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Ang I-converting enzyme (ACE) inhibitors are widely believed to suppress the deleterious cardiac effects of Ang II by inhibiting locally generated Ang II. However, the recent demonstration that chymase, an Ang II-forming enzyme stored in mast cell granules, is present in the heart has added uncertainty to this view. As discussed here, using microdialysis probes tethered to the heart of conscious mice, we have shown that chronic ACE inhibitor treatment did not suppress Ang II levels in the LV interstitial fluid (ISF) despite marked inhibition of ACE. However, chronic ACE inhibition caused a marked bradykinin/B2 receptor-mediated increase in LV ISF chymase activity that was not observed in mast cell-deficient KitW/KitW-v mice. In chronic ACE inhibitor-treated mast cell-sufficient littermates, chymase inhibition decreased LV ISF Ang II levels substantially, indicating the importance of mast cell chymase in regulating cardiac Ang II levels. Chymase-dependent processing of other regulatory peptides also promotes inflammation and tissue remodeling. We found that combined chymase and ACE inhibition, relative to ACE inhibition alone, improved LV function, decreased adverse cardiac remodeling, and improved survival after myocardial infarction in hamsters. These results suggest that chymase inhibitors could be a useful addition to ACE inhibitor therapy in the treatment of heart failure.

BackgroundFear of falling (FoF) is associated with activity restriction (AR) and reduced quality of life (QoL), leading to loss of independence. Physical and cognitive functions are associated with FoF. Inconsistencies in the mediating role of physical and cognitive function and complex interrelationships require further investigation; These relationships may differ between fallers and non-fallers. Our aim was to investigate the direct and indirect pathways between FoF, activity restriction/avoidance, QoL, and the mediating role of latent (unobserved) variables of physical and cognitive function in both fallers and non-fallers in a cohort of community-dwelling older adults.MethodsData from Wave 1 of The Longitudinal Irish Study of Ageing (TILDA) was used (with permission from ISSDA). The study was approved by the University of Sunderland ethics committee (011063). Outcome measures from TILDA include QoL, FoF, AR, physical function (Timed-Up and Go (TUG) and Grip strength), and cognitive function (Mini-mental State Examination (MMSE)). Data were cleaned (e.g., remove missing or NA) and processed in R Studio (version: 1.4.1106). Welch’s T-test was used to model differences in outcome measures between fallers and non-fallers, fallers with/without FoF, and, non-fallers with/without FoF. Mean difference (MD), 95% confidence (compatibility) intervals (CI) are reported for key comparisons. Structural equation modelling (SEM) will be used to model interrelationships between observed and latent variables, adjusting for medical, health and lifestyle covariates. Multiple models will be run, including imputing missing data.ResultsOur preliminary findings indicate 4761 participants (≥50 years of age) with full datasets; Of which 6.3% reported activity avoidance, 20.7% had FoF, and 20.2% had previously fallen. Compared to non-fallers, fallers had lower QoL scores (MD =-1.66 ; 95% CI =-2.19,-1.14 AU), MMSE (MD =-0.11; 95% CI= -0.24, 0.02) and grip strength (MD = -1.49; 95% CI = -2.18 to 0.80 kg) and higher TUG (MD = 0.45; 95% CI = 0.24,0.67). Fallers with FoF had lower QoL, and grip strength and higher TUG (p <0.001), non-fallers with FoF had lower QoL and grip strength and higher TUG.ConclusionPhysical function and cognitive differences are reported between faller and non-faller groups. SEM will allow for modelling these complex interrelationships between FoF, AR and QoL, mediated via our latent variables (physical and cognitive function). The data will inform health- and activity- promoting strategies to improve QoL in older adults with FoF.

