Concerns about global warming, degradation of fragile ecosystems, and environmental and societal collapse have increased interest for lessons and/or solutions for today's environmental issues. ...Popular writers have turned to a classic degradation thesis of deforestation and presumed desertification within the Eastern Mediterranean as a cautionary tale of how past societies have committed ecological suicide. However, degradation and/or collapse is far more complex than the thesis permits, and uncritical adoption of such simplified stories encourages continued use of inaccurate assumptions about human–environment interaction. In Cyprus, such a degradation story materialized 150 y ago, and its promoters aimed to impress on readers their responsibility to reverse past environmental mistakes. Both the British Colonial authorities (1878–1960) and the post-Independence Cypriot government used it to justify their environmental policies. Unfortunately, this thesis was formed around several misunderstandings about Cypriot environments and society: (i) judgment of degradation without appropriate consideration of the difference between degradation and change; (ii) oversimplified representation of ruling powers and those people ruled; and (iii) denigration of the shepherd lifestyle and its presumed environmental impact. A multimethod approach using archival and field research offers a more nuanced understanding of the complexity of human–environment interaction, the underappreciated environmental and societal resilience of areas classified as degraded, and the importance of placing events within changing socioeconomic and political contexts. This study of natural resource management and environmental resilience illustrates that the practices that the colonial government viewed as unsustainable likely were sustainable.
In the cell, DNA is arranged into highly-organised and topologically-constrained (supercoiled) structures. It remains unclear how this supercoiling affects the detailed double-helical structure of ...DNA, largely because of limitations in spatial resolution of the available biophysical tools. Here, we overcome these limitations, by a combination of atomic force microscopy (AFM) and atomistic molecular dynamics (MD) simulations, to resolve structures of negatively-supercoiled DNA minicircles at base-pair resolution. We observe that negative superhelical stress induces local variation in the canonical B-form DNA structure by introducing kinks and defects that affect global minicircle structure and flexibility. We probe how these local and global conformational changes affect DNA interactions through the binding of triplex-forming oligonucleotides to DNA minicircles. We show that the energetics of triplex formation is governed by a delicate balance between electrostatics and bonding interactions. Our results provide mechanistic insight into how DNA supercoiling can affect molecular recognition, that may have broader implications for DNA interactions with other molecular species.
Preterm birth and cardiac function in adulthood Greer, Charlotte; Troughton, Richard W; Adamson, Philip D ...
Heart (British Cardiac Society),
02/2022, Letnik:
108, Številka:
3
Journal Article
Recenzirano
Preterm birth affects 1 in 10 pregnancies worldwide, with increasing survival rates over the last 30 years. However, as this new generation of long-term survivors approaches middle age, recent ...studies have revealed increased cardiovascular risk factors and higher rates of ischaemic heart disease and heart failure. Cardiovascular imaging has identified smaller cardiac chamber size, changes in myocardial mass and impaired ventricular function, particularly under physiological stress. Accordingly, this population should be recognised as having a higher risk of heart failure as they age. In this review, we present current evidence for increased rates of heart failure and evidence of alterations in cardiac structure and function in those born preterm. We discuss potential mechanisms to explain this risk including greater frequency of co-morbidities known to be associated with heart failure. We also explore potential mechanistic links specific to the preterm-born population, including the impact of premature birth on myocardial and vascular development and the effects of perinatal haemodynamic changes and chronic lung disease on the developing heart. We highlight gaps in our knowledge and consider implications for patient management relevant to the adult physician.
