Alzheimer's disease (AD) genetics implies a causal role for innate immune genes, TREM2 and CD33, products that oppose each other in the downstream Syk tyrosine kinase pathway, activating microglial ...phagocytosis of amyloid (Aβ). We report effects of low (Curc-lo) and high (Curc-hi) doses of curcumin on neuroinflammation in APPsw transgenic mice. Results showed that Curc-lo decreased CD33 and increased TREM2 expression (predicted to decrease AD risk) and also increased TyroBP, which controls a neuroinflammatory gene network implicated in AD as well as phagocytosis markers CD68 and Arg1. Curc-lo coordinately restored tightly correlated relationships between these genes' expression levels, and decreased expression of genes characteristic of toxic pro-inflammatory M1 microglia (CD11b, iNOS, COX-2, IL1β). In contrast, very high dose curcumin did not show these effects, failed to clear amyloid plaques, and dysregulated gene expression relationships. Curc-lo stimulated microglial migration to and phagocytosis of amyloid plaques both in vivo and in ex vivo assays of sections of human AD brain and of mouse brain. Curcumin also reduced levels of miR-155, a micro-RNA reported to drive a neurodegenerative microglial phenotype. In conditions without amyloid (human microglial cells in vitro, aged wild-type mice), Curc-lo similarly decreased CD33 and increased TREM2. Like curcumin, anti-Aβ antibody (also reported to engage the Syk pathway, increase CD68, and decrease amyloid burden in human and mouse brain) increased TREM2 in APPsw mice and decreased amyloid in human AD sections ex vivo. We conclude that curcumin is an immunomodulatory treatment capable of emulating anti-Aβ vaccine in stimulating phagocytic clearance of amyloid by reducing CD33 and increasing TREM2 and TyroBP, while restoring neuroinflammatory networks implicated in neurodegenerative diseases.
•Curcumin (Curc) restores innate immune gene expression in AD models.•Curc increased TREM2 and TYROBP, while decreasing CD33 expression.•Curc stimulates phagocytosis and increases CD68 and Arg1 expression.•Curc reduces pro-inflammatory microglia markers CD11b, iNOS, COX-2, IL1β.•These results support a novel mechanism for Curc, which emulates the Aβ vaccine.
Platelet rich plasma (PRP) was tested as a potential therapy for androgenetic alopecia (AGA) through two different clinical protocols in which one population (18 participants) received half-head ...treatment with autologous non-activated PRP (A-PRP) produced by CPunT Preparation System (Biomed Device, Modena, Italy) and the other half-head with placebo, and a second separated population in which all participants (n = 6, 3 participants per group) received treatment with calcium-activated PRP (AA-PRP) produced from one of two different PRP collection devices (Regen Blood Cell Therapy or Arthrex Angel System). For the A-PRP study, three treatments were administered over 30-day intervals. Trichoscan analysis of patients, three months post-treatment, showed a clinical improvement in the number of hairs in the target area (36 ± 3 hairs) and in total hair density (65± 5 hair cm2), whereas negligible improvements in hair count (1.1± 1.4 hairs) and density (1.9 ± 10.2 hair cm2) were seen in the region of the scalp that received placebo. Microscopic evaluation conducted two weeks after treatment showed also an increase in epidermal thickness, Ki67+ keratinocytes, and in the number of follicles. The AA-PRP treatment groups received a singular set of injections, and six months after the treatments were administered, notable differences in clinical outcomes were obtained from the two PRP collection devices (+90 ± 6 hair cm2 versus -73 ± 30 hair cm2 hair densities, Regen versus Arthrex). Growth factor concentrations in AA-PRP prepared from the two collection devices did not differ significantly upon calcium activation.
The acetyltransferases CBP and p300 are multifunctional transcriptional co-activators. Here, we combined quantitative proteomics with CBP/p300-specific catalytic inhibitors, bromodomain inhibitor, ...and gene knockout to reveal a comprehensive map of regulated acetylation sites and their dynamic turnover rates. CBP/p300 acetylates thousands of sites, including signature histone sites and a multitude of sites on signaling effectors and enhancer-associated transcriptional regulators. Time-resolved acetylome analyses identified a subset of CBP/p300-regulated sites with very rapid (<30 min) acetylation turnover, revealing a dynamic balance between acetylation and deacetylation. Quantification of acetylation, mRNA, and protein abundance after CBP/p300 inhibition reveals a kinetically competent network of gene expression that strictly depends on CBP/p300-catalyzed rapid acetylation. Collectively, our in-depth acetylome analyses reveal systems attributes of CBP/p300 targets, and the resource dataset provides a framework for investigating CBP/p300 functions and for understanding the impact of small-molecule inhibitors targeting its catalytic and bromodomain activities.
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•Quantitative acetylomics reveals thousands of in vivo substrates of CBP/p300•CBP/p300-regulated sites display rapid deacetylation kinetics•Histone H2B is prominently acetylated by CBP/p300 at multiple sites•Rapid turnover of CBP/p300-catalyzed acetylation controls gene transcription
A comprehensive look at CBP/p300 acetylation reveals dynamic changes that shape the regulation of protein function and gene expression.
