DNA methylation of promoter sequences is a repressive epigenetic mark that down-regulates gene expression. However, DNA methylation is more prevalent within gene-bodies than seen for promoters, and ...gene-body methylation has been observed to be positively correlated with gene expression levels. This paradox remains unexplained, and accordingly the role of DNA methylation in gene-bodies is poorly understood. We addressed the presence and role of human gene-body DNA methylation using a meta-analysis of human genome-wide methylation, expression and chromatin data sets. Methylation is associated with transcribed regions as genic sequences have higher levels of methylation than intergenic or promoter sequences. We also find that the relationship between gene-body DNA methylation and expression levels is non-monotonic and bell-shaped. Mid-level expressed genes have the highest levels of gene-body methylation, whereas the most lowly and highly expressed sets of genes both have low levels of methylation. While gene-body methylation can be seen to efficiently repress the initiation of intragenic transcription, the vast majority of methylated sites within genes are not associated with intragenic promoters. In fact, highly expressed genes initiate the most intragenic transcription inconsistent with the previously held notion that gene-body methylation serves to repress spurious intragenic transcription to allow for efficient transcriptional elongation. These observations lead us to propose a model to explain the presence of human gene-body methylation. This model holds that the repression of intragenic transcription by gene-body methylation is largely epiphenomenal, and suggests that gene-body methylation levels are predominantly shaped via the accessibility of the DNA to methylating enzyme complexes.
Radiative kernels at the top of the atmosphere are useful for decomposing
changes in atmospheric radiative fluxes due to feedbacks from atmosphere and
surface temperature, water vapor, and surface ...albedo. Here we describe and
validate radiative kernels calculated with the large-ensemble version of
CAM5, CESM1.1.2, at the top of the atmosphere and the surface. Estimates of
the radiative forcing from greenhouse gases and aerosols in RCP8.5 in the
CESM large-ensemble simulations are also diagnosed. As an application,
feedbacks are calculated for the CESM large ensemble. The kernels are freely
available at https://doi.org/10.5065/D6F47MT6, and accompanying software can be
downloaded from https://github.com/apendergrass/cam5-kernels.
The climatic implications of regional aerosol and precursor emissions reductions implemented to protect human health are poorly understood. We investigate the mean and extreme temperature response to ...regional changes in aerosol emissions using three coupled chemistry–climate models: NOAA GFDL CM3, NCAR CESM1, and NASA GISS-E2. Our approach contrasts a long present-day control simulation from each model (up to 400 years with perpetual year 2000 or 2005 emissions) with 14 individual aerosol emissions perturbation simulations (160–240 years each). We perturb emissions of sulfur dioxide (SO2) and/or carbonaceous aerosol within six world regions and assess the statistical significance of mean and extreme temperature responses relative to internal variability determined by the control simulation and across the models. In all models, the global mean surface temperature response (perturbation minus control) to SO2 and/or carbonaceous aerosol is mostly positive (warming) and statistically significant and ranges from +0.17 K (Europe SO2) to -0.06 K (US BC). The warming response to SO2 reductions is strongest in the US and Europe perturbation simulations, both globally and regionally, with Arctic warming up to 1 K due to a removal of European anthropogenic SO2 emissions alone; however, even emissions from regions remote to the Arctic, such as SO2 from India, significantly warm the Arctic by up to 0.5 K. Arctic warming is the most robust response across each model and several aerosol emissions perturbations. The temperature response in the Northern Hemisphere midlatitudes is most sensitive to emissions perturbations within that region. In the tropics, however, the temperature response to emissions perturbations is roughly the same in magnitude as emissions perturbations either within or outside of the tropics. We find that climate sensitivity to regional aerosol perturbations ranges from 0.5 to 1.0 K (W m(exp -2))(exp -1) depending on the region and aerosol composition and is larger than the climate sensitivity to a doubling of CO2 in two of three models. We update previous estimates of regional temperature potential (RTP), a metric for estimating the regional temperature responses to a regional emissions perturbation that can facilitate assessment of climate impacts with integrated assessment models without requiring computationally demanding coupled climate model simulations. These calculations indicate a robust regional response to aerosol forcing within the Northern Hemisphere midlatitudes, regardless of where the aerosol forcing is located longitudinally. We show that regional aerosol perturbations can significantly increase extreme temperatures on the regional scale. Except in the Arctic in the summer, extreme temperature responses largely mirror mean temperature responses to regional aerosol perturbations through a shift of the temperature distributions and are mostly dominated by local rather than remote aerosol forcing.
