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Abstract Three dominant characteristics and underlying dynamics of the seasonal cycle in Baffin Bay are discussed. The study is based on a regional, high‐resolution coupled sea ice‐ocean numerical model that complements our understanding drawn from observations. Subject to forcing from the atmosphere, sea ice, Greenland, and other ocean basins, the ocean circulation exhibits complex seasonal variations that influence Arctic freshwater storage and export. The basin‐scale barotropic circulation is generally stronger (weaker) in summer (winter). The interior recirculation (∼2 Sv) is primarily driven by oscillating along‐topography surface stress. The volume transport along the Baffin Island coast is also influenced by Arctic inflows (∼0.6 Sv) via Smith Sound and Lancaster Sound with maximum (minimum) in June‐August (October‐December). In addition to the barotropic variation, the Baffin Island Current also has changing vertical structure with the upper‐ocean baroclinicity weakened in winter‐spring. It is due to a cross‐shelf circulation associated with spatially variable ice‐ocean stresses that flattens isopycnals. Greenland runoff and sea ice processes dominate buoyancy forcing to Baffin Bay. Opposite to the runoff that freshens the west Greenland shelf, stronger salinification by ice formation compared to freshening by ice melt enables a net densification in the interior of Baffin Bay. Net sea ice formation in the past 30 years contributes to ∼25% of sea ice export via Davis Strait. The seasonal variability in baroclinicity and water mass transformation changes in recent decades based on the simulation. 

Abstract This study investigates the biogeochemical drivers of aragonite saturation state (Ω_Ar) in Baffin Bay, with a focus on the relatively undersampled west Greenland shelf. Our findings reveal two main depth‐dependant processes controlling the spatial distribution of Ω_Arin Baffin Bay; within the upper 200 m, lower Ω_Arcoincides with increasing fractions of Arctic‐outflow waters, while below 200 m organic matter respiration decreases Ω_Ar. A temporal analysis comparing historical measurements from 1997 and 2004 with our 2019 data set reveals a significant decrease in the Ω_Arof Arctic‐outflow waters, coinciding with reduced total alkalinity (TA). However, no discernible anthropogenic ocean acidification signal is identified. Significant Arctic water fractions (20%–40%) are found to be present on the west Greenland shelf, associated with reduced TA and Ω_Ar. A numerical modeling simulation incorporating a passive tracer demonstrates that periodic changes in wind direction lead to a switch from onshore to offshore Ekman transport along the Baffin Island current, transporting Arctic waters toward the west Greenland shelf. This challenges the conventional understanding of Baffin Bay's circulation and underscores the need for further research on the region's physical oceanography. Based on salinity‐TA relationships, surface waters on the west Greenland shelf have a significantly lower meteoric TA end‐member compared to waters of the Baffin Island Current in western Baffin Bay. The low eastern TA freshwater end‐member agrees well with recent glacial meltwater TA measurements, suggesting that glacial meltwater is the main freshwater source to surface waters on the west Greenland shelf. 

Abstract The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) plays a key role in tumor progression and response to therapy. The dense PDAC stroma causes hypovascularity, which leads to hypoxia. Here, we showed that hypoxia drives long-lasting epithelial–mesenchymal transition (EMT) in PDAC primarily through a positive-feedback histone methylation–MAPK signaling axis. Transformed cells preferentially underwent EMT in hypoxic tumor regions in multiple model systems. Hypoxia drove a cell autonomous EMT in PDAC cells, which, unlike EMT in response to growth factors, could last for weeks. Furthermore, hypoxia reduced histone demethylase KDM2A activity, suppressed PP2 family phosphatase expression, and activated MAPKs to post-translationally stabilize histone methyltransferase NSD2, leading to an H3K36me2-dependent EMT in which hypoxia-inducible factors played only a supporting role. Hypoxia-driven EMT could be antagonized in vivo by combinations of MAPK inhibitors. Collectively, these results suggest that hypoxia promotes durable EMT in PDAC by inducing a histone methylation–MAPK axis that can be effectively targeted with multidrug therapies, providing a potential strategy for overcoming chemoresistance. Significance:Integrated regulation of histone methylation and MAPK signaling by the low-oxygen environment of pancreatic cancer drives long-lasting EMT that promotes chemoresistance and shortens patient survival and that can be pharmacologically inhibited.See related commentary by Wirth and Schneider, p. 1739 

A full understanding of cell signaling processes requires knowledge of protein structure–function relationships, protein–protein interactions, and the abilities of pathways to control phenotypes. Computational models offer a valuable framework for integrating that knowledge to predict the effects of system perturbations and interventions in health and disease. Whereas mechanistic models are well suited for understanding the biophysical basis for signal transduction and principles of therapeutic design, data-driven models are particularly suited to distill complex signaling relationships among samples and between multivariate signaling changes and phenotypes. Both approaches have limitations and provide incomplete representations of signaling biology, but their careful implementation and integration can provide new understanding for how manipulating system variables impacts cellular decisions. 

