Recent studies suggest that epigenetic rejuvenation can be achieved using drugs that mimic calorie restriction and techniques such as reprogramming‐induced rejuvenation. To effectively test ...rejuvenation in vivo, mouse models are the safest alternative. However, we have found that the recent epigenetic clocks developed for mouse reduced‐representation bisulphite sequencing (RRBS) data have significantly poor performance when applied to external datasets. We show that the sites captured and the coverage of key CpGs required for age prediction vary greatly between datasets, which likely contributes to the lack of transferability in RRBS clocks. To mitigate these coverage issues in RRBS‐based age prediction, we present two novel design strategies that use average methylation over large regions rather than individual CpGs, whereby regions are defined by sliding windows (e.g. 5 kb), or density‐based clustering of CpGs. We observe improved correlation and error in our regional blood clocks (RegBCs) compared to published individual‐CpG‐based techniques when applied to external datasets. The RegBCs are also more robust when applied to low coverage data and detect a negative age acceleration in mice undergoing calorie restriction. Our RegBCs offer a proof of principle that age prediction of RRBS datasets can be improved by accounting for multiple CpGs over a region, which negates the lack of read depth currently hindering individual‐CpG‐based approaches.
To effectively test rejuvenation techniques on in vivo model organisms, we have developed two novel design strategies that use mean methylation over regions, rather than individual CpGs (an approach which we show is ineffective when applied to external test datasets). Regions are defined by sliding windows (e.g. 5 kb), or density‐based clustering of CpGs. We observe improved correlation and error in our regional blood clocks (RegBCs), increased robustness on low coverage data and negative age acceleration in calorie‐restricted mice.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
The accumulation of senescent cells in the tumor microenvironment can drive tumorigenesis in a paracrine manner through the senescence-associated secretory phenotype (SASP). Using a new p16-FDR mouse ...line, we show that macrophages and endothelial cells are the predominant senescent cell types in murine KRAS-driven lung tumors. Through single cell transcriptomics, we identify a population of tumor-associated macrophages that express a unique array of pro-tumorigenic SASP factors and surface proteins and are also present in normal aged lungs. Genetic or senolytic ablation of senescent cells, or macrophage depletion, result in a significant decrease in tumor burden and increased survival in KRAS-driven lung cancer models. Moreover, we reveal the presence of macrophages with senescent features in human lung pre-malignant lesions, but not in adenocarcinomas. Taken together, our results have uncovered the important role of senescent macrophages in the initiation and progression of lung cancer, highlighting potential therapeutic avenues and cancer preventative strategies.
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For a Figure360 author presentation of this figure, see https://doi.org/10.1016/j.ccell.2023.05.004.
•The p16-FDR mouse model can be used to isolate, trace, and ablate senescent cells•Senescent macrophages in lung tumors and naturally aged lungs are molecularly similar•Senescent macrophage ablation decreases tumor burden by promoting immunosurveillance•Human pre-malignant lung tumors contain macrophages expressing senescent markers
Haston et al. identify a population of senescent macrophages with pro-tumorigenic activities in KRAS-driven murine models of lung adenocarcinoma, which show a unique molecular signature that is conserved in the non-tumorigenic, normal aged lung. They also uncover the presence of macrophages expressing senescent markers in human pre-malignant lung tumors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Many problems in physics, biology, and economics depend upon the duration of time required for a diffusing particle to cross a boundary. As such, calculations of the distribution of first ...passage time, and in particular the mean first passage time, is an active area of research relevant to many disciplines. Exact results for the mean first passage time for diffusion on simple geometries, such as lines, discs and spheres, are well-known. In contrast, computational methods are often used to study the first passage time for diffusion on more realistic geometries where closed-form solutions of the governing elliptic boundary value problem are not available. Here, we develop a perturbation solution to calculate the mean first passage time on irregular domains formed by perturbing the boundary of a disc or an ellipse. Classical perturbation expansion solutions are then constructed using the exact solutions available on a disc and an ellipse. We apply the perturbation solutions to compute the mean first exit time on two naturally-occurring irregular domains: a map of Tasmania, an island state of Australia, and a map of Taiwan. Comparing the perturbation solutions with numerical solutions of the elliptic boundary value problem on these irregular domains confirms that we obtain a very accurate solution with a few terms in the series only. MATLAB software to implement all calculations is available at
https://github.com/ProfMJSimpson/Exit_time
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•Ease of Reverse Categorisation task inconsistent with current accounts of inhibitory development.•Study investigates why this task is easier than other similar tasks.•Two hypotheses (task ...conceptualisation and delay) tested in four experiments.•Data suggest children respond more slowly when sorting items than when making other kinds of response.•Slowing responding reduces the cognitive demands of inhibitory tasks.
