Altered eIF4A1 activity promotes translation of highly structured, eIF4A1-dependent oncogene mRNAs at root of oncogenic translational programmes. It remains unclear how these mRNAs recruit and ...activate eIF4A1 unwinding specifically to facilitate their preferential translation. Here, we show that single-stranded RNA sequence motifs specifically activate eIF4A1 unwinding allowing local RNA structural rearrangement and translation of eIF4A1-dependent mRNAs in cells. Our data demonstrate that eIF4A1-dependent mRNAs contain AG-rich motifs within their 5'UTR which specifically activate eIF4A1 unwinding of local RNA structure to facilitate translation. This mode of eIF4A1 regulation is used by mRNAs encoding components of mTORC-signalling and cell cycle progression, and renders these mRNAs particularly sensitive to eIF4A1-inhibition. Mechanistically, we show that binding of eIF4A1 to AG-rich sequences leads to multimerization of eIF4A1 with eIF4A1 subunits performing distinct enzymatic activities. Our structural data suggest that RNA-binding of multimeric eIF4A1 induces conformational changes in the RNA resulting in an optimal positioning of eIF4A1 proximal to the RNA duplex enabling efficient unwinding. Our data proposes a model in which AG-motifs in the 5'UTR of eIF4A1-dependent mRNAs specifically activate eIF4A1, enabling assembly of the helicase-competent multimeric eIF4A1 complex, and positioning these complexes proximal to stable localised RNA structure allowing ribosomal subunit scanning.
Meteorological frontal passages are recognized as important mechanisms for remobilizing sediment in estuaries along the northern Gulf of Mexico, but few studies have addressed factors beyond wind ...speed as a predictor for resuspension. To better understand resuspension mechanisms during these events, this study investigated the effects of wind, waves, and currents on suspended sediment concentration near the seabed during frontal passages in the shallow, micro-tidal West Galveston Bay located along the Texas coast. In late January and early February 2013, two multi-day deployments of instrumented pods (an acoustic Doppler velocimeter, and an acoustic wave and current profiler) were conducted to capture two separate frontal passages. The results indicate that the bed shear stress under the combined effect of waves and currents showed a much stronger relationship to sediment resuspension (R2 = 0.90) than wind stress alone (R2 = 0.55), or currents alone (R2 = 0.72). Increases in the bed shear stress due to the combined effects of waves and currents resulted from increased wave height, which is strongly related to fetch within the bay. Therefore, understanding fetch-limited wave heights as a function of wind speed and direction, in conjunction with basin geometry, may be a better way to predict sediment resuspension during meteorological frontal passages in the shallow bays of the northern Gulf of Mexico.
•Measured waves, currents, and suspended sediment in a estuary during a cold front.•Wave-current bed shear stress exhibited the strongest relationship to resuspension.•Wave heights and thus resuspension are increased with increased fetch.•Wave generation relative to fetch can better predict resuspension during the event.
The Brazos River is second only to the Mississippi River in terms of sediment load discharged to the Gulf of Mexico (GOM). This study focused on the interaction between a salt wedge and suspended ...sediment in the lower Brazos River, and the implications for sediment export to the coastal ocean. Salinity and turbidity (optical backscatter sensor) data with depth, swath bathymetry, and CHIRP sub-bottom profiling data were collected from 2007 to 2012 over various river discharge stages. Sampling locations included the lower-most 15km river reach and the coastal ocean proximal to the mouth. Results indicated that during low to moderate river discharges a salt wedge was present in the lower river, but absent during elevated fluvial discharge. Quantitative analysis showed the salt wedge within the river modulated sediment export to the GOM by trapping sediment along the lower most 9km reach. Within this reach the trapped sediment formed a decimeter-thick mud layer observed in the CHIRP and bathymetric data. At elevated fluvial discharges the salt wedge was no longer observed in the river, and the lower river reach transitioned from depositional to erosional. Based on the observations and analysis from this study, a fluvial discharge threshold where the salt wedge is not present in the river and sediment export to the coastal ocean was maximized was estimated. This threshold has been met or exceeded only ~10% of time since the 1960s. These conditions imply that sediment transport to the coastal ocean is highly variable, and occurs during irregular, pulsed events. This study highlights how estuarine conditions at the river mouth can impact terrestrial material flux to the coastal ocean.
