-proliferation and anti-migration effects on PDGF-BB-induced human airway smooth muscle cells. Inhibitory effects of Iptakalim could be abolished by glibenclamide, a selective K{sub ATP} channel antagonist. Inhibitory effects of Iptakalim involved the signaling pathways of CaMKII, ERK1/2 and Akt, as well as their downstream, CREB.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Insulin promotes cell migration by regulating PSA-NCAM

Cellular interactions with the extracellular environment are modulated by cell surface polysialic acid (PSA) carried by the neural cell adhesion molecule (NCAM). PSA-NCAM is involved in cellular processes such as differentiation, plasticity, and migration, and is elevated in Alzheimer's disease as well as in metastatic tumour cells. Our previous work demonstrated that insulin enhances the abundance of cell surface PSA by inhibiting PSA-NCAM endocytosis. In the present study we have identified a mechanism for insulin-dependent inhibition of PSA-NCAM turnover affecting cell migration. Insulin enhanced the phosphorylation of the focal adhesion kinase leading to dissociation of αv-integrin/PSA-NCAM clusters, and promoted cell migration. Our results show that αv-integrin plays a key role in the PSA-NCAM turnover process. αv-integrin knockdown stopped PSA-NCAM from being endocytosed, and αv-integrin/PSA-NCAM clusters co-labelled intracellularly with Rab5, altogether indicating a role for αv-integrin as a carrier for PSA-NCAM during internalisation. Furthermore, inhibition of p-FAK caused dissociation of αv-integrin/PSA-NCAM clusters and counteracted the insulin-induced accumulation of PSA at the cell surface and cell migration was impaired. Our data reveal a functional association between the insulin/p-FAK-dependent regulation of PSA-NCAM turnover and cell migration through the extracellular matrix. Most importantly, they identify a novel mechanism for insulin-stimulated cell migration. - Highlights: • Insulin modulates PSA-NCAM turnover through upregulation of p-FAK. • P-FAK modulates αv-integrin/PSA-NCAM clustering. • αv-integrin acts as a carrier for PSA-NCAM endocytosis. • Cell migration is promoted by cell surface PSA. • Insulin promotes PSA-dependent migration in vitro.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Distribution of genetic variation underlying adult migration timing in steelhead of the Columbia River basin

Abstract Fish migrations are energetically costly, especially when moving between freshwater and saltwater, but are a viable strategy for Pacific salmon and trout ( Oncorhynchus spp.) due to the advantageous resources available at various life stages. Anadromous steelhead ( O. mykiss ) migrate vast distances and exhibit variation for adult migration phenotypes that have a genetic basis at candidate genes known as greb1L and rock1 . We examined the distribution of genetic variation at 13 candidate markers spanning greb1L , intergenic, and rock1 regions versus 226 neutral markers for 113 populations ( n = 9,471) of steelhead from inland and coastal lineages in the Columbia River. Patterns of population structure with neutral markers reflected genetic similarity by geographic region as demonstrated in previous studies, but candidate markers clustered populations by genetic variation associated with adult migration timing. Mature alleles for late migration had the highest frequency overall in steelhead populations throughout the Columbia River, with only 9 of 113 populations that had a higher frequency of premature alleles for early migration. While a single haplotype block was evident for the coastal lineage, we identified multiple haplotype blocks for the inland lineage. The inland lineage had one haplotype block that corresponded to candidate markers within the greb1L gene and immediately upstream in the intergenic region, and the second block only contained candidate markers from the intergenic region. Haplotype frequencies had similar patterns of geographic distribution as single markers, but there were distinct differences in frequency between the two haplotype blocks for the inland lineage. This may represent multiple recombination events that differed between lineages where phenotypic differences exist between freshwater entry versus arrival timing as indicated by Micheletti et al. (2018a). Redundancy analyses were used to model environmental effects on allelic frequencies of candidate markers, and significant variables were migration distance, temperature, isothermality, and annual precipitation. This study improves our understanding of the spatial distribution of genetic variation underlying adult migration timing in steelhead as well as associated environmental factors and has direct conservation and management implications.

Collins, Erin E.↗
DOE OSTI2018

Fluid shear stress suppresses ICAM-1-mediated transendothelial migration of leukocytes in coculture model

