Interspecies somatic cell nuclear transfer (iSCNT) involves the transfer of a nucleus or cell from one species into the cytoplasm of an enucleated oocyte from another. Once activated, reconstructed ...oocytes can be cultured in vitro to blastocyst, the final stage of preimplantation development. However, they often arrest during the early stages of preimplantation development; fail to reprogramme the somatic nucleus; and eliminate the accompanying donor cell's mitochondrial DNA (mtDNA) in favour of the recipient oocyte's genetically more divergent population. This last point has consequences for the production of ATP by the electron transfer chain, which is encoded by nuclear and mtDNA. Using a murine-porcine interspecies model, we investigated the importance of nuclear-cytoplasmic compatibility on successful development. Initially, we transferred murine fetal fibroblasts into enucleated porcine oocytes, which resulted in extremely low blastocyst rates (0.48%); and failure to replicate nuclear DNA and express Oct-4, the key marker of reprogramming. Using allele specific-PCR, we detected peak levels of murine mtDNA at 0.14±0.055% of total mtDNA at the 2-cell embryo stage and then at ever-decreasing levels to the blastocyst stage (<0.001%). Furthermore, these embryos had an overall mtDNA profile similar to porcine embryos. We then depleted porcine oocytes of their mtDNA using 10 µM 2',3'-dideoxycytidine and transferred murine somatic cells along with murine embryonic stem cell extract, which expressed key pluripotent genes associated with reprogramming and contained mitochondria, into these oocytes. Blastocyst rates increased significantly (3.38%) compared to embryos generated from non-supplemented oocytes (P<0.01). They also had significantly more murine mtDNA at the 2-cell stage than the non-supplemented embryos, which was maintained throughout early preimplantation development. At later stages, these embryos possessed 49.99±2.97% murine mtDNA. They also exhibited an mtDNA profile similar to murine preimplantation embryos. Overall, these data demonstrate that the addition of species compatible mtDNA and reprogramming factors improves developmental outcomes for iSCNT embryos.
A range of glycopolymers composed of N-acetylgalactosamine were prepared via sequential Cu(I)-mediated polymerization and alkyne-azide click (CuAAC). The resulting polymers were shown, via ...multichannel surface plasmon resonance, to interact specifically with human macrophage galactose lectin (MGL; CD301) with high affinity (K
= 1.11 μM), but they did not bind to the mannose/fucose-selective human lectin dendritic-cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN; CD209). The effect of sugar ligand valency on the binding (so-called "glycoside cluster effect") of poly(N-acetylgalactosamine) to MGL was investigated by varying first the polymer chain length (DP: 100, 64, 40, 23, 12) and then the architecture (4- and 8-arm star glycopolymers). The chain length did not have a significant effect on the binding to MGL (K
= 0.17-0.52 μM); however, when compared to a hepatic C-type lectin of a similar monosaccharide specificity, the asialoglycoprotein receptor (ASGPR), the binding affinity was more noticeably affected (K
= 0.37- 6.65 μM). These data suggest that known differences in the specific configuration/orientation of the carbohydrate recognition domains of MGL and ASGPR are responsible for the differences in binding observed between the different polymers of varied chain length and architecture. In the future, this model has the potential to be employed for the development of tissue-selective delivery systems.
Climate scientists have demonstrated that a substantial fraction of the probability of numerous recent extreme events may be attributed to human‐induced climate change. However, it is likely that for ...temperature extremes occurring over previous decades a fraction of their probability was attributable to anthropogenic influences. We identify the first record‐breaking warm summers and years for which a discernible contribution can be attributed to human influence. We find a significant human contribution to the probability of record‐breaking global temperature events as early as the 1930s. Since then, all the last 16 record‐breaking hot years globally had an anthropogenic contribution to their probability of occurrence. Aerosol‐induced cooling delays the timing of a significant human contribution to record‐breaking events in some regions. Without human‐induced climate change recent hot summers and years would be very unlikely to have occurred.
Key Points
We identify when the first attribution of heat extremes to anthropogenic climate change is possible
Earliest attribution to anthropogenic influences in the 1930s globally and the 1980s in many regions
Aerosol‐induced cooling delayed emergence of the anthropogenic signal in Northern Hemisphere regions
Dendritic cell specific intracellular adhesion molecule-3 (ICAM-3) grabbing nonintegrin (DC-SIGN), a C-type lectin present on the surface of dendritic cells, mediates the initial interaction of ...dendritic cells with T cells by binding to ICAM-3. DC-SIGN and DC-SIGNR, a related receptor found on the endothelium of liver sinusoids, placental capillaries, and lymph nodes, bind to oligosaccharides that are present on the envelope of human immunodeficiency virus (HIV), an interaction that strongly promotes viral infection of T cells. Crystal structures of carbohydrate-recognition domains of DC-SIGN and of DC-SIGNR bound to oligosaccharide, in combination with binding studies, reveal that these receptors selectively recognize endogenous high-mannose oligosaccharides and may represent a new avenue for developing HIV prophylactics.
Abstract Drug reprofiling is emerging as an effective paradigm for discovery of cancer treatments. Herein, an antipsychotic drug is immobilised using the Magic Tag® chemical genomics tool and ...screened against a T7 bacteriophage displayed library of polypeptides from Drosophila melanogaster , as a whole genome model, to uncover an interaction with a section of 17-β-HSD10, a proposed prostate cancer target. A computational study and enzyme inhibition assay with full length human 17-β-HSD10 identifies risperidone as a drug reprofiling candidate. When formulated with rumenic acid, risperidone slows proliferation of PC3 prostate cancer cells in vitro and retards PC3 prostate cancer tumour growth in vivo in xenografts in mice, presenting an opportunity to reprofile risperidone as a cancer treatment.