GPS speed thresholds in women's rugby union are usually based on data derived from the men's game. However, evidence suggests the maximum speeds achieved by female players are 2–8 km.h−1 slower and the volume of high‐intensity running (HIR) in women's rugby may be underestimated. The aim of the study was to examine the effect of adjusting absolute thresholds on the volume of high‐intensity locomotion. GPS units recorded movement data from 58 players across 18 English Premier15 s matches. Distance in HIR and sprint (Spr) zones were calculated using male‐derived criteria: AbsMale (HIR >18 km.h−1; Spr ≥21 km.h−1). Two alternative thresholds were compared: AbsFVmax (HIR >16 km.h−1; Spr ≥19 km.h−1); AbsFemale (HIR >14 km.h−1; Spr ≥17 km.h−1). Data were analysed using one‐way ANOVA and effect sizes to determine differences in distances between thresholds. AbsMale HIR and Spr distances were 63 ± 71 m and 30 ± 53 m. Significantly greater distances at higher‐intensity speeds were observed with female‐adjusted thresholds. AbsFVmax: HIR: 139 ± 116 m (p = 0.01, ES 0.80); Spr: 60 ± 90 m (p = 0.131, ES 0.41) and AbsFemale: HIR: 239 ± 157 m (p < 0.01, ES 1.45); Spr: 137 ± 152 m (p < 0.01, ES 0.94). 24 players (41%) achieved speeds greater than the 21 km·h−1 threshold with the male‐derived thresholds. At AbsFVmax threshold this increased to 44 (76%) and 100% at the AbsFemale threshold. Existing male‐derived thresholds appear to underestimate high‐intensity locomotion of female players. With adjusted thresholds, specifically the AbsFemale, the proportional volume of high‐intensity activity in the women's game (8.2% total distance) aligns more closely to that observed during men's match‐play. Highlights Calculation of the total high‐intensity locomotion in women's rugby union (RU) using male‐derived thresholds (92.3 ± 123.8 m) equates to 2.1% of the total distance covered in games. Adjusting thresholds relative to the speed at the second ventilatory threshold and female maximum velocity increased the proportion of high‐intensity activity to 4.5% and 8.2% of total distance respectively. Reducing GPS high intensity speed thresholds to >14 km.h−1 for high‐intensity running (HIR) and ≥17 km.h−1 for sprinting produce high‐intensity speed distances that are proportionally similar to male rugby players and are more suitable when analysing match demands in women's RU.

Background: Despite the popularity of outdoor music festivals in the UK, no evidence exists of the volume or intensity of movement that occurs through attendance at these festivals and the potential health benefits this may provide. The aim of this study was to accurately record the amount of physical activity and movement at the Glastonbury Festival and to compare it against recommended levels. Methods: 22 attendees wore an Actigraph activity monitor and GPS data-logger to the Glastonbury Festival. Distances travelled, speeds and durations were recorded. Activity levels were identified based on step count thresholds and the total duration spent in moderate to vigorous physical activity (MVPA) was calculated. Results: Mean total distance of 66.1 km was recorded with daily distance (11.01 km), movement duration (11 h 28 min) and steps/day (15,661). Total MVPA of 927 min occurred over the festival period. Conclusions: This study objectively recorded the volume of physical activity that occurred at an outdoor UK festival. Large movement distances and MVPA six times greater than the recommended guidelines for health benefits were found. It can be suggested that attendance at large-scale festivals can be used as a modality for attaining physical activity guidelines alongside commonly suggested fitness activities.

If African American theater is to flourish, a plurality of views are necessary in order to reflect the diversity of African American experiences. This dissertation is an attempt to contribute to this experience through dramatic form. Whereas two of the plays were written with specific historical events in mind, the overall objective is to provide vibrant theatre. Part one will consist of two chapters. The first chapter will link \"negritude\" to African American theatre. It is appropriate to name this collection of plays, Negritude: Three Plays for the African American Theatre, because \"Negritude\" was an international literary movement that romanticized African culture and history. This movement was greatly influenced by the Harlem Renaissance. The title of this dissertation underscores the connection of African American theatre with the evolution of critical thought regarding the black aesthetic. The second chapter will discuss historical accuracy and the playwright's responsibility to \"truth.\" Several examples will illuminate various types of historical dramas and demonstrate the use of history as an incentive for dramatic action. The essay will address a primary concern in the creation of dramatic action, which is the dramatist's use of fact versus fiction. In addition, relevant historical events essential to the dramatic action of the original plays will be examined. Part two includes the original plays Ray & Sons, An Evening With Ira Aldridge, and Autumn's Song. Ray & Sons is about a father and his two sons who run a barber shop on the west side of Chicago. The play is set in April 1968 and various issues such as the Vietnam war, Black Nationalism, and civil rights are addressed. An Evening With Ira Aldridge is a biographical drama about the first African American actor of international repute. The play is a mixture of fictional episodes about his personal life and historical evidence of his illustrious career. Autumn's Song is set in 1996 and is about a woman's attempt to confront her troubled past. Although sexual abuse is a central issue in the play, past and present relationships, loyalty, and the inevitable changes in life are key themes.

