The identification of genes and interventions that slow or reverse aging is hampered by the lack of non-invasive metrics that can predict the life expectancy of pre-clinical models. Frailty Indices ...(FIs) in mice are composite measures of health that are cost-effective and non-invasive, but whether they can accurately predict health and lifespan is not known. Here, mouse FIs are scored longitudinally until death and machine learning is employed to develop two clocks. A random forest regression is trained on FI components for chronological age to generate the FRIGHT (Frailty Inferred Geriatric Health Timeline) clock, a strong predictor of chronological age. A second model is trained on remaining lifespan to generate the AFRAID (Analysis of Frailty and Death) clock, which accurately predicts life expectancy and the efficacy of a lifespan-extending intervention up to a year in advance. Adoption of these clocks should accelerate the identification of longevity genes and aging interventions.
A decline in capillary density and blood flow with age is a major cause of mortality and morbidity. Understanding why this occurs is key to future gains in human health. NAD precursors reverse ...aspects of aging, in part, by activating sirtuin deacylases (SIRT1–SIRT7) that mediate the benefits of exercise and dietary restriction (DR). We show that SIRT1 in endothelial cells is a key mediator of pro-angiogenic signals secreted from myocytes. Treatment of mice with the NAD+ booster nicotinamide mononucleotide (NMN) improves blood flow and increases endurance in elderly mice by promoting SIRT1-dependent increases in capillary density, an effect augmented by exercise or increasing the levels of hydrogen sulfide (H2S), a DR mimetic and regulator of endothelial NAD+ levels. These findings have implications for improving blood flow to organs and tissues, increasing human performance, and reestablishing a virtuous cycle of mobility in the elderly.
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•Reduced blood flow with age is due to loss of endothelial NAD+-SIRT1 activity•NAD+ and H2S control muscle angiogenesis and increase endurance in old mice•The NAD precursor NMN mimics and augments exercise by inhibiting NICD-Notch•Neovascularization is as important as mitochondria for rejuvenating muscle
Endothelial SIRT1 regulates pro-angiogenic signals secreted from myocytes and improves muscle health. Treatment of mice with NAD precursor nicotinamide mononucleotide improves vascular and increases endurance in aging mice.
Metal oxides are the key ingredients for the development of many advanced functional materials and smart devices. Nanostructuring has emerged as one of the best tools to unlock their full potential. ...Tungsten oxides (WOx) are unique materials that have been rigorously studied for their chromism, photocatalysis, and sensing capabilities. However, they exhibit further important properties and functionalities that have received relatively little attention in the past. This Feature Article presents a general review of nanostructured WOx, their properties, methods of synthesis, and a description of how they can be used in unique ways for different applications.
Tungsten oxides (WOx) are unique functional materials that can be obtained in a vast variety of nanostructured forms. This Feature Article presents a comprehensive review on the properties of WOx that goes beyond chromism and photocatalysis, for which they are usually investigated for. This is followed by a survey of their synthesis methods and implementations for different applications.
The War on Drugs popularized a set of policies and practices that dramatically increased the number of drug arrests, particularly for low-level drug offenses. The War's tactics have affected ...Americans of every race; however, minorities have been most dramatically affected. There are several explanations for the observed racial disparity in drug arrests, but relatively little research directly tests these explanations. In this study, we test three common explanations of racial disparities in drug arrest rates. We find that racial disparities in drug arrests cannot be explained by differences in drug offending, nondrug offending, or residing in the kinds of neighborhoods likely to have heavy police emphasis on drug offending. Our findings are most consistent with explanations focusing on racial bias in drug sanctions.
The evolution of the ratite birds has been widely attributed to vicariant speciation, driven by the Cretaceous breakup of the supercontinent Gondwana. The early isolation of Africa and Madagascar ...implies that the ostrich and extinct Madagascan elephant birds (Aepyornithidae) should be the oldest ratite lineages. We sequenced the mitochondrial genomes of two elephant birds and performed phylogenetic analyses, which revealed that these birds are the closest relatives of the New Zealand kiwi and are distant from the basal ratite lineage of ostriches. This unexpected result strongly contradicts continental vicariance and instead supports flighted dispersal in all major ratite lineages. We suggest that convergence toward gigantism and flightlessness was facilitated by early Tertiary expansion into the diurnal herbivory niche after the extinction of the dinosaurs.
What is a home range? Powell, Roger A.; Mitchell, Michael S.
Journal of mammalogy,
08/2012, Letnik:
93, Številka:
4
Journal Article
Recenzirano
Odprti dostop
“Home range” is a standard concept in animal ecology and behavior but few people try to understand what home ranges mean to the animals that have them and often assume that a home-range estimate, ...quantified using some method, is the home range. This leads to 2 problems. First, researchers put much energy into discerning and using the “best” methods for estimating home ranges while no one understands, really, what a home range is. Second, maps delineating home-range estimates may have little connection with what home ranges are and what they mean to the animals that have them. To gain insight into these problems, Roger Powell (hereafter, Roger) documented his own use of space for 65 days, obtaining complete data on where he went, what he did, and how much energy and money he expended and gained in each place. Roger's use of space is consistent with how other mammals use space and, therefore, examination of his data provides insight into what a home range is and how ecologists should approach quantifying other animals' home ranges. We present estimates of Roger's home range in 5 different metrics, or currencies, that provide important and different insights. Home-range estimators that combine different types of information to estimate the spatial distribution and qualities of resources that structure animal behavior (i.e., fitness surfaces) will probably provide the most insight into animals' home ranges. To make reasonable estimates of home ranges, researchers must collect data on habitat, resources, and other attributes of the landscape, so that they can understand basic behaviors of animals and understand how animals may view their environment. We propose that the best concept of a home range is that part of an animal's cognitive map of its environment that it chooses to keep updated.