Heterotrimeric G proteins were originally discovered through efforts to understand the effects of hormones, such as glucagon and epinephrine, on glucose metabolism. On the other hand, many cellular ...metabolites, including glucose, serve as ligands for G protein-coupled receptors. Here we investigate the consequences of glucose-mediated receptor signaling, and in particular the role of a Gα subunit Gpa2 and a non-canonical Gβ subunit, known as Asc1 in yeast and RACK1 in animals. Asc1/RACK1 is of particular interest because it has multiple, seemingly unrelated, functions in the cell. The existence of such “moonlighting” operations has complicated the determination of phenotype from genotype. Through a comparative analysis of individual gene deletion mutants, and by integrating transcriptomics and metabolomics measurements, we have determined the relative contributions of the Gα and Gβ protein subunits to glucose-initiated processes in yeast. We determined that Gpa2 is primarily involved in regulating carbohydrate metabolism while Asc1 is primarily involved in amino acid metabolism. Both proteins are involved in regulating purine metabolism. Of the two subunits, Gpa2 regulates a greater number of gene transcripts and was particularly important in determining the amplitude of response to glucose addition. We conclude that the two G protein subunits regulate distinct but complementary processes downstream of the glucose-sensing receptor, as well as processes that lead ultimately to changes in cell growth and metabolism.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The DNA methylation-based 'epigenetic clock' correlates strongly with chronological age, but it is currently unclear what drives individual differences. We examine cross-sectional and longitudinal ...associations between the epigenetic clock and four mortality-linked markers of physical and mental fitness: lung function, walking speed, grip strength and cognitive ability.
DNA methylation-based age acceleration (residuals of the epigenetic clock estimate regressed on chronological age) were estimated in the Lothian Birth Cohort 1936 at ages 70 (n = 920), 73 (n = 299) and 76 (n = 273) years. General cognitive ability, walking speed, lung function and grip strength were measured concurrently. Cross-sectional correlations between age acceleration and the fitness variables were calculated. Longitudinal change in the epigenetic clock estimates and the fitness variables were assessed via linear mixed models and latent growth curves. Epigenetic age acceleration at age 70 was used as a predictor of longitudinal change in fitness. Epigenome-wide association studies (EWASs) were conducted on the four fitness measures.
Cross-sectional correlations were significant between greater age acceleration and poorer performance on the lung function, cognition and grip strength measures (r range: -0.07 to -0.05, P range: 9.7 x 10(-3) to 0.024). All of the fitness variables declined over time but age acceleration did not correlate with subsequent change over 6 years. There were no EWAS hits for the fitness traits.
Markers of physical and mental fitness are associated with the epigenetic clock (lower abilities associated with age acceleration). However, age acceleration does not associate with decline in these measures, at least over a relatively short follow-up.
DNA methylation changes with age. Chronological age predictors built from DNA methylation are termed 'epigenetic clocks'. The deviation of predicted age from the actual age ('age acceleration ...residual', AAR) has been reported to be associated with death. However, it is currently unclear how a better prediction of chronological age affects such association.
In this study, we build multiple predictors based on training DNA methylation samples selected from 13,661 samples (13,402 from blood and 259 from saliva). We use the Lothian Birth Cohorts of 1921 (LBC1921) and 1936 (LBC1936) to examine whether the association between AAR (from these predictors) and death is affected by (1) improving prediction accuracy of an age predictor as its training sample size increases (from 335 to 12,710) and (2) additionally correcting for confounders (i.e., cellular compositions). In addition, we investigated the performance of our predictor in non-blood tissues.
We found that in principle, a near-perfect age predictor could be developed when the training sample size is sufficiently large. The association between AAR and mortality attenuates as prediction accuracy increases. AAR from our best predictor (based on Elastic Net, https://github.com/qzhang314/DNAm-based-age-predictor ) exhibits no association with mortality in both LBC1921 (hazard ratio = 1.08, 95% CI 0.91-1.27) and LBC1936 (hazard ratio = 1.00, 95% CI 0.79-1.28). Predictors based on small sample size are prone to confounding by cellular compositions relative to those from large sample size. We observed comparable performance of our predictor in non-blood tissues with a multi-tissue-based predictor.
This study indicates that the epigenetic clock can be improved by increasing the training sample size and that its association with mortality attenuates with increased prediction of chronological age.