Highlights: • EC-SMC coculture condition stimulates mononuclear leukocyte migration. • Coculture of SMCs increases ICAM-1 expression of ECs. • Exposure to shear stress decreases leukocytes migration and ICAM-1 expression. The adhesion and migration of leukocytes to arterial endothelial cells (ECs), one of the indicators of early atherogenesis, is believed to be correlated with the blood flow conditions and interactions between vascular cells including vascular smooth muscle cells (SMCs). In this study, we investigated the effect of fluid shear stress on the transendothelial migration of leukocytes in a coculture model (CM) composed of human umbilical ECs and SMCs, a layer of collagen type I, and a porous membrane. Following exposure to a fluid shear stress of 1.5 Pa for 24 h, human mononuclear leukocytes were seeded on the EC surface and cultured for 1 h. Leukocytes migrating across the EC layer were observed by confocal laser scanning microscopy. The number of migrating leukocytes in the statically cultured CM was significantly larger than that in the static EC monoculture model. The exposure to the shear stress significantly decreased the leukocyte migration induced by the coculture condition. In the static CM, fluorescence staining and Western blotting showed a higher expression of intercellular adhesion molecule-1 (ICAM-1) of ECs. These results indicate that SMC-derived bioactive soluble factors may stimulate the ICAM-1 expression of cocultured ECs, possibly leading to leukocyte migration into the subendothelial space.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

On the long-term migration of uranyl in bentonite barrier for high-level radioactive waste repositories: The effect of different host rocks

Repositories for high level radioactive waste hosted in argillite or granite with bentonite backfill are the two disposal concepts that been extensively studied. A general perception is that granite has very low sorption capacity and therefore is disadvantageous in retarding the migration of radionuclides in comparison with argillite. However, when there is bentonite backfill, does the sorption capacity of granite really matter for the migration of radionuclides? How different host rocks would affect the migration of U(VI) through the bentonite backfill of an engineered barrier system (EBS), and which properties of the host rocks cause those differences in migration, given that migration of radionuclides is a critical measure in assessing the performance of a repository? Here we present two coupled thermal, hydrological, and chemical models for the transport of U(VI), each with an identical setup except for the type of host rock (argillite vs granite rock). Comparisons between our models show that the different host rocks exert their influence on migration of U(VI) via regulating the chemical conditions in the bentonite, which affect the concentration of U(VI) at the source and the adsorption of U(VI) in the bentonite. The key chemical conditions are pH, Ca + , and HCO 3 - concentration in pore-water, which are strongly affected by soluble carbonate minerals. Our models also show the occurrence of illitization (dissolution of smectite and precipitation of illite) in the bentonite, which affects the migration of U(VI) through changing pH and the quantity of adsorbents. Although generalization of current model results for granite and argillite should be done carefully, the simulations highlight the importance of pore-water chemistry in host rock, as well as bentonite-host rock interactions, when assessing the performance of a repository. In comparison to properties such as thermal conductivity, permeability, and adsorption capacity, properties that have been studied intensively, the pore-water chemistry of host rocks deserve equal or even more attention because of its strong influence on radionuclide migration.

58 GEOSCIENCES↗
DOE OSTI2024

Cobalt-60, Barium-133, Cesium-137, and Europium-152 migration from cementitious sources through sediment under field conditions

Safe and effective storage of radioactive waste is essential to protect human and environmental health. Due to the potential for accidental releases and the severity of the associated risks, it is imperative to further understand radionuclide transport should an accident occur. This study was the second set of measurements conducted in 2022 of an ongoing experiment that has analyzed the vadose zone migration of radionuclides from cementitious wasteforms at the Savannah River Site over the last ten years. The radionuclides introduced within the sources are prominent constituents of radioactive waste or analogs for other groups or series of radionuclides. Lysimeters were first analyzed in 2016 using a collimated high-purity germanium gamma-ray spectrometer to non-destructively measure the concentration of each radionuclide in the sediment column as a function of depth. Following these measurements, the lysimeters were redeployed for another 4 years. All radionuclides in all lysimeters were observed to transport further during the redeployment period; however, the extent of migration varied with the material used for introduction. Except for 137Cs, migration through the sediment control system increased with decreasing ionic potential (ionic charge/radius); migration order: 152Eu<137Cs<60Co<133Ba. Overall, the cementitious wasteforms were observed to decrease radionuclide migration extent relative to natural vadose zone conditions. In both cementitious wasteforms, the migration extent increased in the order 152Eu<133Ba<60Co<137Cs. However, less migration was measured when the radionuclides were incorporated into a reducing grout wasteform. The novelty of this paper is the demonstration of a technique capable of creating non-destructive measurements over decade time scales. Ultimately, this work provides insight into the long-term migration of alkali, alkali earth, divalent transition metal, and trivalent (e.g., lanthanide and actinide element) isotopes.

