The tumor suppressor p53 functions primarily as a transcription factor. Mutation of the TP53 gene alters its response pathway, and is central to the development of many cancers. The discovery of a ...large number of p53 target genes, which confer p53's tumor suppressor function, has led to increasingly complex models of p53 function. Recent meta-analysis approaches, however, are simplifying our understanding of how p53 functions as a transcription factor. In the survey presented here, a total set of 3661 direct p53 target genes is identified that comprise 3509 potential targets from 13 high-throughput studies, and 346 target genes from individual gene analyses. Comparison of the p53 target genes reported in individual studies with those identified in 13 high-throughput studies reveals limited consistency. Here, p53 target genes have been evaluated based on the meta-analysis data, and the results show that high-confidence p53 target genes are involved in multiple cellular responses, including cell cycle arrest, DNA repair, apoptosis, metabolism, autophagy, mRNA translation and feedback mechanisms. However, many p53 target genes are identified only in a small number of studies and have a higher likelihood of being false positives. While numerous mechanisms have been proposed for mediating gene regulation in response to p53, recent advances in our understanding of p53 function show that p53 itself is solely an activator of transcription, and gene downregulation by p53 is indirect and requires p21. Taking into account the function of p53 as an activator of transcription, recent results point to an unsophisticated means of regulation.
Understanding core formation in meteorite parent bodies is critical for constraining the fundamental processes of protoplanet accretion and differentiation within the solar protoplanetary disk. We ...report variations of 5 to 20 parts per million in (182)W, resulting from the decay of now-extinct (182)Hf, among five magmatic iron meteorite groups. These (182)W variations indicate that core formation occurred over an interval of ~1 million years and may have involved an early segregation of Fe-FeS and a later segregation of Fe melts. Despite this protracted interval of core formation, the iron meteorite parent bodies probably accreted concurrently ~0.1 to 0.3 million years after the formation of Ca-Al-rich inclusions. Variations in volatile contents among these bodies, therefore, did not result from accretion at different times from an incompletely condensed solar nebula but must reflect local processes within the nebula.
Abstract
Cardiac output (CO) measurement is crucial for the guidance of therapeutic decisions in critically ill and high-risk surgical patients. Newly developed completely non-invasive CO ...technologies are commercially available; however, their accuracy and precision have not recently been evaluated in a meta-analysis. We conducted a systematic search using PubMed, Cochrane Library of Clinical Trials, Scopus, and Web of Science to review published data comparing CO measured by bolus thermodilution with commercially available non-invasive technologies including pulse wave transit time, non-invasive pulse contour analysis, thoracic electrical bioimpedance/bioreactance, and CO2 rebreathing. The non-invasive CO technology was considered acceptable if the pooled estimate of percentage error was <30%, as previously recommended. Using a random-effects model, sd, pooled mean bias, and mean percentage error were calculated. An I2 statistic was also used to evaluate the inter-study heterogeneity. A total of 37 studies (1543 patients) were included. Mean CO of both methods was 4.78 litres min−1. Bias was presented as the reference method minus the tested methods in 15 studies. Only six studies assessed the random error (repeatability) of the tested device. The overall random-effects pooled bias (limits of agreement) and the percentage error were −0,13 −2.38 , 2.12 litres min−1 and 47%, respectively. Inter-study sensitivity heterogeneity was high (I2=83%, P<0.001). With a wide percentage error, completely non-invasive CO devices are not interchangeable with bolus thermodilution. Additional studies are warranted to demonstrate their role in improving the quality of care.
The Russian heatwave in 2010 killed tens of thousands of people, and was by far the worst event in Europe since at least 1950, according to recent studies and a novel universal heatwave index ...capturing both the duration and magnitude of heatwaves. Here, by taking an improved version of this index, namely the heat wave magnitude index daily, we rank the top ten European heatwaves that occurred in the period 1950-2014, and show the spatial distribution of the magnitude of the most recent heatwave in summer 2015. We demonstrate that all these events had a strong impact reported in historical newspapers. We further reveal that the 1972 heatwave in Finland had a comparable spatial extent and magnitude as the European heatwave of 2003, considered the second strongest heatwave of the observational era. In the next two decades (2021-2040), regional climate projections suggest that Europe experiences an enhanced probability for heatwaves comparable to or greater than the magnitude, extent and duration of the Russian heatwave in 2010. We demonstrate that the probability of experiencing a major European heatwave in the coming decades is higher in RCP8.5 than RCP4.5 even though global mean temperature projections do not differ substantially. This calls for a proactive vulnerability assessment in Europe in support of formulating heatwave adaptation strategies to reduce the adverse impacts of heatwaves.
