2,380 research outputs found
Investigating the mechanism of clonal expansion of deleted mtDNA species
PhD ThesisMitochondrial DNA deletions are a primary cause of inherited and sporadic
mitochondrial disease, whilst somatic mtDNA deletions contribute to the focal
respiratory chain deficiency observed in post-mitotic cells associated with ageing and
neurodegenerative disorders. As mtDNA deletions only cause cellular pathology at high
levels of heteroplasmy, an mtDNA deletion formed within a cell must accumulate by a
process known as clonal expansion to levels which result in biochemical dysfunction.
The mechanism driving clonal expansion remains uncertain; this research aimed to
investigate clonally expanded mtDNA deletions in sporadic and inherited
mitochondrial myopathies in order to elucidate this mechanism.
A number of different approaches were taken to assess the mechanism driving
accumulation of mtDNA deletions. The effect of the mtDNA deletion size on clonal
expansion was first investigated by assessing the longitudinal spread of mtDNA
deletions in single muscle fibres isolated from patients presenting with mtDNA
maintenance disorders; no relationship was found to exist between mtDNA deletion
size and the area over which the mutation has accumulated. A longitudinal study was
carried out using tissue acquired over a 13-year period from a single patient with a
sporadic mtDNA deletion, to identify whether the mtDNA deletion heteroplasmy level
continued to increase over time, as would be expected if the mutation displayed a
selective advantage over wildtype mtDNA â however, both the genetic and
biochemical defect were found to be stable over time in this patient. A subsequent
study aimed to identify a correlation between mtDNA deletion size and heteroplasmy
levels at the whole tissue level in a cohort of patients with sporadic single mtDNA
deletions, but no evidence was found to suggest that larger mtDNA deletions
accumulate to higher levels of heteroplasmy. Finally, single cytochrome c oxidase-
deficient muscle fibres were investigated using single-molecule PCR to assess whether
clonal expansion of multiple mtDNA deletions could be observed in single cells.
Evidence of multiple clonally expanded mtDNA species was found in approximately
40% of all examined fibres, with no correlation between mtDNA deletion size and level
of accumulation.
Each of these four studies has highlighted accumulation by random genetic drift to be
the most likely mechanism for clonal expansion of mtDNA deletions in human muscle;
no evidence has been found to support the presence of a selective advantage for
mtDNA deletion species over wildtype mtDNA
Rededication Ceremony
Program from the rededication ceremony for the Alexander Campbell King Law Library which had been extensively remodeled and refurbished
Consistency is key when setting a new world record for running 10 marathons in 10 days
Background: We describe the requirements and physiological changes when running 10 consecutive marathons in 10 days at the same consistent pace by a female ultra-endurance
athlete. Methods: Sharon Gayter (SG) 54 yrs, 162.5 cm, 49.3 kg maximal oxygen uptake (VO2 max) 53 mL/kgâ1/minâ1
. SG completed 42.195 km on a treadmill every day for 10 days. We measured heart rate (HR), Rating of Perceived Exertion (RPE), oxygen uptake (VO2), weight, body
composition, blood parameters, nutrition, and hydration. Results: SG broke the previous record by ~2.5 h, with a cumulative completion time of 43 h 51 min 39 s. Over the 10 days, weight decreased from 51 kg to 48.4 kg, bodyfat mass from 9.1 kg to 7.2 kg (17.9% to 14.8%), and muscle mass
from 23.2 kg to 22.8 kg. For all marathons combined, exercise intensity was ~60% VO2 max; VO2 1.6 ± 0.1 L.minâ1/32.3 ± 1.1 mL.kgâ1 .minâ1, RER 0.8 ± 0, HR 143 ± 4 b.minâ1
. Energy expenditure
(EE) was 2030 ± 82 kcal/marathon, total EE for 10 days (including BMR) was 33,056 kcal, daily energy intake (EI) 2036 ± 418 kcal (20,356 kcal total), resulting an energy deficit (ED) of 12,700 kcal.
Discussion: Performance and pacing were highly consistent across all 10 marathons without any substantial hysiological decrements. Although overall EI did not match EE, leading to a significant ED, resulting in a 2.6 kg weight loss and decreases in bodyfat and skeletal muscle mass, this did not
affect performance
Plasma levels of mannan-binding lectin-associated serine proteases are increased in type 1 diabetes patients with insulin resistance.
