Diabetic nephropathy is characterized by damage to both the glomerulus and tubulointerstitium, but relatively little is known about accompanying cell-specific changes in gene expression. We performed ...unbiased single-nucleus RNA sequencing (snRNA-seq) on cryopreserved human diabetic kidney samples to generate 23,980 single-nucleus transcriptomes from 3 control and 3 early diabetic nephropathy samples. All major cell types of the kidney were represented in the final dataset. Side-by-side comparison demonstrated cell-type–specific changes in gene expression that are important for ion transport, angiogenesis, and immune cell activation. In particular, we show that the diabetic thick ascending limb, late distal convoluted tubule, and principal cells all adopt a gene expression signature consistent with increased potassium secretion, including alterations in Na⁺/K⁺-ATPase, WNK1, mineralocorticoid receptor, and NEDD4L expression, as well as decreased paracellular calcium and magnesium reabsorption. We also identify strong angiogenic signatures in glomerular cell types, proximal convoluted tubule, distal convoluted tubule, and principal cells. Taken together, these results suggest that increased potassium secretion and angiogenic signaling represent early kidney responses in human diabetic nephropathy.
The response of Earth’s climate system to orbital forcing has been highly state dependent over the past 66 million years.
The states of past climate
Deep-sea benthic foraminifera preserve an ...essential record of Earth's past climate in their oxygen- and carbon-isotope compositions. However, this record lacks sufficient temporal resolution and/or age control in some places to determine which climate forcing and feedback mechanisms were most important. Westerhold
et al.
present a highly resolved and well-dated record of benthic carbon and oxygen isotopes for the past 66 million years. Their reconstruction and analysis show that Earth's climate can be grouped into discrete states separated by transitions related to changing greenhouse gas levels and the growth of polar ice sheets. Each climate state is paced by orbital cycles but responds to variations in radiative forcing in a state-dependent manner.
Science
, this issue p.
1383
Much of our understanding of Earth’s past climate comes from the measurement of oxygen and carbon isotope variations in deep-sea benthic foraminifera. Yet, long intervals in existing records lack the temporal resolution and age control needed to thoroughly categorize climate states of the Cenozoic era and to study their dynamics. Here, we present a new, highly resolved, astronomically dated, continuous composite of benthic foraminifer isotope records developed in our laboratories. Four climate states—Hothouse, Warmhouse, Coolhouse, Icehouse—are identified on the basis of their distinctive response to astronomical forcing depending on greenhouse gas concentrations and polar ice sheet volume. Statistical analysis of the nonlinear behavior encoded in our record reveals the key role that polar ice volume plays in the predictability of Cenozoic climate dynamics.
The cause of the end-Cretaceous mass extinction is vigorously debated, owing to the occurrence of a very large bolide impact and flood basalt volcanism near the boundary. Disentangling their relative ...importance is complicated by uncertainty regarding kill mechanisms and the relative timing of volcanogenic outgassing, impact, and extinction. We used carbon cycle modeling and paleotemperature records to constrain the timing of volcanogenic outgassing. We found support for major outgassing beginning and ending distinctly before the impact, with only the impact coinciding with mass extinction and biologically amplified carbon cycle change. Our models show that these extinction-related carbon cycle changes would have allowed the ocean to absorb massive amounts of carbon dioxide, thus limiting the global warming otherwise expected from postextinction volcanism.
Thousands of transiting exoplanets have been discovered, but spectral analysis of their atmospheres has so far been dominated by a small number of exoplanets and data spanning relatively narrow ...wavelength ranges (such as 1.1-1.7 micrometres). Recent studies show that some hot-Jupiter exoplanets have much weaker water absorption features in their near-infrared spectra than predicted. The low amplitude of water signatures could be explained by very low water abundances, which may be a sign that water was depleted in the protoplanetary disk at the planet's formation location, but it is unclear whether this level of depletion can actually occur. Alternatively, these weak signals could be the result of obscuration by clouds or hazes, as found in some optical spectra. Here we report results from a comparative study of ten hot Jupiters covering the wavelength range 0.3-5 micrometres, which allows us to resolve both the optical scattering and infrared molecular absorption spectroscopically. Our results reveal a diverse group of hot Jupiters that exhibit a continuum from clear to cloudy atmospheres. We find that the difference between the planetary radius measured at optical and infrared wavelengths is an effective metric for distinguishing different atmosphere types. The difference correlates with the spectral strength of water, so that strong water absorption lines are seen in clear-atmosphere planets and the weakest features are associated with clouds and hazes. This result strongly suggests that primordial water depletion during formation is unlikely and that clouds and hazes are the cause of weaker spectral signatures.