Thin-film dye-sensitized solar cells (DSCs) based on mesoporous semiconductor electrodes are low-cost alternatives to conventional silicon devices. High-efficiency DSCs typically operate as ...photoanodes (n-DSCs), where photocurrents result from dye-sensitized electron injection into n-type semiconductors. Dye-sensitized photocathodes (p-DSCs) operate in an inverse mode, where dye-excitation is followed by rapid electron transfer from a p-type semiconductor to the dye (dye-sensitized hole injection). Such p-DSCs and n-DSCs can be combined to construct tandem solar cells (pn-DSCs) with a theoretical efficiency limitation well beyond that of single-junction DSCs (ref. 4). Nevertheless, the efficiencies of such tandem pn-DSCs have so far been hampered by the poor performance of the available p-DSCs (refs 3, 5-15). Here we show for the first time that p-DSCs can convert absorbed photons to electrons with yields of up to 96%, resulting in a sevenfold increase in energy conversion efficiency compared with previously reported photocathodes. The donor-acceptor dyes, studied as photocathodic sensitizers, comprise a variable-length oligothiophene bridge, which provides control over the spatial separation of the photogenerated charge carriers. As a result, charge recombination is decelerated by several orders of magnitude and tandem pn-DSCs can be constructed that exceed the efficiency of their individual components.
Recombinant adeno-associated virus (AAV) is the leading vector for gene therapy in the retina. As non-pathogenic, non-integrating, replication deficient vector, the recombinant virus efficiently ...transduces all key retinal cell populations. Successful testing of AAV vectors in clinical trials of inherited retinal diseases led to the recent approval of voretigene neparvovec (Luxturna) for the treatment of RPE65 mutation-associated retinal dystrophies. However, studies applying AAV-mediated retinal gene therapy independently reported intraocular inflammation and/or loss of efficacy after initial functional improvements. Both observations might be explained by targeted removal of transduced cells via anti-viral defence mechanisms. AAV has been shown to activate innate pattern recognition receptors (PRRs) such as toll-like receptor (TLR)-2 and TLR-9 resulting in the release of inflammatory cytokines and type I interferons. The vector can also induce capsid-specific and transgene-specific T cell responses and neutralizing anti-AAV antibodies which both limit the therapeutic effect. However, the target organ of retinal gene therapy, the eye, is known as an immune-privileged site. It is characterized by suppression of inflammation and promotion of immune tolerance which might prevent AAV-induced immune responses. This review evaluates AAV-related immune responses, toxicity and inflammation in studies of retinal gene therapy, identifies influencing variables of these responses and discusses potential strategies to modulate immune reactions to AAV vectors to increase the safety and efficacy of ocular gene therapy.
Severe, extreme, and exceptional heat waves, such as those that occurred over the Balkans (2007), France (2003), or Russia (2010), are associated with increased mortality, human discomfort and ...reduced labour productivity. Based on the results of a very high-resolution global model, we show that, even at 1.5 °C warming, a significant increase in heat wave magnitude is expected over Africa, South America, and Southeast Asia. Compared to a 1.5 °C world, under 2 °C warming the frequency of extreme heat waves would double over most of the globe. In a 1.5 °C world, 13.8% of the world population will be exposed to severe heat waves at least once every 5 years. This fraction becomes nearly three times larger (36.9%) under 2 °C warming, i.e. a difference of around 1.7 billion people. Limiting global warming to 1.5 °C will also result in around 420 million fewer people being frequently exposed to extreme heat waves, and ~65 million to exceptional heat waves. Nearly 700 million people (9.0% of world population) will be exposed to extreme heat waves at least once every 20 years in a 1.5 °C world, but more than 2 billion people (28.2%) in a 2 °C world. With current emission trends threatening even the 2 °C target, our study is helpful to identify regions where limiting the warming to 1.5 °C would have the strongest benefits in reducing population exposure to extreme heat.
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