•Salt wedge intrusion traps sediment in lower river.•Trapped sediment forms mud layer.•Presence of salt wedge modulates sediment flux to coastal ocean.•Salt wedge has impacted sediment export over 90% of the time.•Study highlights the importance of river mouth conditions for sediment export to the ocean.
The Brazos River Delta is located in the northwestern Gulf of Mexico. Sedimentation on the Brazos River subaqueous delta has been largely understudied. Swath bathymetry data collected across the ...subaqueous delta reveals a noticeable asymmetry with much deeper water depths and greater cross-shelf slopes along the eastern, up drift side of the delta than along the western, down-drift side. End-member sampling reveals that Brazos River derived sediment is red, red-brown, or brown in color, exhibits increased bulk density, and is enriched in calcium a function of carbonate-rich areas of the watershed, whereas the Gulf of Mexico inner shelf muds are gray to black and have a relatively lower calcium content. Analyses of a series of 33 submersible vibra cores collected across the subaqueous delta reveal alternating beds of Brazos River derived sediment and Gulf of Mexico shelf dominated sediment. Excess 210Pb geochronologies of select cores reveal that sediment accumulation has been a combination of fluvial flood event deposition, and deposition of remobilized sediment from the proximal shelf and older portions of the delta rather than steady state accumulation. Because the Brazos River is susceptible to local climatic cycles, fluvial flood events that create the event layers are intermittent between prolonged periods where marine processes drive accumulation. Results also show that the primary depocenter of the subaqueous delta has migrated southwestward over time, and the erosion of earlier depocenters and proximal shelf sediment has contributed to accumulation on the delta. Over the past ~50years the subaqueous delta has reached an equilibrium where flood event beds can be completely remobilized within a year, and net accumulation approximates relative sea level rise. This study highlights relatively rapid clinoform migration due to natural and anthropogenic changes to the system, and demonstrates subaqueous delta growth through a combination of direct fluvial and marine-derived sediment input.
•Sediment accumulated from flood events and reworked proximal shelf sediments•The depocenter migrated over time due to changes in the fluvial sediment supply•Current event beds can be completely remobilized within a year of deposition•Study shows delta accumulation through fluvial and marine-derived sediment inputs
A series of large storms attributed to Atmospheric River conditions struck the California coast in the winter of 1861-2. Although historical accounts document inland flooding, little is known about ...how the 1861-2 storms impacted the now heavily-developed California coast. Here we show that the 1861-2 storms emplaced a deposit of beach sand up to 50 cm thick over 450 m inland within a southern California salt marsh. This deposit is unprecedented in the post-European sediments of the marsh and more extensive than that derived from any other historical event. It is comparable in scale to hurricane and tsunami washover fans in back-barrier environments along other coastlines. The presence of overwash deposits in Carpinteria suggests that the 1861-2 storm season was erosive enough to remove coastal barriers, allowing for inundation of parts of the coastline currently developed. Efforts to prepare for a recurrence of an 1861-2-like storm season should address potential coastal impacts; likewise, interpretations of past washover deposits should consider these unusually prolonged stormy periods in addition to hurricane and tsunami inundation.
•1861-2 storms emplaced up to 50 cm of beach sand 450 m inland in a California estuary•First physical evidence that coastal erosion and inundation was produced by these storms•Deposit is comparable in scale to other hurricane and tsunami washover fans.•Duration of storm activity suppressed barrier recovery, maintaining a temporary inlet
Globally, deltas are increasingly threatened by anthropogenic activities. As a result, deltas now evolve through the combined effects of natural and human-induced processes occurring throughout the ...fluvial–deltaic system. The Brazos River delta, located along the Texas coast in the northwestern Gulf of Mexico, and its watershed have been impacted by direct and indirect human activities since the late 19th century. This provides an opportunity to investigate how such alterations have shaped the evolution of a delta in the Anthropocene, a time when humans are drivers of geological change. Historic alteration to the delta and watershed include extensive agricultural activity, jetty construction at the mouth in the late 1890s, mouth diversion ~10km to the southwest in 1929, and reservoir construction throughout the early and mid 20th Century. Three subaerial deltaic geometries provided the framework to connect subaerial deltaic responses, to the anthropogenic alterations, to the resulting stratigraphic characteristics observed in the subaqueous delta. This study utilized high-resolution geophysical data (swath bathymetry, side scan sonar, CHIRP subbottom profiling) on the subaqueous delta to investigate the subaqueous delta stratigraphy and infer the processes that shaped the deltaic record over time. The results showed distinct areas across the subaqueous delta that were dominated by erosion and deposition. Erosional areas corresponded to earlier growth phase depocenters being exposed at the surface, while the depositional areas corresponded to areas with the most recent growth phase depocenter overlying the earlier depocenters. These results highlight that the subaqueous depocenter has migrated westward over time, consistent with the observed changes to the subaerial delta. Additionally, the data showed that evidence for these past growth phases and depocenters may be preserved within the subaqueous delta, even after subaerial portions of the delta returned to pre-Anthropocene configurations. In general, this study showed that the subaqueous delta, similar to the subaerial delta, is impacted by human-driven alterations to the fluvial–deltaic system, and may preserve a more complete record of the evolution of deltas during the Anthropocene.