Given the Paris Agreement it is imperative there is greater understanding of the consequences of limiting global warming to the target 1.5° and 2°C levels above preindustrial conditions. It is ...challenging to quantify changes across a small increment of global warming, so a pattern-scaling approach may be considered. Here we investigate the validity of such an approach by comprehensively examining how well local temperatures and warming trends in a 1.5°C world predict local temperatures at global warming of 2°C. Ensembles of transient coupled climate simulations from multiple models under different scenarios were compared and individual model responses were analyzed. For many places, the multimodel forced response of seasonal-average temperatures is approximately linear with global warming between 1.5° and 2°C. However, individual model results vary and large contributions from nonlinear changes in unforced variability or the forced response cannot be ruled out. In some regions, such as East Asia, models simulate substantially greater warming than is expected from linear scaling. Examining East Asia during boreal summer, we find that increased warming in the simulated 2°C world relative to scaling up from 1.5°C is related to reduced anthropogenic aerosol emissions. Our findings suggest that, where forcings other than those due to greenhouse gas emissions change, the warming experienced in a 1.5°C world is a poor predictor for local climate at 2°C of global warming. In addition to the analysis of the linearity in the forced climate change signal, we find that natural variability remains a substantial contribution to uncertainty at these low-warming targets.
Both the dendritic cell receptor DC-SIGN and the closely related endothelial cell receptor DC-SIGNR bind human immunodeficiency virus and enhance infection. However, biochemical and structural ...comparison of these receptors now reveals that they have very different physiological functions. By screening an extensive glycan array, we demonstrated that DC-SIGN and DC-SIGNR have distinct ligand-binding properties. Our structural and mutagenesis data explain how both receptors bind high-mannose oligosaccharides on enveloped viruses and why only DC-SIGN binds blood group antigens, including those present on microorganisms. DC-SIGN mediates endocytosis, trafficking as a recycling receptor and releasing ligand at endosomal pH, whereas DC-SIGNR does not release ligand at low pH or mediate endocytosis. Thus, whereas DC-SIGN has dual ligand-binding properties and functions both in adhesion and in endocytosis of pathogens, DC-SIGNR binds a restricted set of ligands and has only the properties of an adhesion receptor.
Quantitative measurements of velocity for a low aspect ratio underexpanded elliptical jet are presented. Four jets at nozzle pressure ratios NPR = 2.2, 2.6, 3.4, 4.2 are studied for a smoothly ...contoured elliptical nozzle with an aspect ratio
a
/
b
= 2. High-resolution planar particle image velocimetry is used to extract information about the velocity fields and turbulent statistics. All four jets display the expected axis switching phenomenon, with the axis switching gaining strength with increasing pressure ratio. Evidence of regular reflection is seen for jets at pressure ratios of 2.6 and above. Measurements of fluctuating velocity indicate an oscillatory flapping mode in the minor axis plane for all but the highest pressure ratio. At the highest pressure ratio of NPR = 4.2, there is evidence of a cut-and-connect vortex bifurcation previously only observed for jets with higher aspect ratio.
Recent work has shown that the vertical structure of the Arctic polar vortex during different types of sudden stratospheric warming (SSW) events can be very distinctive. Specifically, SSWs can be ...classified into polar vortex displacement events or polar vortex splitting events. This paper aims to study the Arctic stratosphere during such events, with a focus on the stratopause using the Modern Era-Restrospective analysis for Research and Applications reanalysis data set. The reanalysis dataset is compared against two independent satellite reconstructions for validation purposes. During vortex displacement events, the stratopause temperature and pressure exhibit a wave-1 structure and are in quadrature whereas during vortex splitting events they exhibit a wave-2 structure. For both types of SSW the temperature anomalies at the stratopause are shown to be generated by ageostrophic vertical motions. Transformed Eulerian mean diagnostics are used to show differences in the planetary wave activity between displacement and splitting events. The convergence of Eliassen-Palm flux, which leads to SSWs is longer for displacement events and a persistent mesospheric Eliassen-Palm flux divergence can be observed about 20 days after displacement events. Finally, although this work focuses on the stratopause at high latitudes, associated observations of the equatorial middle atmosphere are also examined to explore links between the equator and polar evolution during SSWs.
U.K. Climate Projections Lo, Y. T. Eunice; Mitchell, Daniel M.; Bohnenstengel, Sylvia I. ...
Journal of climate,
10/2020, Volume:
33, Issue:
20
Journal Article
Peer reviewed
Open access
In the United Kingdom, where 90% of residents are projected to live in urban areas by 2050, projecting changes in urban heat islands (UHIs) is essential to municipal adaptation. Increased summer ...temperatures are linked to increased mortality. Using the new regional U.K. Climate Projections, UKCP18-regional, we estimate the 1981–2079 trends in summer urban and rural near-surface air temperatures and in UHI intensities during day and at night in the 10 most populous built-up areas in England. Summer temperatures increase by 0.45°–0.81°C per decade under RCP8.5, depending on the time of day and location. Nighttime temperatures increase more in urban than rural areas, enhancing the nighttime UHI by 0.01°–0.05°C per decade in all cities. When these upward UHI signals emerge from 2008–18 variability, positive summer nighttime UHI intensities of up to 1.8°C are projected in most cities. However, we can prevent most of these upward nighttime UHI signals from emerging by stabilizing climate to the Paris Agreement target of 2°C above preindustrial levels. In contrast, daytime UHI intensities decrease in nine cities, at rates between −0.004° and −0.05°C per decade, indicating a trend toward a reduced daytime UHI effect. These changes reflect different feedbacks over urban and rural areas and are specific to UKCP18-regional. Future research is important to better understand the drivers of these UHI intensity changes.
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