Understanding the processes that create inhibitory demands is central to understanding the role of inhibitory control in all aspects of development. The processes that create inhibitory demands on most developmental tasks seem clear and well understood. However, there is one inhibitory task that appears substantially easier than the others: the Reverse Categorization task, in which children are asked to “reverse sort” items (e.g., put large items in a small box and put small items in a large box). This finding is both surprising and problematic because it cannot be explained by any existing account of inhibitory development. Four experiments with 3- and 4-year-olds sought to explain why the Reverse Categorization task is easy. Two experiments (N = 64) investigated the hypothesis that children conceptualize the task in a way that reduces its inhibitory demands; and two experiments (N = 56) tested the hypothesis that the task is easier because children sort items slowly. The data indicate that children spontaneously respond more slowly on the Reverse Categorization task than on other inhibitory tasks and that this slowing reduces the task’s cognitive demands. The way in which slowed responding works, and its relation to other inhibition-reducing interventions, is discussed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background & Aims Liver regeneration requires functional liver macrophages, which provide an immune barrier that is compromised after liver injury. The numbers of liver macrophages are controlled by ...macrophage colony-stimulating factor (CSF1). We examined the prognostic significance of the serum level of CSF1 in patients with acute liver injury and studied its effects in mice. Methods We measured levels of CSF1 in serum samples collected from 55 patients who underwent partial hepatectomy at the Royal Infirmary Edinburgh between December 2012 and October 2013, as well as from 78 patients with acetaminophen-induced acute liver failure admitted to the Royal Infirmary Edinburgh or the University of Kansas Medical Centre. We studied the effects of increased levels of CSF1 in uninjured mice that express wild-type CSF1 receptor or a constitutive or inducible CSF1-receptor reporter, as well as in chemokine receptor 2 (Ccr2)-/- mice; we performed fate-tracing experiments using bone marrow chimeras. We administered CSF1-Fc (fragment, crystallizable) to mice after partial hepatectomy and acetaminophen intoxication, and measured regenerative parameters and innate immunity by clearance of fluorescent microbeads and bacterial particles. Results Serum levels of CSF1 increased in patients undergoing liver surgery in proportion to the extent of liver resected. In patients with acetaminophen-induced acute liver failure, a low serum level of CSF1 was associated with increased mortality. In mice, administration of CSF1-Fc promoted hepatic macrophage accumulation via proliferation of resident macrophages and recruitment of monocytes. CSF1-Fc also promoted transdifferentiation of infiltrating monocytes into cells with a hepatic macrophage phenotype. CSF1-Fc increased innate immunity in mice after partial hepatectomy or acetaminophen-induced injury, with resident hepatic macrophage as the main effector cells. Conclusions Serum CSF1 appears to be a prognostic marker for patients with acute liver injury. CSF1 might be developed as a therapeutic agent to restore innate immune function after liver injury.
Abstract DNA methylation (DNAm) is one of the most reliable biomarkers of aging across mammalian tissues. While the age-dependent global loss of DNAm has been well characterized, DNAm gain is less ...characterized. Studies have demonstrated that CpGs which gain methylation with age are enriched in Polycomb Repressive Complex 2 (PRC2) targets. However, whole-genome examination of all PRC2 targets as well as determination of the pan-tissue or tissue-specific nature of these associations is lacking. Here, we show that low-methylated regions (LMRs) which are highly bound by PRC2 in embryonic stem cells (PRC2 LMRs) gain methylation with age in all examined somatic mitotic cells. We estimated that this epigenetic change represents around 90% of the age-dependent DNAm gain genome-wide. Therefore, we propose the “PRC2-AgeIndex,” defined as the average DNAm in PRC2 LMRs, as a universal biomarker of cellular aging in somatic cells which can distinguish the effect of different anti-aging interventions.