•Delta evolution resulting from natural and anthropogenic forcing.•Subaerial delta changes corresponded to subaqueous delta changes.•Depocenter migration from anthropogenic alterations to the system.•Depocenter migration results in clinoform initiation and abandonment cycles.•Record of Anthropocene evolution may be better preserved in the subaqueous delta.
Tumor hypoxia is commonly observed in primary solid malignancies but the hypoxic status of subclinical micrometastatic disease is largely unknown. The distribution of hypoxia in microscopic tumors ...was studied in animal models of disseminated peritoneal disease and intradermal (i.d.) growing tumors. Tumors derived from human colorectal adenocarcinoma cell lines HT29 and HCT-8 ranged in size from a few hundred microns to several millimeters in diameter. Hypoxia was detected by immunofluorescent visualization of pimonidazole and the hypoxia-regulated protein carbonic anhydrase 9. Tumor blood perfusion, cellular proliferation, and vascularity were visualized using Hoechst 33342, bromodeoxyuridine, and CD31 staining, respectively. In general, tumors of <1 mm diameter were intensely hypoxic, poorly perfused, and possessed little to no vasculature. Larger tumors (approximately 1-4 mm diameter) were well perfused with widespread vasculature and were not significantly hypoxic. Patterns of hypoxia in disseminated peritoneal tumors and i.d. tumors were similar. Levels of hypoxia in microscopic peritoneal tumors were reduced by carbogen breathing. Peritoneal and i.d. tumor models are suitable for studying hypoxia in microscopic tumors. If the patterns of tumor hypoxia in human patients are similar to those observed in these animal experiments, then the efficacy of systemic treatments of micrometastatic disease may be compromised by hypoxic resistance.
Tumor hypoxia and perfusion are independent prognostic indicators of patient outcome. We developed the methodology for and investigated the utility of multiparametric imaging of tumor hypoxia and ...perfusion with
18
F-fluoromisonidazole (
18
F-FMISO) dynamic PET (dPET) in head and neck cancer.
Methods:
One hundred twenty head and neck cancer patients underwent 0- to 30-min
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F-FMISO dPET in a customized immobilization mask, followed by 10-min static acquisitions starting at 93 ± 6 and 160 ± 13 min after injection. A total of 248 lesions (≥2 cm
3
) were analyzed. Voxelwise pharmacokinetic modeling was conducted using an irreversible 1-plasma 2-tissue-compartment model to calculate surrogate biomarkers of tumor hypoxia (
k
3
), perfusion (
K
1
), and
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F-FMISO distribution volume. The analysis was repeated with truncated dPET datasets.
Results:
Substantial inter- and intratumor heterogeneity was observed for all investigated metrics. Equilibration between the blood and unbound
18
F-FMISO was rapid in all tumors.
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F-FMISO distribution volume deviated from the expected value of unity, causing discrepancy between
k
3
maps and total
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F-FMISO uptake and reducing the dynamic range of total
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F-FMISO uptake for quantifying the degree of hypoxia. Both positive and negative trends between hypoxia and perfusion were observed in individual lesions. All investigated metrics were reproducible when calculated from a truncated 20-min dataset.
Conclusion:
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F-FMISO dPET provides the data necessary to generate parametric maps of tumor hypoxia, perfusion, and radiotracer distribution volume. These data clarify the ambiguity in interpreting
18
F-FMISO uptake and improve the characterization of lesions. We show total acquisition times can be reduced to 20 min, facilitating the translation of
18
F-FMISO dPET into the clinic.
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