Telomeres are repetitive DNA sequences at the ends of chromosomes which contribute to maintaining chromosomal stability. Telomere shortening is a hallmark of aging and shorter blood leukocyte telomere length (LTL) has been associated with increased risk for age-related diseases, however, little is understood about the biology of brain telomeres and how they may be involved in disease. Considering the increased neuropathologic burden of phosphorylated tau (ptau) with age, we investigated how shorter brain telomere length (brain-TL) may relate to increased ptau burden. We studied a cohort of 112 individuals with primary age-related tauopathy (PART), a neuropathological diagnosis characterized by mild-to-moderate tau burden (Braak=I-IV) primarily in the medial temporal lobe, with the relative absence of amyloid-beta plaques (CERAD=0). These individuals had both brain-TL (mean length by telomere qPCR, blinded) and DNA methylation measures from the frontal cortex, along with semi-quantitative Aperio ptau measures from the hippocampus. A subset (n = 81) had SNP genotyping data available. In an independent cohort (n = 10, Braak=0-VI, CERAD=0-3), we performed quantitative fluorescence in-situ hybridization (FISH) microscopy to measure the average ratio of telomere to centromere DNA content in nuclei from the frontal and visual cortices. In linear regression models, frontal cortex brain-TL did not relate to age. When age-adjusted, shorter brain-TL related to higher hippocampal ptau (β=-1.06, CI=-1.92--0.195, p = 0.017). A previously established DNA methylation model predictive of hippocampal ptau partially mediated the relationship between brain-TL and hippocampal ptau (proportion mediated=0.664, CI=0.246-1.33, p = 0.012, Figure 1). A polygenic score for LTL did not relate to either age, brain-TL or hippocampal ptau. With FISH, we observed that individuals with CERAD=0 had shorter telomeres in the frontal cortex compared to individuals with CERAD=3. Within the CERAD=0 group, an individual with Braak=II had shorter telomeres than an individual with Braak=I. These patterns were not observed in the visual cortex. In a PART cohort, shorter frontal cortex brain-TL was related to higher hippocampal ptau, and this relationship was partially mediated by a DNA methylation model predictive of hippocampal ptau. A polygenic score for LTL was not predictive of brain-TL or hippocampal ptau. Together, this further emphasizes the importance of tissue-specific epigenetic modifiers of age-related ptau neuropathology.

The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall, the project provides new insights into the organization and regulation of our genes and genome, and is an expansive resource of functional annotations for biomedical research.

Background Telomeres are repetitive DNA sequences at the ends of chromosomes which contribute to maintaining chromosomal stability. Telomere shortening is a hallmark of aging and shorter blood leukocyte telomere length (LTL) has been associated with increased risk for age‐related diseases, however, little is understood about the biology of brain telomeres and how they may be involved in disease. Considering the increased neuropathologic burden of phosphorylated tau (ptau) with age, we investigated how shorter brain telomere length (brain‐TL) may relate to increased ptau burden. Methods We studied a cohort of 112 individuals with primary age‐related tauopathy (PART), a neuropathological diagnosis characterized by mild‐to‐moderate tau burden (Braak=I‐IV) primarily in the medial temporal lobe, with the relative absence of amyloid‐beta plaques (CERAD=0). These individuals had both brain‐TL (mean length by telomere qPCR, blinded) and DNA methylation measures from the frontal cortex, along with semi‐quantitative Aperio ptau measures from the hippocampus. A subset (n = 81) had SNP genotyping data available. In an independent cohort (n = 10, Braak=0‐VI, CERAD=0‐3), we performed quantitative fluorescence in‐situ hybridization (FISH) microscopy to measure the average ratio of telomere to centromere DNA content in nuclei from the frontal and visual cortices. Results In linear regression models, frontal cortex brain‐TL did not relate to age. When age‐adjusted, shorter brain‐TL related to higher hippocampal ptau (β=‐1.06, CI=‐1.92–‐0.195, p = 0.017). A previously established DNA methylation model predictive of hippocampal ptau partially mediated the relationship between brain‐TL and hippocampal ptau (proportion mediated=0.664, CI=0.246–1.33, p = 0.012, Figure 1). A polygenic score for LTL did not relate to either age, brain‐TL or hippocampal ptau. With FISH, we observed that individuals with CERAD=0 had shorter telomeres in the frontal cortex compared to individuals with CERAD=3. Within the CERAD=0 group, an individual with Braak=II had shorter telomeres than an individual with Braak=I. These patterns were not observed in the visual cortex. Conclusions In a PART cohort, shorter frontal cortex brain‐TL was related to higher hippocampal ptau, and this relationship was partially mediated by a DNA methylation model predictive of hippocampal ptau. A polygenic score for LTL was not predictive of brain‐TL or hippocampal ptau. Together, this further emphasizes the importance of tissue‐specific epigenetic modifiers of age‐related ptau neuropathology.