Short periods of intense rainfall may be associated with significant impacts on society, particularly urban flooding. Climate model projections have suggested an intensification of precipitation ...under scenarios of climate change. This is in accordance with the hypothesis that precipitation intensities will increase with temperature according to the thermodynamic Clausius-Clapyeron (CC) relation (a rate of ∼6-7% °C−1)-a warmer atmosphere being capable of holding more moisture. Consequently, CC scaling between temperature and extreme precipitation has been demonstrated in numerous studies and in different locations, with higher than CC scaling (so-called super CC scaling) observed for sub-daily extremes. Here we use a new dataset of UK hourly precipitation to identify seasonal scaling relationships between mean daily temperature and 99th percentile hourly precipitation intensities. Pooling the data for the whole UK indicates only slightly higher than CC scaling in spring and summer at higher temperatures, notably less than the 2xCC scaling observed in other regions. Both the highest hourly intensities and the highest scaling in the UK occur in summer and so for this season the dependency of the scaling relationship on large scale circulation conditions is examined using a set of air flow indices. A shear vorticity index (indicative of large-scale flow cyclonicity) is noted to have the greatest influence on the relationship, approaching 2xCC at higher temperatures when shear vorticity is negative (anticyclonic rotation). An examination of the occurrence of intense events indicates that these can occur under cyclonic and anticyclonic conditions but that in the south-east of England the latter conditions disproportionately favour their occurrence. These results suggest that changes in circulation regimes could modify the expected changes in precipitation intensities prescribed by CC scaling and arising as a consequence of future warming.
One third of deceased donor kidneys for transplantation in the UK are donated following cardiac death (DCD). Such kidneys have a high rate of delayed graft function (DGF) following transplantation. ...We conducted a multicenter, randomized controlled trial to determine whether kidney preservation using cold, pulsatile machine perfusion (MP) was superior to simple cold storage (CS) for DCD kidneys. One kidney from each DCD donor was randomly allocated to CS, the other to MP. A sequential trial design was used with the primary endpoint being DGF, defined as the necessity for dialysis within the first 7 days following transplant. The trial was stopped when data were available for 45 pairs of kidneys. There was no difference in the incidence of DGF between kidneys assigned to MP or CS (58% vs. 56%, respectively), in the context of an asystolic period of 15 min and median cold ischemic times of 13.9 h for MP and 14.3 h for CS kidneys. Renal function at 3 and 12 months was similar between groups, as was graft and patient survival. For kidneys from controlled DCD donors (with mean cold ischemic times around 14 h), MP offers no advantage over CS, which is cheaper and more straightforward.
Machine perfusion and simple cold storage of DCD kidneys produce equivalent transplant outcome in a UK multicentre randomised controlled trial. See editorial by Irish & Katz on page 1955.
Evidence that extreme rainfall intensity is increasing at the global scale has strengthened considerably in recent years. Research now indicates that the greatest increases are likely to occur in ...short‐duration storms lasting less than a day, potentially leading to an increase in the magnitude and frequency of flash floods. This review examines the evidence for subdaily extreme rainfall intensification due to anthropogenic climate change and describes our current physical understanding of the association between subdaily extreme rainfall intensity and atmospheric temperature. We also examine the nature, quality, and quantity of information needed to allow society to adapt successfully to predicted future changes, and discuss the roles of observational and modeling studies in helping us to better understand the physical processes that can influence subdaily extreme rainfall characteristics. We conclude by describing the types of research required to produce a more thorough understanding of the relationships between local‐scale thermodynamic effects, large‐scale atmospheric circulation, and subdaily extreme rainfall intensity.
Key Points
Significant increases in rainfall intensity are expected at subdaily time scalesDescribes link between subdaily extreme rainfall and atmospheric temperatureDiscusses role of observations and modeling to help understand future change
For more than a decade, scientists have argued about the warmth of the current interglaciation. Was the warmth of the preindustrial late Holocene natural in origin, the result of orbital changes that ...had not yet driven the system into a new glacial state? Or was it in considerable degree the result of humans intervening in the climate system through greenhouse gas emissions from early agriculture? Here we summarize new evidence that moves this debate forward by testing both hypotheses. By comparing late Holocene responses to those that occurred during previous interglaciations (in section 2), we assess whether the late Holocene responses look different (and thus anthropogenic) or similar (and thus natural). This comparison reveals anomalous (anthropogenic) signals. In section 3, we review paleoecological and archaeological syntheses that provide ground truth evidence on early anthropogenic releases of greenhouse gases. The available data document large early anthropogenic emissions consistent with the anthropogenic ice core anomalies, but more information is needed to constrain their size. A final section compares natural and anthropogenic interpretations of the δ13C trend in ice core CO2.