The inclusion of ethnicity in equations for estimating the glomerular filtration rate (eGFR) from serum creatinine levels has been challenged since ethnicity is socially defined and therefore a poor ...proxy for biological differences. We hypothesized that genetic ancestry (GA) would be more strongly associated with creatinine levels among healthy individuals than self-identified ethnicity. We studied a diverse cohort of 35,590 participants characterized as part of the UK Biobank, grouped by self-reported ethnicity: Black, East Asian, Mixed, Other, South Asian, and White. We used multivariable modeling to test for associations between ethnicity, GA, socioeconomic deprivation, and serum creatinine levels, including covariates for age, sex, height, and body mass index. Model fit comparisons and relative importance analysis were used to compare the effects of ethnicity and GA on creatinine levels. Black ethnicity shows a positive effect on participant serum creatinine levels (β = 9.36 ± 0.38), whereas East Asian (β = -1.80 ± 0.66) and South Asian (β = -0.28 ± 0.36) ethnicity show negative effects on creatinine. Male sex (β = 17.69 ± 0.34) and height (β = 0.13 ± 0.02) also show high positive associations with creatinine levels, while socioeconomic deprivation (β = -0.04 ± 0.04) shows no significant association. African ancestry has the highest association (β = 13.81 ± 0.52) with creatinine levels. Overall, GA (9.06%) explains significantly more of the variation in creatinine levels than ethnicity (4.96%), with African ancestry (6.36%) alone explaining more of the variation than ethnicity. We found that GA explains more of the variation in serum creatinine levels than socioeconomic deprivation, suggesting the possibility that ethnic differences in creatinine are shaped by genetic rather than social factors.
Results are presented from experiments performed with the Community Climate System Model, version 4 (CCSM4) for the Coupled Model Intercomparison Project phase 5 (CMIP5). These include multiple ...ensemble members of twentieth-century climate with anthropogenic and natural forcings as well as single-forcing runs, sensitivity experiments with sulfate aerosol forcing, twenty-first-century representative concentration pathway (RCP) mitigation scenarios, and extensions for those scenarios beyond 2100–2300. Equilibrium climate sensitivity of CCSM4 is 3.20°C, and the transient climate response is 1.73°C. Global surface temperatures averaged for the last 20 years of the twenty-first century compared to the 1986–2005 reference period for six-member ensembles from CCSM4 are +0.85°, +1.64°, +2.09°, and +3.53°C for RCP2.6, RCP4.5, RCP6.0, and RCP8.5, respectively. The ocean meridional overturning circulation (MOC) in the Atlantic, which weakens during the twentieth century in the model, nearly recovers to early twentieth-century values in RCP2.6, partially recovers in RCP4.5 and RCP6, and does not recover by 2100 in RCP8.5. Heat wave intensity is projected to increase almost everywhere in CCSM4 in a future warmer climate, with the magnitude of the increase proportional to the forcing. Precipitation intensity is also projected to increase, with dry days increasing in most subtropical areas. For future climate, there is almost no summer sea ice left in the Arctic in the high RCP8.5 scenario by 2100, but in the low RCP2.6 scenario there is substantial sea ice remaining in summer at the end of the century.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The unintended climatic implications of aerosol and precursor emission reductions implemented to protect public health are poorly understood. We investigate the precipitation response to regional ...changes in aerosol emissions using three coupled chemistry-climate models: NOAA Geophysical Fluid Dynamics Laboratory Coupled Model 3 (GFDL-CM3), NCAR Community Earth System Model (CESM1), and NASA Goddard Institute for Space Studies ModelE2 (GISS-E2). Our approach contrasts a long present-day control simulation from each model (up to 400 years with perpetual year 2000 or 2005 emissions) with 14 individual aerosol emissions perturbation simulations (160-240 years each). We perturb emissions of sulfur dioxide and/or carbonaceous aerosol within six world regions and assess the significance of precipitation responses relative to internal variability