The tripeptide glutathione suppresses the iron-dependent, non-apoptotic cell death process of ferroptosis. How glutathione abundance is regulated in the cell and how this regulation alters ...ferroptosis sensitivity is poorly understood. Using genome-wide human haploid genetic screening technology coupled to fluorescence-activated cell sorting (FACS), we directly identify genes that regulate intracellular glutathione abundance and characterize their role in ferroptosis regulation. Disruption of the ATP binding cassette (ABC)-family transporter multidrug resistance protein 1 (MRP1) prevents glutathione efflux from the cell and strongly inhibits ferroptosis. High levels of MRP1 expression decrease sensitivity to certain pro-apoptotic chemotherapeutic drugs, while collaterally sensitizing to all tested pro-ferroptotic agents. By contrast, disruption of KEAP1 and NAA38, leading to the stabilization of the transcription factor NRF2, increases glutathione levels but only weakly protects from ferroptosis. This is due in part to concomitant NRF2-mediated upregulation of MRP1. These results pinpoint glutathione efflux as an unanticipated regulator of ferroptosis sensitivity.
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•FACS-based screening can identify genetic regulators of glutathione abundance•MRP1 effluxes glutathione, which accelerates ferroptosis•NAA38 and KEAP1 regulate expression of NRF2 and also MRP1•High MRP1 expression promotes collateral sensitivity to ferroptosis-inducing agents
Glutathione suppresses the non-apoptotic cell death process of ferroptosis. Using genome-wide human haploid cell mutagenesis and FACS-based detection, Cao et al. identify negative regulators of intracellular glutathione abundance that affect glutathione efflux and NRF2 protein levels, altering ferroptosis sensitivity.
The Canadian Earth System Model version 5 (CanESM5) is a global
model developed to simulate historical climate change and variability, to
make centennial-scale projections of future climate, and to ...produce
initialized seasonal and decadal predictions. This paper describes the model
components and their coupling, as well as various aspects of model
development, including tuning, optimization, and a reproducibility strategy.
We also document the stability of the model using a long control simulation,
quantify the model's ability to reproduce large-scale features of the
historical climate, and evaluate the response of the model to external
forcing. CanESM5 is comprised of three-dimensional atmosphere (T63 spectral
resolution equivalent roughly to 2.8∘) and ocean (nominally 1∘) general
circulation models, a sea-ice model, a land surface scheme, and explicit
land and ocean carbon cycle models. The model features relatively coarse
resolution and high throughput, which facilitates the production of large
ensembles. CanESM5 has a notably higher equilibrium climate sensitivity
(5.6 K) than its predecessor, CanESM2 (3.7 K), which we briefly discuss, along
with simulated changes over the historical period. CanESM5 simulations
contribute to the Coupled Model Intercomparison Project phase 6 (CMIP6)
and will be employed for climate science and service applications in Canada.
Most known extrasolar planets (exoplanets) have been discovered using the radial velocity or transit methods. Both are biased towards planets that are relatively close to their parent stars, and ...studies find that around 17-30% (refs 4, 5) of solar-like stars host a planet. Gravitational microlensing, on the other hand, probes planets that are further away from their stars. Recently, a population of planets that are unbound or very far from their stars was discovered by microlensing. These planets are at least as numerous as the stars in the Milky Way. Here we report a statistical analysis of microlensing data (gathered in 2002-07) that reveals the fraction of bound planets 0.5-10 AU (Sun-Earth distance) from their stars. We find that 17(+6)(-9)% of stars host Jupiter-mass planets (0.3-10 M(J), where M(J) = 318 M(⊕) and M(⊕) is Earth's mass). Cool Neptunes (10-30 M(⊕)) and super-Earths (5-10 M(⊕)) are even more common: their respective abundances per star are 52(+22)(-29)% and 62(+35)(-37)%. We conclude that stars are orbited by planets as a rule, rather than the exception.
Non-nutritive sweeteners like sucralose are consumed by billions of people. While animal and human studies have demonstrated a link between synthetic sweetener consumption and metabolic ...dysregulation, the mechanisms responsible remain unknown. Here we use a diet supplemented with sucralose to investigate the long-term effects of sweet/energy imbalance. In flies, chronic sweet/energy imbalance promoted hyperactivity, insomnia, glucose intolerance, enhanced sweet taste perception, and a sustained increase in food and calories consumed, effects that are reversed upon sucralose removal. Mechanistically, this response was mapped to the ancient insulin, catecholamine, and NPF/NPY systems and the energy sensor AMPK, which together comprise a novel neuronal starvation response pathway. Interestingly, chronic sweet/energy imbalance promoted increased food intake in mammals as well, and this also occurs through an NPY-dependent mechanism. Together, our data show that chronic consumption of a sweet/energy imbalanced diet triggers a conserved neuronal fasting response and increases the motivation to eat.
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•Chronic sucralose diet triggers increased food intake•Dietary sucralose creates a sweet/energy imbalance•Sweet/energy imbalance activates a conserved neuronal starvation response•Sucralose effect on feeding is conserved from flies to mammals
Wang et al. show that chronic consumption of the synthetic sweetener sucralose causes increased food intake in the fruit fly. This effect involves a neuronal starvation pathway, and a similar effect was observed in mice. These findings suggest that disrupting the sweet/energy balance of food may have unanticipated consequences.
Using rainfall, public relief, and election data from India, we examine how governments respond to adverse shocks and how voters react to these responses. The data show that voters punish the ...incumbent party for weather events beyond its control. However, fewer voters punish the ruling party when its government responds vigorously to the crisis, indicating that voters reward the government for responding to disasters. We also find evidence suggesting that voters only respond to rainfall and government relief efforts during the year immediately preceding the election. In accordance with these electoral incentives, governments appear to be more generous with disaster relief in election years. These results describe how failures in electoral accountability can lead to suboptimal policy outcomes.
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