Key Points
Holocene ice core and ocean sediment trends are anomalous compared to previous interglaciations
Paleoecology and archaeology show that early farmers emitted large amounts of CO2 and CH4
Large early agricultural emissions are consistent with geochemical constraints
Inflammasomes are protein complexes assembled upon recognition of infection or cell damage signals, and serve as platforms for clustering and activation of procaspase-1. Oligomerisation of initiating ...proteins such as AIM2 (absent in melanoma-2) and NLRP3 (NOD-like receptor family, pyrin domain-containing-3) recruits procaspase-1 via the inflammasome adapter molecule ASC (apoptosis-associated speck-like protein containing a CARD). Active caspase-1 is responsible for rapid lytic cell death termed pyroptosis. Here we show that AIM2 and NLRP3 inflammasomes activate caspase-8 and -1, leading to both apoptotic and pyroptotic cell death. The AIM2 inflammasome is activated by cytosolic DNA. The balance between pyroptosis and apoptosis depended upon the amount of DNA, with apoptosis seen at lower transfected DNA concentrations. Pyroptosis had a higher threshold for activation, and dominated at high DNA concentrations because it happens more rapidly. Gene knockdown showed caspase-8 to be the apical caspase in the AIM2- and NLRP3-dependent apoptotic pathways, with little or no requirement for caspase-9. Procaspase-8 localised to ASC inflammasome 'specks' in cells, and bound directly to the pyrin domain of ASC. Thus caspase-8 is an integral part of the inflammasome, and this extends the relevance of the inflammasome to cell types that do not express caspase-1.
An mRNA Vaccine against SARS-CoV-2 - Preliminary Report Jackson, Lisa A; Anderson, Evan J; Rouphael, Nadine G ...
New England journal of medicine/The New England journal of medicine,
11/2020, Volume:
383, Issue:
20
Journal Article
Peer reviewed
Open access
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 and spread globally, prompting an international effort to accelerate development of a vaccine. The candidate ...vaccine mRNA-1273 encodes the stabilized prefusion SARS-CoV-2 spike protein.
We conducted a phase 1, dose-escalation, open-label trial including 45 healthy adults, 18 to 55 years of age, who received two vaccinations, 28 days apart, with mRNA-1273 in a dose of 25 μg, 100 μg, or 250 μg. There were 15 participants in each dose group.
After the first vaccination, antibody responses were higher with higher dose (day 29 enzyme-linked immunosorbent assay anti-S-2P antibody geometric mean titer GMT, 40,227 in the 25-μg group, 109,209 in the 100-μg group, and 213,526 in the 250-μg group). After the second vaccination, the titers increased (day 57 GMT, 299,751, 782,719, and 1,192,154, respectively). After the second vaccination, serum-neutralizing activity was detected by two methods in all participants evaluated, with values generally similar to those in the upper half of the distribution of a panel of control convalescent serum specimens. Solicited adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site. Systemic adverse events were more common after the second vaccination, particularly with the highest dose, and three participants (21%) in the 250-μg dose group reported one or more severe adverse events.
The mRNA-1273 vaccine induced anti-SARS-CoV-2 immune responses in all participants, and no trial-limiting safety concerns were identified. These findings support further development of this vaccine. (Funded by the National Institute of Allergy and Infectious Diseases and others; mRNA-1273 ClinicalTrials.gov number, NCT04283461).