determined by the control simulation and across the models. Global and regional precipitation mostly increases when we reduce regional aerosol emissions in the models, with the strongest responses occurring for sulfur dioxide emissions reductions from Europe and the United States. Precipitation responses to aerosol emissions reductions are largest in the tropics and project onto the El Nino Southern Oscillation (ENSO). Regressing precipitation onto an Indo-Pacific zonal sea level pressure gradient index (a proxy for ENSO) indicates that the ENSO component of the precipitation response to regional aerosol removal can be as large as 20% of the total simulated response. Precipitation increases in the Sahel in response to aerosol reductions in remote regions because an anomalous interhemispheric temperature gradient alters the position of the Intertropical Convergence Zone (ITCZ). This mechanism holds across multiple aerosol reduction simulations and models.
This study uses coupled climate model experiments to identify the influence of atmospheric physics Community Atmosphere Model, versions 4 and 5 (CAM4; CAM5) and ocean model complexity (slab ocean, ...full-depth ocean) on the equilibrium Arctic climate response to an instantaneous CO₂ doubling. In slab ocean model (SOM) experiments using CAM4 and CAM5, local radiative feedbacks, not atmospheric heat flux convergence, are the dominant control on the Arctic surface response to increased greenhouse gas forcing. Equilibrium Arctic surface air temperature warming and amplification are greater in the CAM5 SOM experiment than in the equivalent CAM4 SOM experiment. Larger 2 × CO₂ radiative forcing, more positive Arctic surface albedo feedbacks, and less negative Arctic shortwave cloud feedbacks all contribute to greater Arctic surface warming and sea ice loss in CAM5 as compared to CAM4. When CAM4 is coupled to an active full-depth ocean model, Arctic Ocean horizontal heat flux convergence increases in response to the instantaneous CO₂ doubling. Though this increased ocean northward heat transport slightly enhances Arctic sea ice extent loss, the representation of atmospheric processes (CAM4 versus CAM5) has a larger influence on the equilibrium Arctic surface climate response than the degree of ocean coupling (slab ocean versus full-depth ocean). These findings underscore that local feedbacks can be more important than northward heat transport for explaining the equilibrium Arctic surface climate response and response differences in coupled climate models. That said, the processes explaining the equilibrium climate response differences here may be different than the processes explaining intermodel spread in transient climate projections.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cancer-derived extracellular vesicles (EVs) are membrane-enclosed structures of highly variable size. EVs contain a myriad of substances (proteins, lipid, RNA, DNA) that provide a reservoir of ...circulating molecules, thus offering a good source of biomarkers. We demonstrate here that large EVs (L-EV) (large oncosomes) isolated from prostate cancer (PCa) cells and patient plasma are an EV population that is enriched in chromosomal DNA, including large fragments up to 2 million base pair long. While L-EVs and small EVs (S-EV) (exosomes) isolated from the same cells contained similar amounts of protein, the DNA was more abundant in L-EVs, despite S-EVs being more numerous. Consistent with in vitro observations, the abundance of DNA in L-EV obtained from PCa patient plasma was variable but frequently high. Conversely, negligible amounts of DNA were present in the S-EVs from the same patients. Controlled experimental conditions, with spike-ins of L-EVs and S-EVs from cancer cells in human plasma from healthy subjects, showed that circulating DNA is almost exclusively enclosed in L-EVs. Whole genome sequencing revealed that the DNA in L-EVs reflects genetic aberrations of the cell of origin, including copy number variations of genes frequently altered in metastatic PCa (i.e. MYC, AKT1, PTK2, KLF10 and PTEN). These results demonstrate that L-EV-derived DNA reflects the genomic make-up of the tumour of origin. They also support the conclusion that L-EVs are the fraction of plasma EVs with DNA content that should be interrogated for tumour-derived genomic alterations.