11 NUCLEAR FUEL CYCLE AND FUEL MATERIALS↗
DOE OSTI2015

Role of human pulmonary fibroblast-derived MCP-1 in cell activation and migration in experimental silicosis

Background: Silicosis is a systemic disease caused by inhaling silicon dioxide (SiO{sub 2}). Phagocytosis of SiO{sub 2} in the lung initiates an inflammatory cascade that results in fibroblast proliferation and migration and subsequent fibrosis. Clinical evidence indicates that the activation of alveolar macrophages by SiO{sub 2} produces rapid and sustained inflammation that is characterized by the generation of monocyte chemotactic protein 1 (MCP-1), which induces fibrosis. Pulmonary fibroblast-derived MCP-1 may play a critical role in fibroblast proliferation and migration. Methods and results: Experiments using primary cultured adult human pulmonary fibroblasts (HPF-a) demonstrated the following results: 1) SiO{sub 2} treatment resulted in the rapid and sustained induction of MCP-1 as well as the elevation of the CC chemokine receptor type 2 (CCR2) protein levels; 2) pretreatment of HPF-a with RS-102895, a specific CCR2 inhibitor, abolished the SiO{sub 2}-induced increase in cell activation and migration in both 2D and 3D culture systems; and 3) RNA interference targeting CCR2 prevented the SiO{sub 2}-induced increase in cell migration. Conclusion: These data demonstrated that the up-regulation of pulmonary fibroblast-derived MCP-1 is involved in pulmonary fibroblast migration induced by SiO{sub 2}. CCR2 was also up-regulated in response to SiO{sub 2}, and this up-regulation facilitated the effect of MCP-1 on fibroblasts. Our study deciphered the link between fibroblast-derived MCP-1 and SiO{sub 2}-induced cell migration. This finding provides novel insight into the potential of MCP-1 in the development of novel therapeutic strategies for silicosis. - Highlights: • Role of pulmonary fibroblast-derived MCP-1 in experimental silicosis was studied. • SiO{sub 2} induced MCP-1 release from cultured human pulmonary fibroblast (HPF-a). • SiO{sub 2} directly activated HPF-a via the MCP-1/CCR2 pathway. • SiO{sub 2} increased HPF-a migration in both 2D and 3D model via the MCP-1/CCR2 pathway. • RNA-i of MCP-1/CCR2 decreased HPF-a activation and migration induced by SiO{sub 2}.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Overexpression of histone demethylase Fbxl10 leads to enhanced migration in mouse embryonic fibroblasts

Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing, immune responses and invasive tumors all require the orchestrated movement of cells to specific locations. Histone demethylase proteins alter transcription by regulating the chromatin state at specific gene loci. FBXL10 is a conserved and ubiquitously expressed member of the JmjC domain-containing histone demethylase family and is implicated in the demethylation of H3K4me3 and H3K36me2 and thereby removing active chromatin marks. However, the physiological role of FBXL10 in vivo remains largely unknown. Therefore, we established an inducible gain of function model to analyze the role of Fbxl10 and compared wild-type with Fbxl10 overexpressing mouse embryonic fibroblasts (MEFs). Our study shows that overexpression of Fbxl10 in MEFs doesn’t influence the proliferation capability but leads to an enhanced migration capacity in comparison to wild-type MEFs. Transcriptome and ChIP-seq experiments demonstrated that Fbxl10 binds to genes involved in migration like Areg, Mdk, Lmnb1, Thbs1, Mgp and Cxcl12. Taken together, our results strongly suggest that Fbxl10 plays a critical role in migration by binding to the promoter region of migration-associated genes and thereby might influences cell behaviour to a possibly more aggressive phenotype. - Highlights: • Migration capability of MEFs is enhanced after Fbxl10 upregulation. • Overexpression of Fbxl10 induced migration-associated genes. • Fbxl10 binds directly to migration-associated genes.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Hedgehog signaling contributes to basic fibroblast growth factor-regulated fibroblast migration

Fibroblast migration is a central process in skin wound healing, which requires the coordination of several types of growth factors. bFGF, a well-known fibroblast growth factor (FGF), is able to accelerate fibroblast migration; however, the underlying mechanism of bFGF regulation fibroblast migration remains unclear. Through the RNA-seq analysis, we had identified that the hedgehog (Hh) canonical pathway genes including Smoothened (Smo) and Gli1, were regulated by bFGF. Further analysis revealed that activation of the Hh pathway via up-regulation of Smo promoted fibroblast migration, invasion, and skin wound healing, but which significantly reduced by GANT61, a selective antagonist of Gli1/Gli2. Western blot analyses and siRNA transfection assays demonstrated that Smo acted upstream of phosphoinositide 3-kinase (PI3K)-c-Jun N-terminal kinase (JNK)-β-catenin to promote cell migration. Moreover, RNA-seq and qRT-PCR analyses revealed that Hh pathway genes including Smo and Gli1 were under control of β-catenin, suggesting that β-catenin turn feedback activates Hh signaling. Taken together, our analyses identified a new bFGF-regulating mechanism by which Hh signaling regulates human fibroblast migration, and the data presented here opens a new avenue for the wound healing therapy. - Highlights: • bFGF regulates Hedgehog (Hh) signaling in fibroblasts. • The Smo and Gli two master regulators of Hh signaling positively regulate fibroblast migration. • Smo facilitates β-catenin nuclear translocation via activation PI3K/JNK/GSK3β. • β-catenin positively regulates fibroblast cell migration and the expression of Hh signaling genes including Smo and Gli.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

