Cataclysmic eruption of Mount St. Helens (USA) in 1980 reset 30 km of upper North Fork Toutle River (NFTR) valley to a zero‐state fluvial condition. Consequently, a new channel system evolved. ...Initially, a range of streamflows eroded channels (tens of meters incision, hundreds of meters widening) and transported immense sediment loads. Now, single, large‐magnitude, or multiple moderate‐magnitude events are needed to accomplish substantial channel modification. Three large floods (two ≥100‐year events; one ∼10–25‐year event along lower Toutle River) from 1996 to 2015 indicate flood effectiveness in this environment is affected by both geomorphic and environmental factors. The largest and smallest of these floods (February 1996, November 2006) transported the most sediment by single floods since 1982; erosion and sediment transport by an ∼100‐year flood in December 2015 was not exceptional. Strong coupling between NFTR and its tall corridor banks, local geologic and hydraulic conditions promoting threshold erosion, event sequencing, and possibly a longitudinal gradient in stream power are important factors affecting event effectiveness on channel modification. In addition, environmental factors have also been influential, as variations in snowpack, storm trajectories and rainfall distributions, and episodic mobilization of debris flows have also influenced geomorphic response. Other factors such as vegetation anchoring, strong channel–hillside coupling, disparities between flood frequencies and perturbation relaxation times, and large variations in flood duration do not appear to be critical influences. Climate forecasts for warmer temperatures and a shift from snowfall to rainfall at high elevations may promote further acute geomorphic responses.
Key Points
Three large floods affected an evolving, cataclysmically disturbed river system over a 20‐year span and produced varied geomorphic responses
Event responses were influenced by storm character, snowpack cover, geomorphic process, and local hydraulic and geologic conditions
Single, large‐magnitude, or multiple moderate‐magnitude events are currently needed to accomplish substantial channel modification
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
We sought to determine whether nucleolin, a bcl-2 mRNA-binding protein, has a role in the regulation of bcl-2 mRNA stability in MCF-7 and MDA-MB-231 breast cancer cells. Furthermore, we examined the ...efficacy of the aptamer AS1411 in targeting nucleolin and inducing bcl-2 mRNA instability and cytotoxicity in these cells. AS1411 at 5 micromol/L inhibited the growth of MCF-7 and MDA-MB-231 cells, whereas 20 micromol/L AS1411 had no effect on the growth rate or viability of normal MCF-10A mammary epithelial cells. This selectivity of AS1411 was related to a greater uptake of AS1411 into the cytoplasm of MCF-7 cells compared with MCF-10A cells and to a 4-fold higher level of cytoplasmic nucleolin in MCF-7 cells. Stable siRNA knockdown of nucleolin in MCF-7 cells reduced nucleolin and bcl-2 protein levels and decreased the half-life of bcl-2 mRNA from 11 to 5 hours. Similarly, AS1411 (10 micromol/L) decreased the half-life of bcl-2 mRNA in MCF-7 and MDA-MB-231 cells to 1.0 and 1.2 hours, respectively. In contrast, AS1411 had no effect on the stability of bcl-2 mRNA in normal MCF-10A cells. AS1411 also inhibited the binding of nucleolin to the instability element AU-rich element 1 of bcl-2 mRNA in a cell-free system and in MCF-7 cells. Together, the results suggest that AS1411 acts as a molecular decoy by competing with bcl-2 mRNA for binding to cytoplasmic nucleolin in these breast cancer cell lines. This interferes with the stabilization of bcl-2 mRNA by nucleolin and may be one mechanism by which AS1411 induces tumor cell death.
AS1411 is a DNA aptamer that is in phase II clinical trials for relapsed or refractory acute myeloid leukemia and for renal
cell carcinoma. AS1411 binds to nucleolin, a protein that is overexpressed ...in the cytoplasm and on the plasma membrane of
some tumor cells compared with normal cells. Studies were performed to determine whether cell surface nucleolin is a receptor
for AS1411 in the acute myeloid leukemia cell line MV4-11. Biotinylation of MV4-11 cell surface proteins followed by immunoblotting
of the biotinylated proteins showed that full-length (106 kDa) and truncated forms of nucleolin were present on the cell surface.