Astrocytes are critical for the development and function of the central nervous system. In developing brains, immature astrocytes undergo morphological, molecular, cellular, and functional changes as ...they mature. Although the mechanisms that regulate the maturation of other major cell types in the central nervous system such as neurons and oligodendrocytes have been extensively studied, little is known about the cellular and molecular mechanisms that control astrocyte maturation. Here, we identified molecular markers of astrocyte maturation and established an in vitro assay for studying the mechanisms of astrocyte maturation. Maturing astrocytes in vitro exhibit similar molecular changes and represent multiple molecular subtypes of astrocytes found in vivo. Using this system, we found that astrocyte‐to‐astrocyte contact strongly promotes astrocyte maturation. In addition, secreted signals from microglia, oligodendrocyte precursor cells, or endothelial cells affect a small subset of astrocyte genes but do not consistently change astrocyte maturation. To identify molecular mechanisms underlying astrocyte maturation, we treated maturing astrocytes with molecules that affect the function of tumor‐associated genes. We found that a positive feedback loop of heparin‐binding epidermal growth factor‐like growth factor (HBEGF) and epidermal growth factor receptor (EGFR) signaling regulates astrocytes maturation. Furthermore, HBEGF, EGFR, and tumor protein 53 (TP53) affect the expression of genes important for cilium development, the circadian clock, and synapse function. These results revealed cellular and molecular mechanisms underlying astrocytes maturation with implications for the understanding of glioblastoma.
Main Points
Astrocyte‐to‐astrocyte contact promotes astrocyte maturation.
A positive feed back loop of HBEGF‐EGFR signaling regulates astrocyte maturation.
Microglia, OPCs, and endothelial cells affect astrocyte gene expression.
Strong Loophole-Free Test of Local Realism Shalm, Lynden K; Meyer-Scott, Evan; Christensen, Bradley G ...
Physical review letters,
2015-Dec-18, Letnik:
115, Številka:
25
Journal Article
Recenzirano
Odprti dostop
We present a loophole-free violation of local realism using entangled photon pairs. We ensure that all relevant events in our Bell test are spacelike separated by placing the parties far enough apart ...and by using fast random number generators and high-speed polarization measurements. A high-quality polarization-entangled source of photons, combined with high-efficiency, low-noise, single-photon detectors, allows us to make measurements without requiring any fair-sampling assumptions. Using a hypothesis test, we compute p values as small as 5.9×10^{-9} for our Bell violation while maintaining the spacelike separation of our events. We estimate the degree to which a local realistic system could predict our measurement choices. Accounting for this predictability, our smallest adjusted p value is 2.3×10^{-7}. We therefore reject the hypothesis that local realism governs our experiment.
Background and Aims
We evaluated the safety and efficacy of cilofexor (formerly GS‐9674), a small‐molecule nonsteroidal agonist of farnesoid X receptor, in patients with nonalcoholic steatohepatitis ...(NASH).
Approach and Results
In this double‐blind, placebo‐controlled, phase 2 trial, 140 patients with noncirrhotic NASH, diagnosed by magnetic resonance imaging–proton density fat fraction (MRI‐PDFF) ≥8% and liver stiffness ≥2.5 kPa by magnetic resonance elastography (MRE) or historical liver biopsy, were randomized to receive cilofexor 100 mg (n = 56), 30 mg (n = 56), or placebo (n = 28) orally once daily for 24 weeks. MRI‐PDFF, liver stiffness by MRE and transient elastography, and serum markers of fibrosis were measured at baseline and week 24. At baseline, median MRI‐PDFF was 16.3% and MRE‐stiffness was 3.27 kPa. At week 24, patients receiving cilofexor 100 mg had a median relative decrease in MRI‐PDFF of −22.7%, compared with an increase of 1.9% in those receiving placebo (P = 0.003); the 30‐mg group had a relative decrease of −1.8% (P = 0.17 vs. placebo). Declines in MRI‐PDFF of ≥30% were experienced by 39% of patients receiving cilofexor 100 mg (P = 0.011 vs. placebo), 14% of those receiving cilofexor 30 mg (P = 0.87 vs. placebo), and 13% of those receiving placebo. Serum gamma‐glutamyltransferase, C4, and primary bile acids decreased significantly at week 24 in both cilofexor treatment groups, whereas significant changes in Enhanced Liver Fibrosis scores and liver stiffness were not observed. Cilofexor was generally well‐tolerated. Moderate to severe pruritus was more common in patients receiving cilofexor 100 mg (14%) than in those receiving cilofexor 30 mg (4%) and placebo (4%).
Conclusions
Cilofexor for 24 weeks was well‐tolerated and provided significant reductions in hepatic steatosis, liver biochemistry, and serum bile acids in patients with NASH. ClinicalTrials.gov No. NCT02854605.
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