Summary
For the past two decades, therapeutic and industrially important proteins have been expressed in plants with varying levels of success. The two major challenges hindering the economical ...production of plant‐made recombinant proteins include inadequate accumulation levels and the lack of efficient purification methods. To address these limitations, several fusion protein strategies have been recently developed to significantly enhance the production yield of plant‐made recombinant proteins, while simultaneously assisting in their subsequent purification. Elastin‐like polypeptides are thermally responsive biopolymers composed of a repeating pentapeptide ‘VPGXG’ sequence that are valuable for the purification of recombinant proteins. Hydrophobins are small fungal proteins capable of altering the hydrophobicity of their respective fusion partner, thus enabling efficient purification by surfactant‐based aqueous two‐phase systems. Zera, a domain of the maize seed storage protein γ‐zein, can induce the formation of protein storage bodies, thus facilitating the recovery of fused proteins using density‐based separation methods. These three novel protein fusion systems have also been shown to enhance the accumulation of a range of different recombinant proteins, while concurrently inducing the formation of protein bodies. The packing of these fusion proteins into protein bodies may exclude the recombinant protein from normal physiological turnover. Furthermore, these systems allow for quick, simple and inexpensive nonchromatographic purification of the recombinant protein, which can be scaled up to industrial levels of protein production. This review will focus on the similarities and differences of these artificial storage organelles, their biogenesis and their implication for the production of recombinant proteins in plants and their subsequent purification.
Elastin-like polypeptides are synthetic biopolymers composed of a repeating pentapeptide 'VPGXG' sequence that are valuable for the simple non-chromatographic purification of recombinant proteins. In ...addition, elastin-like polypeptide fusions have been shown to enhance the accumulation of a range of different recombinant proteins in plants, thus addressing the major limitation of plant-based expression systems, which is a low production yield. This study's main objectives were to determine the general utility of elastin-like polypeptide protein fusions in various intracellular compartments and to elucidate elastin-like polypeptide's mechanism of action for increasing recombinant protein accumulation in the endoplasmic reticulum of plants.
The effect of elastin-like polypeptide fusions on the accumulation of green fluorescent protein targeted to the cytoplasm, chloroplasts, apoplast, and endoplasmic reticulum was evaluated. The endoplasmic reticulum was the only intracellular compartment in which an elastin-like polypeptide tag was shown to significantly enhance recombinant protein accumulation. Interestingly, endoplasmic reticulum-targeted elastin-like polypeptide fusions induced the formation of a novel type of protein body, which may be responsible for elastin-like polypeptide's positive effect on recombinant protein accumulation by excluding the heterologous protein from normal physiological turnover. Although expressed in the leaves of plants, these novel protein bodies appeared similar in size and morphology to the prolamin-based protein bodies naturally found in plant seeds. The elastin-like polypeptide-induced protein bodies were highly mobile organelles, exhibiting various dynamic patterns of movement throughout the cells, which were dependent on intact actin microfilaments and a functional actomyosin motility system.
An endoplasmic reticulum-targeted elastin-like polypeptide fusion approach provides an effective strategy for depositing large amounts of concentrated heterologous protein within the limited space of the cell via storage in stable protein bodies. Furthermore, encapsulation of recombinant proteins into physiologically inert organelles can function to insulate the protein from normal cellular mechanisms, thus limiting unnecessary stress to the host cell. Since elastin-like polypeptide is a mammalian-derived protein, this study demonstrates that plant seed-specific factors are not required for the formation of protein bodies in vegetative plant tissues, suggesting that the endoplasmic reticulum possesses an intrinsic ability to form protein body-like accretions in eukaryotic cells when overexpressing particular proteins.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