In contrast, K-562 cells, which are 4-fold less sensitive than MV4-11 cells to AS1411, showed no full-length nucleolin and
lesser amounts of the truncated forms of nucleolin on the cell surface. Incubation of MV4-11 cells with 32 PAS1411 and immunoprecipitation of the plasma membrane fraction with anti-nucleolin antibody demonstrated the presence of
32 PAS1411-nucleolin complexes. Anti-nucleolin antibody inhibited binding of fluorescein isothiocyanate (FITC)-AS1411 to plasma
membrane nucleolin 56 ± 10% SE ( P < 0.01) compared with cells incubated with FITC-AS1411 only. Cellular uptake of 32 PAS1411 into MV4-11 cells was blocked by a 20-fold excess of unlabeled AS1411 but not by a 20-fold excess of the biologically
inactive oligonucleotide CRO-26. Uptake was approximately 3-fold faster into MV4-11 cells than into K-562 cells. Partial knockdown
of plasma membrane and cytosolic nucleolin in MCF-7 cells resulted in a 3-fold decrease in AS1411 uptake. These results provide
evidence that plasma membrane nucleolin is a functional receptor for AS1411 in MV4-11 cells.
bcl-2 mRNA contains an AU-rich element (ARE) that functions in regulating bcl-2 stability. Our earlier studies indicated that taxol- or okadaic acid-induced bcl-2 mRNA destabilization in HL-60 cells ...is associated with decreased binding of trans-acting factors to the ARE. To identify factors that play a role in the regulation of bcl-2 mRNA stability, bcl-2 ARE-binding proteins were purified from HL-60 cells. Three polypeptides of 100, 70, and 32 kDa were isolated from a bcl-2 ARE affinity matrix. Matrix-assisted laser desorption ionization mass spectroscopy analysis identified these proteins as full-length nucleolin and proteolytic fragments of nucleolin. RNA gel shifts assays indicated that recombinant nucleolin (residues 284–707) binds specifically to bcl-2 ARE RNA. In addition, recombinant nucleolin decreases the rate of decay of mRNA in HL-60 cell extracts in an ARE-dependent manner. Taxol or okadaic acid treatment of HL-60 cells results in proteolysis of nucleolin in a similar time frame as drug-induced bcl-2 mRNA down-regulation. These findings suggest that nucleolin functions as a bcl-2-stabilizing factor and that taxol and okadaic acid treatment induces apoptosis in HL-60 cells through a process that involves down-regulation of nucleolin and destabilization of bcl-2 mRNA.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Using the two-centre wave-packet convergent close-coupling approach, we continue our study of the proton–helium collision system. This method uses a correlated two-electron wave function to describe ...the helium target and discretises the continuum using wave-packet pseudostates. The cross section differential in the electron-emission energy and emission angle is calculated for incident-projectile energies in the intermediate range from 70 to 300 keV, where coupling between various channels and electron–electron correlation effects are important. We also apply an alternative, simpler approach that reduces the target to an effective single-electron system. Overall, the present results from both methods agree well with the available experimental data. This positions both implementations of the two-centre wave-packet convergent close-coupling approach well to further study other doubly differential, as well as fully differential, cross sections of single ionisation in proton–helium collisions.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Perinatal infection with Streptococcus agalactiae, or Group B Streptococcus (GBS), is associated with preterm birth, neonatal sepsis, and stillbirth. Here, we study the interactions of GBS with ...macrophages, essential sentinel immune cells that defend the gravid reproductive tract. Transcriptional analyses of GBS-macrophage co-cultures reveal enhanced expression of a gene encoding a putative metal resistance determinant, cadD. Deletion of cadD reduces GBS survival in macrophages, metal efflux, and resistance to metal toxicity. In a mouse model of ascending infection during pregnancy, the ΔcadD strain displays attenuated bacterial burden, inflammation, and cytokine production in gestational tissues. Furthermore, depletion of host macrophages alters cytokine expression and decreases GBS invasion in a cadD-dependent fashion. Our results indicate that GBS cadD plays an important role in metal detoxification, which promotes immune evasion and bacterial proliferation in the pregnant host.