The intergalactic medium was not completely reionized until approximately a billion years after the Big Bang, as revealed by observations of quasars with redshifts of less than 6.5. It has been ...difficult to probe to higher redshifts, however, because quasars have historically been identified in optical surveys, which are insensitive to sources at redshifts exceeding 6.5. Here we report observations of a quasar (ULAS J112001.48+064124.3) at a redshift of 7.085, which is 0.77 billion years after the Big Bang. ULAS J1120+0641 has a luminosity of 6.3 × 10(13)L(⊙) and hosts a black hole with a mass of 2 × 10(9)M(⊙) (where L(⊙) and M(⊙) are the luminosity and mass of the Sun). The measured radius of the ionized near zone around ULAS J1120+0641 is 1.9 megaparsecs, a factor of three smaller than is typical for quasars at redshifts between 6.0 and 6.4. The near-zone transmission profile is consistent with a Lyα damping wing, suggesting that the neutral fraction of the intergalactic medium in front of ULAS J1120+0641 exceeded 0.1.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
We present a search for metal absorption line systems at the highest redshifts to date using a deep (30 h) Very Large Telescope/X-Shooter spectrum of the z = 7.084 quasi-stellar object (QSO) ...ULAS J1120+0641. We detect seven intervening systems at z > 5.5, with the highest redshift system being a C iv absorber at z = 6.51. We find tentative evidence that the mass density of C iv remains flat or declines with redshift at z < 6, while the number density of C ii systems remains relatively flat over 5 < z < 7. These trends are broadly consistent with models of chemical enrichment by star formation-driven winds that include a softening of the ultraviolet background towards higher redshifts. We find a larger number of weak (W
rest < 0.3 Å) Mg ii systems over 5.9 < z < 7.0 than predicted by a power-law fit to the number density of stronger systems. This is consistent with trends in the number density of weak Mg ii systems at z ≲ 2.5, and suggests that the mechanisms that create these absorbers are already in place at z ∼ 7. Finally, we investigate the associated narrow Si iv, C iv and N v absorbers located near the QSO redshift, and find that at least one component shows evidence of partial covering of the continuum source.
Abstract
While most plants die below a threshold of water content, desiccation-tolerant species display specific responses that allow them to survive extreme dehydration. Some of these responses are ...activated at critical stages during water loss and could represent the difference between desiccation tolerance (DT) and death. Here, we report the development of a simple and reproducible system to determine DT in Selaginella species. The system is based on exposure of excised tissue to a dehydration agent inside small containers, and subsequent evaluation for tissue viability. We evaluated several methodologies to determine viability upon desiccation including: triphenyltetrazolium chloride (TTC) staining, the quantum efficiency of PSII, antioxidant potential, and relative electrolyte leakage. Our results show that the TTC test is a simple and accurate assay to identify novel desiccation-tolerant Selaginella species, and can also indicate viability in other desiccation-tolerant models (i.e. ferns and mosses). The system we developed is particularly useful to identify critical points during the dehydration process. We found that a desiccation-sensitive Selaginella species shows a change in viability when dehydrated to 40% relative water content, indicating the onset of a critical condition at this water content. Comparative studies at critical stages could provide a better understanding of DT mechanisms and unravel insights into the key responses to survive desiccation.
A simple and efficient system to determine critical stages during dehydration in Selaginellathat can be applied to identify desiccation-tolerant plants.
Background & Aims Full length keratin-18 (FL-K18) and High Mobility Group Box-1 (HMGB1) represent circulating indicators of necrosis during acetaminophen (APAP) hepatotoxicity in vivo. In addition, ...the caspase-cleaved fragment of K18 (cK18) and hyper-acetylated HMGB1 represent serum indicators of apoptosis and immune cell activation, respectively. The study aim was to assess their mechanistic utility to establish the balance between apoptosis, necrosis, and immune cell activation throughout the time course of clinical APAP hepatotoxicity. Methods HMGB1 (total, acetylated) and K18 (apoptotic, necrotic) were identified and quantified by novel LC–MS/MS assays in APAP overdose patients (n = 78). Results HMGB1 (total; 15.4 ± 1.9 ng/ml, p <0.01, acetylated; 5.4 ± 2.6 ng/ml, p <0.001), cK18 (5649.8 ± 721.0 U/L, p <0.01), and FL-K18 (54770.2 ± 6717.0 U/L, p <0.005) were elevated in the sera of APAP overdose patients with liver injury compared to overdose patients without liver injury and healthy volunteers. HMGB1 and FL-K18 correlated with alanine aminotransferase (ALT) activity (R2 = 0.60 and 0.58, respectively, p <0.0001) and prothrombin time (R2 = 0.62 and 0.71, respectively, p <0.0001). Increased total and acetylated HMGB1 and FL-K18 were associated with worse prognosis (King’s College Criteria) or patients that died/required liver transplant compared to spontaneous survivors (all p <0.05–0.001), a finding not reflected by ALT and supported by ROC analysis. Acetylated HMGB1 was a better predictor of outcome than the other markers of cell death. Conclusions K18 and HMGB1 represent blood-based tools to investigate the cell death balance clinical APAP hepatotoxicity. Activation of the immune response was seen later in the time course as shown by the distinct profile of acetylated HMGB1 and was associated with worse outcome.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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