Abstract
The Piacenzian stage of the Pliocene (2.6 to 3.6 Ma) is the most recent past interval of sustained global warmth with mean global temperatures markedly higher (by ~2–3 °C) than today. ...Quantifying CO
2
levels during the mid-Piacenzian Warm Period (mPWP) provides a means, therefore, to deepen our understanding of Earth System behaviour in a warm climate state. Here we present a new high-resolution record of atmospheric CO
2
using the δ
11
B-pH proxy from 3.35 to 3.15 million years ago (Ma) at a temporal resolution of 1 sample per 3–6 thousand years (kyrs). Our study interval covers both the coolest marine isotope stage of the mPWP, M2 (~3.3 Ma) and the transition into its warmest phase including interglacial KM5c (centered on ~3.205 Ma) which has a similar orbital configuration to present. We find that CO
2
ranged from
$${{\bf{394}}}_{{\boldsymbol{-}}{\bf{9}}}^{{\boldsymbol{+}}{\bf{34}}}$$
394
−
9
+
34
ppm to
$${{\bf{330}}}_{{\boldsymbol{-}}{\bf{21}}}^{{\boldsymbol{+}}{\bf{14}}}$$
330
−
21
+
14
ppm: with CO
2
during the KM5c interglacial being
$${{\bf{391}}}_{{\boldsymbol{-}}{\bf{28}}}^{{\boldsymbol{+}}{\bf{30}}}$$
391
−
28
+
30
ppm (at 95% confidence). Our findings corroborate the idea that changes in atmospheric CO
2
levels played a distinct role in climate variability during the mPWP. They also facilitate ongoing data-model comparisons and suggest that, at present rates of human emissions, there will be more CO
2
in Earth’s atmosphere by 2025 than at any time in at least the last 3.3 million years.
Abstract There have been many developments in operative dentistry in recent years, including a progressive shift to the use of resin composites, rather than dental amalgam, in the restoration of ...posterior teeth. This shift allows the adoption of minimal intervention approaches, thereby helping to conserve and preserve remaining tooth tissues and structures. This paper presents the position of the Academy of Operative Dentistry European Section (AODES) in relation to posterior resin composites. The AODES considers adhesively bonded resin composites of suitable composition and properties to be the “material of choice” for use in direct minimal intervention approaches to the restoration of posterior teeth. In so doing, the AODES emphasises the importance of the practice of evidence-based minimal intervention dentistry, including the use of refurbishment and repair techniques to extend the longevity of restorations. Guidance, based on best available evidence, has been made in relation to certain aspects of resin composite placement techniques in posterior teeth.
Dredging can have significant impacts on aquatic environments, but the direct effects on fish have not been critically evaluated. Here, a meta‐analysis following a conservative approach is used to ...understand how dredging‐related stressors, including suspended sediment, contaminated sediment, hydraulic entrainment and underwater noise, directly influence the effect size and the response elicited in fish across all aquatic ecosystems and all life‐history stages. This is followed by an in‐depth review summarizing the effects of each dredging‐related stressor on fish. Across all dredging‐related stressors, studies that reported fish mortality had significantly higher effect sizes than those that describe physiological responses, although indicators of dredge impacts should endeavour to detect effects before excessive mortality occurs. Studies examining the effects of contaminated sediment also had significantly higher effect sizes than studies on clean sediment alone or noise, suggesting additive or synergistic impacts from dredging‐related stressors. The early life stages such as eggs and larvae were most likely to suffer lethal impacts, while behavioural effects were more likely to occur in adult catadromous fishes. Both suspended sediment concentration and duration of exposure greatly influenced the type of fish response observed, with both higher concentrations and longer exposure durations associated with fish mortality. The review highlights the need for in situ studies on the effects of dredging on fish which consider the interactive effects of multiple dredging‐related stressors and their impact on sensitive species of ecological and fisheries value. This information will improve the management of dredging projects and ultimately minimize their impacts on fish.
Computational methods for image-based profiling are under active development, but their success hinges on assays that can capture a wide range of phenotypes. We have developed a multiplex cytological ...profiling assay that "paints the cell" with as many fluorescent markers as possible without compromising our ability to extract rich, quantitative profiles in high throughput. The assay detects seven major cellular components. In a pilot screen of bioactive compounds, the assay detected a range of cellular phenotypes and it clustered compounds with similar annotated protein targets or chemical structure based on cytological profiles. The results demonstrate that the assay captures subtle patterns in the combination of morphological labels, thereby detecting the effects of chemical compounds even though their targets are not stained directly. This image-based assay provides an unbiased approach to characterize compound- and disease-associated cell states to support future probe discovery.
The human reference genome assembly plays a central role in nearly all aspects of today's basic and clinical research. GRCh38 is the first coordinate-changing assembly update since 2009; it reflects ...the resolution of roughly 1000 issues and encompasses modifications ranging from thousands of single base changes to megabase-scale path reorganizations, gap closures, and localization of previously orphaned sequences. We developed a new approach to sequence generation for targeted base updates and used data from new genome mapping technologies and single haplotype resources to identify and resolve larger assembly issues. For the first time, the reference assembly contains sequence-based representations for the centromeres. We also expanded the number of alternate loci to create a reference that provides a more robust representation of human population variation. We demonstrate that the updates render the reference an improved annotation substrate, alter read alignments in unchanged regions, and impact variant interpretation at clinically relevant loci. We additionally evaluated a collection of new de novo long-read haploid assemblies and conclude that although the new assemblies compare favorably to the reference with respect to continuity, error rate, and gene completeness, the reference still provides the best representation for complex genomic regions and coding sequences. We assert that the collected updates in GRCh38 make the newer assembly a more robust substrate for comprehensive analyses that will promote our understanding of human biology and advance our efforts to improve health.
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