B-cell chronic lymphocytic leukemia (CLL) is characterized by the accumulation of clonal B cells that are resistant to apoptosis as a result of bcl2 oncogene overexpression. Studies were done to ...determine the mechanism for the up-regulation of bcl-2 protein observed in CD19+ CLL cells compared with CD19+ B cells from healthy volunteers. The 11-fold higher level of bcl-2 protein in CLL cells was positively correlated with a 26-fold elevation in the cytosolic level of nucleolin, a bcl2 mRNA–stabilizing protein. Measurements of the bcl2 heterogeneous nuclear/bcl2 mRNA (hnRNA)/mRNA ratios and the rates of bcl2 mRNA decay in cell extracts indicated that the 3-fold higher steady-state level of bcl2 mRNA in CLL cells was the result of increased bcl2 mRNA stability. Nucleolin was present throughout the nucleus and cytoplasm of CLL cells, whereas in normal B cells nucleolin was only detected in the nucleus. The addition of recombinant human nucleolin to extracts of normal B cells markedly slowed the rate of bcl2 mRNA decay. SiRNA knockdown of nucleolin in MCF-7 cells resulted in decreased levels of bcl2 mRNA and protein but no change in β-actin. These results indicate that bcl-2 overexpression in CLL cells is related to stabilization of bcl2 mRNA by nucleolin.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The antiapoptotic Bcl-2 protein is overexpressed in a variety of cancers, particularly leukemias. In some cell types this is the result of enhanced stability of bcl-2 mRNA, which is controlled by ...elements in its 3′-untranslated region. Nucleolin is one of the proteins that binds to bcl-2 mRNA, thereby increasing its half-life. Here, we examined the site on the bcl-2 3′-untranslated region that is bound by nucleolin as well as the protein binding domains important for bcl-2 mRNA recognition. RNase footprinting and RNA fragment binding assays demonstrated that nucleolin binds to a 40-nucleotide region at the 5′ end of the 136-nucleotide bcl-2 AU-rich element (AREbcl-2). The first two RNA binding domains of nucleolin were sufficient for high affinity binding to AREbcl-2. In RNA decay assays, AREbcl-2 transcripts were protected from exosomal decay by the addition of nucleolin. AUF1 has been shown to recruit the exosome to mRNAs. When MV-4-11 cell extracts were immunodepleted of AUF1, the rate of decay of AREbcl-2 transcripts was reduced, indicating that nucleolin and AUF1 have opposing roles in bcl-2 mRNA turnover. When the function of nucleolin in MV-4-11 cells was impaired by treatment with the nucleolin-targeting aptamer AS1411, association of AUF1 with bcl-2 mRNA was increased. This suggests that the degradation of bcl-2 mRNA induced by AS1411 results from both interference with nucleolin protection of bcl-2 mRNA and recruitment of the exosome by AUF1. Based on our findings, we propose a model that illustrates the opposing roles of nucleolin and AUF1 in regulating bcl-2 mRNA stability.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Conventional measurements of river flows are costly, time-consuming, and frequently dangerous. This report evaluates the use of a continuous wave microwave radar, a monostatic UHF Doppler radar, a ...pulsed Doppler microwave radar, and a ground-penetrating radar to measure river flows continuously over long periods and without touching the water with any instruments. The experiments duplicate the flow records from conventional stream gauging stations on the San Joaquin River in California and the Cowlitz River in Washington. The purpose of the experiments was to directly measure the parameters necessary to compute flow: surface velocity (converted to mean velocity) and cross-sectional area, thereby avoiding the uncertainty, complexity, and cost of maintaining rating curves. River channel cross sections were measured by ground-penetrating radar suspended above the river. River surface water velocity was obtained by Bragg scattering of microwave and UHF Doppler radars, and the surface velocity data were converted