Arctic Ocean gateway fluxes play a crucial role in linking the Arctic with the global ocean and affecting climate and marine ecosystems. We reviewed past studies on Arctic–Subarctic ocean linkages and examined their changes and driving mechanisms. Our review highlights that radical changes occurred in the inflows and outflows of the Arctic Ocean during the 2010s. Specifically, the Pacific inflow temperature in the Bering Strait and Atlantic inflow temperature in the Fram Strait hit record highs, while the Pacific inflow salinity in the Bering Strait and Arctic outflow salinity in the Davis and Fram straits hit record lows. Both the ocean heat convergence from lower latitudes to the Arctic and the hydrological cycle connecting the Arctic with Subarctic seas were stronger in 2000–2020 than in 1980–2000. CMIP6 models project a continuing increase in poleward ocean heat convergence in the 21st century, mainly due to warming of inflow waters. They also predict an increase in freshwater input to the Arctic Ocean, with the largest increase in freshwater export expected to occur in the Fram Strait due to both increased ocean volume export and decreased salinity. Fram Strait sea ice volume export hit a record low in the 2010s and is projected to continue to decrease along with Arctic sea ice decline. We quantitatively attribute the variability of the volume, heat, and freshwater transports in the Arctic gateways to forcing within and outside the Arctic based on dedicated numerical simulations and emphasize the importance of both origins in driving the variability. 

Activation of the epidermal growth factor (EGF) receptor (EGFR) at the cell surface initiates signaling through the RAS-RAF-MAPK/ERK1/2 pathway and receptor endocytosis. Whether this signaling continues from endosomes remains unclear, because RAS is predominantly located on the plasma membrane, and the localization of endogenous RAF kinases, downstream effectors of RAS, is not defined. To examine RAF localization, we labeled endogenous RAF1 with mVenus using gene editing. From 10 to 15% of RAF1-mVenus (<2000 molecules/cell), which was initially entirely cytosolic, transiently translocated to the plasma membrane after EGF stimulation. Following an early burst of translocation, the membrane-associated RAF1-mVenus was undetectable by microscopy or subcellular fractionation, and this pool was estimated to be <200 molecules per cell. In contrast, persistent EGF-dependent translocation of RAF1-mVenus to the plasma membrane was driven by the RAF inhibitor sorafenib, which increases the affinity of Ras-GTP:RAF1 interactions. RAF1-mVenus was not found in EGFR-containing endosomes under any conditions. Computational modeling of RAF1 dynamics revealed that RAF1 membrane abundance is controlled most prominently by association and dissociation rates from RAS-GTP and by RAS-GTP concentration. The model further suggested that the relatively protracted activation of the RAF-MEK1/2-ERK1/2 module, in comparison with RAF1 membrane localization, may involve multiple rounds of cytosolic RAF1 rebinding to active RAS at the membrane. 

Abstract BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta variant has caused a dramatic resurgence in infections in the United Sates, raising questions regarding potential transmissibility among vaccinated individuals. MethodsBetween October 2020 and July 2021, we sequenced 4439 SARS-CoV-2 full genomes, 23% of all known infections in Alachua County, Florida, including 109 vaccine breakthrough cases. Univariate and multivariate regression analyses were conducted to evaluate associations between viral RNA burden and patient characteristics. Contact tracing and phylogenetic analysis were used to investigate direct transmissions involving vaccinated individuals. ResultsThe majority of breakthrough sequences with lineage assignment were classified as Delta variants (74.6%) and occurred, on average, about 3 months (104 ± 57.5 days) after full vaccination, at the same time (June-July 2021) of Delta variant exponential spread within the county. Six Delta variant transmission pairs between fully vaccinated individuals were identified through contact tracing, 3 of which were confirmed by phylogenetic analysis. Delta breakthroughs exhibited broad viral RNA copy number values during acute infection (interquartile range, 1.2-8.64 Log copies/mL), on average 38% lower than matched unvaccinated patients (3.29-10.81 Log copies/mL, P < .00001). Nevertheless, 49% to 50% of all breakthroughs, and 56% to 60% of Delta-infected breakthroughs exhibited viral RNA levels above the transmissibility threshold (4 Log copies/mL) irrespective of time after vaccination. ConclusionsDelta infection transmissibility and general viral RNA quantification patterns in vaccinated individuals suggest limited levels of sterilizing immunity that need to be considered by public health policies. In particular, ongoing evaluation of vaccine boosters should specifically address whether extra vaccine doses curb breakthrough contribution to epidemic spread.