We present an analysis of the orbital motion of the four substellar objects orbiting HR 8799. Our study relies on the published astrometric history of this system augmented with an epoch obtained ...with the Project 1640 coronagraph with an integral field spectrograph (IFS) installed at the Palomar Hale telescope. We first focus on the intricacies associated with astrometric estimation using the combination of an extreme adaptive optics system (PALM-3000), a coronagraph, and an IFS. We introduce two new algorithms. The first one retrieves the stellar focal plane position when the star is occulted by a coronagraphic stop. The second one yields precise astrometric and spectrophotometric estimates of faint point sources even when they are initially buried in the speckle noise. The second part of our paper is devoted to studying orbital motion in this system. In order to complement the orbital architectures discussed in the literature, we determine an ensemble of likely Keplerian orbits for HR 8799bcde, using a Bayesian analysis with maximally vague priors regarding the overall configuration of the system. Although the astrometric history is currently too scarce to formally rule out coplanarity, HR 8799d appears to be misaligned with respect to the most likely planes of HR 8799bce orbits. This misalignment is sufficient to question the strictly coplanar assumption made by various authors when identifying a Laplace resonance as a potential architecture. Finally, we establish a high likelihood that HR 8799de have dynamical masses below 13 M sub(jup), using a loose dynamical survival argument based on geometric close encounters. We illustrate how future dynamical analyses will further constrain dynamical masses in the entire system.
The goal of topical and cutaneous delivery is to deliver therapeutic and other substances to a desired target site in the skin at appropriate doses to achieve a safe and efficacious outcome.
...Normally, however, when the stratum corneum is intact and the skin barrier is uncompromised, this is limited to molecules that are relatively lipophilic, small and uncharged, thereby excluding many potentially useful therapeutic peptides, proteins, vaccines, gene fragments or drug-carrying particles. In this review we will describe how nanosystems are being increasingly exploited for topical and cutaneous delivery, particularly for these previously difficult substances. This is also being driven by the development of novel technologies, which include minimally invasive delivery systems and more precise fabrication techniques. While there is a vast array of nanosystems under development and many undergoing advanced clinical trials, relatively few have achieved full translation to clinical practice. This slow uptake may be due, in part, to the need for a rigorous demonstration of safety in these new nanotechnologies. Some of the safety aspects associated with nanosystems will be considered in this review.
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Current global warming necessitates a detailed understanding of the relationships between climate and global ice volume. Highly resolved and continuous sea-level records are essential for quantifying ...ice-volume changes. However, an unbiased study of the timing of past ice-volume changes, relative to polar climate change, has so far been impossible because available sea-level records either were dated by using orbital tuning or ice-core timescales, or were discontinuous in time. Here we present an independent dating of a continuous, high-resolution sea-level record in millennial-scale detail throughout the past 150,000 years. We find that the timing of ice-volume fluctuations agrees well with that of variations in Antarctic climate and especially Greenland climate. Amplitudes of ice-volume fluctuations more closely match Antarctic (rather than Greenland) climate changes. Polar climate and ice-volume changes, and their rates of change, are found to covary within centennial response times. Finally, rates of sea-level rise reached at least 1.2 m per century during all major episodes of ice-volume reduction.
Increasing evidence suggests that circulating tumour cells (CTCs) are responsible for metastatic relapse and this has fuelled interest in their detection and quantification. Although numerous methods ...have been developed for the enrichment and detection of CTCs, none has yet reached the ‘gold’ standard. Since epithelial cell adhesion molecule (EpCAM)-based enrichment of CTCs offers several advantages, it is one of the most commonly used and has been adapted for high-throughput technology. However, emerging evidence suggests that CTCs are highly heterogeneous: they consist of epithelial tumour cells, epithelial-to-mesenchymal transition (EMT) cells, hybrid (epithelial/EMT+) tumour cells, irreversible EMT+ tumour cells, and circulating tumour stem cells (CTSCs). The EpCAM-based approach does not detect CTCs expressing low levels of EpCAM and non-epithelial phenotypes such as CTSCs and those that have undergone EMT and no longer express EpCAM. Thus, the approach may lead to underestimation of the significance of CTCs, in general, and CTSCs and EMT+ tumour cells, in particular, in cancer dissemination. Here, we provide a critical review of research literature on the evolving concept of CTCs and the inadequacy of their enrichment by EpCAM-based technology for basic and clinical cancer research. The review also outlines future perspectives in the field.
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