to mean velocity on the basis of detailed velocity profiles measured by current meters and hydroacoustic instruments. Experiments using these radars to acquire a continuous record of flow were conducted for 4 weeks on the San Joaquin River and for 16 weeks on the Cowlitz River. At the San Joaquin River the radar noncontact measurements produced discharges more than 20% higher than the other independent measurements in the early part of the experiment. After the first 3 days, the noncontact radar discharge measurements were within 5% of the rating values. On the Cowlitz River at Castle Rock, correlation coefficients between the USGS stream gauging station rating curve discharge and discharge computed from three different Doppler radar systems and GPR data over the 16 week experiment were 0.883, 0.969, and 0.992. Noncontact radar results were within a few percent of discharge values obtained by gauging station, current meter, and hydroacoustic methods. Time series of surface velocity obtained by different radars in the Cowlitz River experiment also show small-amplitude pulsations not found in stage records that reflect tidal energy at the gauging station. Noncontact discharge measurements made during a flood on 30 January 2004 agreed with the rated discharge to within 5%. Measurement at both field sites confirm that lognormal velocity profiles exist for a wide range of flows in these rivers, and mean velocity is approximately 0.85 times measured surface velocity. Noncontact methods of flow measurement appear to (1) be as accurate as conventional methods, (2) obtain data when standard contact methods are dangerous or cannot be obtained, and (3) provide insight into flow dynamics not available from detailed stage records alone.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Previous (separately performed) perfusion CT (PCT) and PET studies have been inconclusive regarding the correlation of functional tumor characteristics. The purpose of this study was to perform dual ...assessment of head and neck squamous cell carcinomas (SCCAs) to examine the relationship between perfusion measurements derived from PCT and glucose standardized uptake values (SUV).
We prospectively evaluated 15 primary and recurrent SCCAs using combined positron-emission tomography (PET) and CT of the head and neck. SUV(mean), SUV(max), blood flow (BF), blood volume (BV), mean transit time (MTT), and permeability (PS) values were calculated with use of manually drawn regions of interest (ROIs) over the lesions and the healthy muscle tissue. Parametric comparison test, correlation coefficients, and regression analysis were performed.
The mean (+/- SD) SUV(mean), SUV(max), BF, BV, MTT, and PS values in the tumor tissue were 6.26 (+/- 1.48), 15.25 (+/- 3.81), 91.50 (+/- 24.69), 5.08 (+/- 1.17), 7.51 (+/- 2.24), and 23.08 (+/- 8.77), respectively. All PET/CT and PCT parameters of muscle versus tumor tissue were statistically different (.0001 < P < .001). There were significant correlations between BF and SUV(max) as well as SUV(mean) (r = 0.57; P = .02 and r = 0.63; P = .011, respectively) in the tumors. Significant correlation was also found between PS and SUV(mean) (r = 0.53; P = .04) in the tumors. Regression analysis showed: SUV(max) = 0.09 x BF + 7.2 (R(2) = 0.33; P = .02), SUV(mean) = 0.05 x BF + 2.22 (R(2) = 0.45; P = .011), and SUV(mean) = 0.05 x PS + 5.36 (R(2) = 0.35; P = .04). The tumor to nontumor (muscle) SUV(mean) and SUV(max) ratio was 9.45 (+/- 3.55) and 17.58 (+/- 4.32), respectively. BF-ratio SUV(mean) and BF-ratio SUV(max) showed significant correlations (r = 0.64; P = .01 and r = 0.53; P = .04, respectively). Regression analysis showed ratio SUV(mean) = 0.14 x BF-3.48 (R(2) = 0.42; P = .01) and ratio SUV(max) = 0.14 x BF + 4.51 (R(2) = 0.29; P = .04).
Tissue perfusion-metabolic coupling is evident in head and neck SCCAs and may provide additional diagnostic information in patients undergoing PET/CT studies.
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