K-ras mutation promotes ionizing radiation-induced invasion and migration of lung cancer in part via the Cathepsin L/CUX1 pathway

Highlights: • CTSL has important roles in the regulation of invasion and migration in NSCLC and is promoted by mutated K-ras. • Mutated K-ras and IR-induced CTSL play crucial roles in the EMT in the lung cancer. • The regulatory effects of CTSL on the EMT are attributed to proteolytic processing of the transcription factor CUX1. • Inhibition of CTSL or CUX1 may be a promising therapeutic target. • CTSL is a promising therapeutic target to overcome the invasion and migration induced by IR. K-ras mutation is involved in cancer progression including invasion and migration, but the underlying mechanism is not yet clear. Cathepsin L is a lysosomal cysteine protease and has recently been associated with invasion and migration in human cancers when it is overexpressed. Our recent studies have shown that ionizing radiation (IR) enhanced expression of cathepsin L and increased invasion and migration of tumor cells, but the molecular mechanism is still unclear. In the present study, the effects of K-ras mutation and IR induced invasion and migration of lung cancer as well as the underlying mechanisms were investigated both in vitro and in vivo. Firstly, the levels of cathepsin L and epithelial mesenchymal transition (EMT) marker proteins remarkably changed in A549 (K-ras mutant) after irradiation compared with H1299 (K-ras wild), thereby promoting invasion and migration. Additionally, cathepsin L and its downstream transcription factor CUX1/p110 were increased after irradiation in A549 transfected with CUX1/p200, and the proteolytic processing of CUX1 by cathepsin L was remarkably increased after co-transfection of CUX1/p200 and cathepsin L-lentivirus in H1299. In addition, delivery of a mutant K-ras (V12) into HEK 293 cells stimulated EMT after irradiation due to the accumulation of cathepsin L. Moreover, mutated K-ras was associated with IR-induced cathepsin L and EMT in BALB/c nude mice. Finally, the level of cathepsin L expression was higher in samples carrying a K-ras mutation than in wild-type K-ras samples and the mesenchymal markers were upregulated in the samples of mutant K-ras, whereas the epithelial marker E-cadherin was downregulated in non-small cell lung cancers tissues. In conclusion, the findings demonstrated that mutated K-ras promotes cathepsin L expression and plays a pivotal role in EMT of human lung cancer. The regulatory effect of IR-induced cathepsin L on lung cancer invasion and migration was partially attributed to the Cathepsin L /CUX1-mediated EMT signaling pathway. This study will provide cathepsin L as a potential target for tumor therapy.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

The role and mechanism of KCa3.1 channels in human monocyte migration induced by palmitic acid

Highlights: • Palmitic acid upregulates K{sub Ca}3.1 channels in human monocytes. • TLR2/4, p38-MAPK and NF-κB pathway is involved in the effect of palmitic acid. • The migration of monocytes induced by palmitic acid is mediated by K{sub Ca}3.1 channels. • K{sub Ca}3.1 channels contribute to palmitic acid-induced MCP-1 production in monocytes. Monocyte migration into diseased tissues contributes to the pathogenesis of diseases. Intermediate-conductance Ca{sup 2+}-activated K{sup +} (K{sub Ca}3.1) channels play an important role in cell migration. However, the role of K{sub Ca}3.1 channels in mediating monocyte migration induced by palmitic acid (PA) is still unclear. Using cultured THP-1 cells and peripheral blood mononuclear cells from healthy subjects, we investigated the role and signaling mechanisms of K{sub Ca}3.1 channels in mediating the migration induced by PA. Using methods of Western blotting analysis, RNA interference, cell migration assay and ELISA, we found that PA-treated monocytes exhibited increment of the protein levels of K{sub Ca}3.1 channel and monocyte chemoattractant protein-1 (MCP-1), and the effects were reversed by co-incubation of PA with anti-TLR2/4 antibodies or by specific inhibitors of p38-MAPK, or NF-κB. In addition, PA increased monocyte migration, which was abolished by a specific K{sub Ca}3.1 channel blocker, TRAM-34, or K{sub Ca}3.1 small interfering RNA (siRNA). The expression and secretion of MCP-1 induced by PA was also similarly prevented by TRAM-34 and K{sub Ca}3.1 siRNA. These results demonstrate for the first time that PA upregulates K{sub Ca}3.1 channels through TLR2/4, p38-MAPK and NF-κB pathway to promote the expression of MCP-1, and then induce the trans-endothelial migration of monocytes.

60 APPLIED LIFE SCIENCES↗