Individuals of the same chronological age exhibit disparate rates of biological ageing. Consequently, a number of methodologies have been proposed to determine biological age and primarily exploit ...variation at the level of DNA methylation (DNAm). A novel epigenetic clock, termed 'DNAm GrimAge' has outperformed its predecessors in predicting the risk of mortality as well as many age-related morbidities. However, the association between DNAm GrimAge and cognitive or neuroimaging phenotypes remains unknown. We explore these associations in the Lothian Birth Cohort 1936 (n = 709, mean age 73 years). Higher DNAm GrimAge was strongly associated with all-cause mortality over the eighth decade (Hazard Ratio per standard deviation increase in GrimAge: 1.81, P < 2.0 × 10
). Higher DNAm GrimAge was associated with lower age 11 IQ (β = -0.11), lower age 73 general cognitive ability (β = -0.18), decreased brain volume (β = -0.25) and increased brain white matter hyperintensities (β = 0.17). There was tentative evidence for a longitudinal association between DNAm GrimAge and cognitive decline from age 70 to 79. Sixty-nine of 137 health- and brain-related phenotypes tested were significantly associated with GrimAge. Adjusting all models for childhood intelligence attenuated to non-significance a small number of associations (12/69 associations; 6 of which were cognitive traits), but not the association with general cognitive ability (33.9% attenuation). Higher DNAm GrimAge associates with lower cognitive ability and brain vascular lesions in older age, independently of early-life cognitive ability. This epigenetic predictor of mortality associates with different measures of brain health and may aid in the prediction of age-related cognitive decline.
In Luke-Acts, Jesus can be seen to take on the attributes of the Davidic shepherd king, a representation successfully conveyed through specific narrative devices. The presence of the shepherds in the ...birth narrative can be understood as an indication of this understanding of Jesus. Sarah Harris analyses the multiple ways scholars have viewed the shepherds as characters in the narrative, and uses this as an example of how the theme of Jesus’ shepherd nature is interwoven into the narrative as a whole. From the starting point of Jesus’ human life, Harris moves to later events portrayed in Jesus’ ministry in which he is seen to enact his message as God’s faithful Davidic shepherd, in particular, the parable of the Lost Sheep and the Zacchaeus pericope (19:1-10). Harris uses this latter encounter to underline that Jesus may be hailed as a King by the crowds as he enters Jerusalem, but he is not simply a king. He is God’s Davidic Shepherd King, as prophesied in Micah 5 and Ezekiel 34, who brings the gospel of peace and salvation to the earth.
Telomere length and DNA methylation have been proposed as biological clock measures that track chronological age. Whether they change in tandem, or contribute independently to the prediction of ...chronological age, is not known.
We address these points using data from two Scottish cohorts: the Lothian Birth Cohorts of 1921 (LBC1921) and 1936 (LBC1936). Telomere length and epigenetic clock estimates from DNA methylation were measured in 920 LBC1936 participants (ages 70, 73 and 76 years) and in 414 LBC1921 participants (ages 79, 87 and 90 years).
The epigenetic clock changed over time at roughly the same rate as chronological age in both cohorts. Telomere length decreased at 48-67 base pairs per year on average. Weak, non-significant correlations were found between epigenetic clock estimates and telomere length. Telomere length explained 6.6% of the variance in age in LBC1921, the epigenetic clock explained 10.0%, and combined they explained 17.3% (allP< 1 × 10
). Corresponding figures for the LBC1936 cohort were 14.3%, 11.7% and 19.5% (allP< 1 × 10
). In a combined cohorts analysis, the respective estimates were 2.8%, 28.5% and 29.5%. Also in a combined cohorts analysis, a one standard deviation increase in baseline epigenetic age was linked to a 22% increased mortality risk (P= 2.6 × 10
) whereas, in the same model, a one standard deviation increase in baseline telomere length was independently linked to an 11% decreased mortality risk (P= 0.06).
These results suggest that telomere length and epigenetic clock estimates are independent predictors of chronological age and mortality risk.
Determining the genetic influences on cognitive ability in old age and in cognitive ageing are important areas of research in an increasingly ageing society. Heritability studies indicate that ...genetic variants strongly influence cognitive ability differences throughout the lifespan, including in old age. To date, however, only the genes encoding apolipoprotein E ( APOE) and possibly catechol- O -methyl transferase ( COMT) , brain-derived neurotrophic factor ( BDNF ) and dystrobrevin binding protein 1 ( DTNBP1 ) have repeatedly been associated in candidate gene studies with cognitive decline or with cognitive ability in older individuals. Genome-wide association studies have identified further potential loci, but results are tentative. Advances in exome and/or whole-genome sequencing, transcriptomics, proteomics and methylomics hold significant promise for uncovering the genetic underpinnings of cognitive ability and decline in old age.
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