Franksecher9357

Further analysis showed that hypomethylation in the promoter region enhanced miR-196b-5p expression in NSCLC. Our findings indicate that QKI-5 may exhibit novel anticancer mechanisms by regulating miRNA in NSCLC, and targeting the QKI5∼miR-196b-5p∼GATA6/TSPAN12 pathway may enable effectively treating some NSCLCs.Anthrax lethal toxin (LT) is a protease virulence factor produced by Bacillus anthracis that is required for its pathogenicity. LT treatment causes a rapid degradation of c-Jun protein that follows inactivation of the MEK1/2-Erk1/2 signaling pathway. Here we identify COP1 as the ubiquitin E3 ligase that is essential for LT-induced c-Jun degradation. COP1 knockdown using siRNA prevents degradation of c-Jun, ETV4, and ETV5 in cells treated with either LT or the MEK1/2 inhibitor, U0126. Immunofluorescence staining reveals that COP1 preferentially localizes to the nuclear envelope, but it is released from the nuclear envelope into the nucleoplasm following Erk1/2 inactivation. AZ 628 At baseline, COP1 attaches to the nuclear envelope via interaction with translocated promoter region (TPR), a component of the nuclear pore complex. Disruption of this COP1-TPR interaction, through Erk1/2 inactivation or TPR knockdown, leads to rapid COP1 release from the nuclear envelope into the nucleoplasm where it degrades COP1 substrates. COP1-mediated degradation of c-Jun protein, combined with LT-mediated blockade of the JNK1/2 signaling pathway, inhibits cellular proliferation. This effect on proliferation is reversed by COP1 knockdown and ectopic expression of an LT-resistant MKK7-4 fusion protein. Taken together, this study reveals that the nuclear envelope acts as a reservoir, maintaining COP1 poised for action. Upon Erk1/2 inactivation, COP1 is rapidly released from the nuclear envelope, promoting the degradation of its nuclear substrates, including c-Jun, a critical transcription factor that promotes cellular proliferation. This regulation allows mammalian cells to respond rapidly to changes in extracellular cues and mediates pathogenic mechanisms in disease states.Global perturbations to the Early Jurassic environment (∼201 to ∼174 Ma), notably during the Triassic-Jurassic transition and Toarcian Oceanic Anoxic Event, are well studied and largely associated with volcanogenic greenhouse gas emissions released by large igneous provinces. The long-term secular evolution, timing, and pacing of changes in the Early Jurassic carbon cycle that provide context for these events are thus far poorly understood due to a lack of continuous high-resolution δ13C data. Here we present a δ13CTOC record for the uppermost Rhaetian (Triassic) to Pliensbachian (Lower Jurassic), derived from a calcareous mudstone succession of the exceptionally expanded Llanbedr (Mochras Farm) borehole, Cardigan Bay Basin, Wales, United Kingdom. Combined with existing δ13CTOC data from the Toarcian, the compilation covers the entire Lower Jurassic. The dataset reproduces large-amplitude δ13CTOC excursions (>3‰) recognized elsewhere, at the Sinemurian-Pliensbachian transition and in the lower Toarcian serpentinum zone, as well as several previously identified medium-amplitude (∼0.5 to 2‰) shifts in the Hettangian to Pliensbachian interval. In addition, multiple hitherto undiscovered isotope shifts of comparable amplitude and stratigraphic extent are recorded, demonstrating that those similar features described earlier from stratigraphically more limited sections are nonunique in a long-term context. These shifts are identified as long-eccentricity (∼405-ky) orbital cycles. Orbital tuning of the δ13CTOC record provides the basis for an astrochronological duration estimate for the Pliensbachian and Sinemurian, giving implications for the duration of the Hettangian Stage. Overall the chemostratigraphy illustrates particular sensitivity of the marine carbon cycle to long-eccentricity orbital forcing. Copyright © 2020 the Author(s). Published by PNAS.Because few ice core records from the Himalayas exist, understanding of the onset and timing of the human impact on the atmosphere of the "roof of the world" remains poorly constrained. We report a continuous 500-y trace metal ice core record from the Dasuopu glacier (7,200 m, central Himalayas), the highest drilling site on Earth. We show that an early contamination from toxic trace metals, particularly Cd, Cr, Mo, Ni, Sb, and Zn, emerged at high elevation in the Himalayas at the onset of the European Industrial Revolution (∼1780 AD). This was amplified by the intensification of the snow accumulation (+50% at Dasuopu) likely linked to the meridional displacement of the winter westerlies from 1810 until 1880 AD. During this period, the flux and crustal enrichment factors of the toxic trace metals were augmented by factors of 2 to 4 and 2 to 6, respectively. We suggest this contamination was the consequence of the long-range transport and wet deposition of fly ash from the combustion of coal (likely from Western Europe where it was almost entirely produced and used during the 19th century) with a possible contribution from the synchronous increase in biomass burning emissions from deforestation in the Northern Hemisphere. The snow accumulation decreased and dry winters were reestablished in Dasuopu after 1880 AD when lower than expected toxic metal levels were recorded. This indicates that contamination on the top of the Himalayas depended primarily on multidecadal changes in atmospheric circulation and secondarily on variations in emission sources during the last 200 y.Although regional haze adversely affects human health and possibly counteracts global warming from increasing levels of greenhouse gases, the formation and radiative forcing of regional haze on climate remain uncertain. By combining field measurements, laboratory experiments, and model simulations, we show a remarkable role of black carbon (BC) particles in driving the formation and trend of regional haze. Our analysis of long-term measurements in China indicates declined frequency of heavy haze events along with significantly reduced SO2, but negligibly alleviated haze severity. Also, no improving trend exists for moderate haze events. Our complementary laboratory experiments demonstrate that SO2 oxidation is efficiently catalyzed on BC particles in the presence of NO2 and NH3, even at low SO2 and intermediate relative humidity levels. Inclusion of the BC reaction accounts for about 90-100% and 30-50% of the sulfate production during moderate and heavy haze events, respectively. Calculations using a radiative transfer model and accounting for the sulfate formation on BC yield an invariant radiative forcing of nearly zero W m-2 on the top of the atmosphere throughout haze development, indicating small net climatic cooling/warming but large surface cooling, atmospheric heating, and air stagnation.