Activation of the lectin pathway of the complement system, as demonstrated by elevated levels of mannan-binding lectin proteins (MBL), contributes to vascular pathology in type 1 diabetes (T1D). Vascular complications are greatest in T1D individuals with concomitant insulin resistance (IR), however, whether IR amplifies activiation of the lectin pathway in T1D is unknown. We pooled pre-treatment data from two RCTs and performed a cross-sectional analysis on 46 T1D individuals. We employed estimated glucose disposal rate (eGDR), a validated IR surrogate with cut-points of: 8.7Â mg/kg/min to determine IR status, with lower eGDR values conferring higher degrees of IR. Plasma levels of MBL-associated proteases (MASP-1, MASP-2, MASP-3) and their regulatory protein MAp44 were compared among eGDR classifications. In a subset of 14 individuals, we assessed change in MASPs and MAp44 following improvement in IR. We found that MASP-1, MASP-2, MASP-3, and MAp44 levels increased in a stepwise fashion across eGDR thresholds with elevated MASPs and MAp44 levels conferring greater degrees of IR. In a subset of 14 patients, improvement in IR was associated with significant reductions in MASPs, but not MAp44, levels. In conclusion, IR in T1D amplifies levels of MASP-1/2/3 and their regulator MAp44, and improvement of IR normalises MASP-1/2/3 levels. Given that elevated levels of these proteins contribute to vascular pathology, amplification of the lectin pathway of the complement system may offer mechanistic insight into the relationship between IR and vascular complications in T1D
The long-term impact of folic acid in pregnancy on offspring DNA methylation : follow-up of the Aberdeen folic acid supplementation trial (AFAST)
Funding This work was supported by the NIHR Bristol Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. R.C.R., G.C.S., N.K., T.G., G.D.S. and C.L.R. work in a unit that receives funds from the University of Bristol and the UK Medical Research Council (MC_UU_12013/1, MC_UU_12013/2 and MC_UU_12013/8). This work was also supported by CRUK (grant number C18281/A19169) and the ESRC (grant number ES/N000498/1). C.M.T. is supported by a Wellcome Trust Career Re-entry Fellowship (grant number 104077/Z/14/Z).Peer reviewedPublisher PD
Exile Vol. XLV No. 2
43rd Year
Title Page 3
Epigraph by Ezra Pound 5
Table of Contents 7
Contributors Notes 74-75
Editorial Board 76
INTERVIEWS
The Art of Hearing: Interview with Stanley Plumly by Alison Stine \u2700 23-27
ART
Self-Portrait by Angela Bliss \u2799 8
For a Living by Angela Bliss \u2799 12
Untitled by Frazier Taylor \u2702 22
Untitled by Amy Deaner \u2799 29
Perfect Knee by David Tulkin \u2701 34
Untitled by Amy Deaner \u2799 43
Still Light by Angela Bliss \u2799 62
Hiding Nature by Amy Deaner \u2799 64
Self-Portrait A by Sarah Leyrer \u2701 73
POETRY
Bolted Back by Michelle Grindstaff \u2702 9
Squall by Georgia Riepe \u2702 10
Loaves and Fishes by Maeghan Demmons \u2701 11
World Cafe by Katie Kroner \u2701 28
Gurney Surfer by Tom Hankinson \u2702 31
Japanese Beetles by Alison Stine \u2700 32-33
Shoveling by Bekah Taylor \u2700 40
Tobacco Country by K. Moore \u2701 41
Winton Place by Rachel Colina \u2702 42
Bottom of the Ninth by Michelle Grindstaff \u2702 61
Fall Burning by Alison Stine \u2700 63
rocking by Bekah Taylor \u2700 71
The Armor of the Beach by Georgia Riepe \u2702 72
PROSE
In the Aisles of the Night by Tom Dussel \u2701 13-21
From Those Uninvolved by Justin Walker \u2799 30
Frame by Paul Durica \u2700 35-39
The Rose by Rachel Bolton \u2799 44-60
Stop at the Soldier by Hillary Campbell \u2700 65-70
All submissions are reviewed on an anonymous basis, and all editorial decisions are shared equally among the members of the Editorial Board. -76
Cover Art Untitled by Kris Lewis \u2799 / Back Cover Art Figure 25 by Todd Gys \u2799 -76
Printed by Printing Arts Press -7
Water, Sanitation, and Hygiene (WASH): a critical component for sustainable soil-transmitted helminth and schistosomiasis control
Soil-transmitted helminths (STH) and
schistosomes are parasites that affect the
worldâs poorest people, causing losses of
up to 39 million and 70 million disability
adjusted life years (DALYs) respectively. The World Health Organization
(WHO) is at the forefront of developing
policy for the control of STH and
schistosomiasis, advocating for chemotherapy
as the cornerstone of control, with the
objective of reducing infection-associated
morbidity. Global uptake of chemotherapy
with albendazole or mebendazole
for STH and praziquantel for schistosomiasis
has significantly increased and
remains the principal control strategy. It is
cost-effective and reduces STH and
schistosome infections in human hosts.SJC is funded by an Australian Postgraduate Award and a University of Queensland Advantage
Scholarship, ACAC is an Australian National Health and Medical Research Council (NHMRC) Career
Development Fellow (631619), RJSM is funded by a Post-doctoral Research Fellowship from the University
of Queensland (41795457), JSM is an Australian National Health and Medical Research Council Practitioner
Fellow, and DJG is an Australian Research Council (DECRA) Fellow. This work is funded by an NHMRC
Partnership project in collaboration with WaterAid Australia
Recommended from our members
HDAC9 is implicated in atherosclerotic aortic calcification and affects vascular smooth muscle cell phenotype.
Aortic calcification is an important independent predictor of future cardiovascular events. We performed a genome-wide association meta-analysis to determine SNPs associated with the extent of abdominal aortic calcification (nâ=â9,417) or descending thoracic aortic calcification (nâ=â8,422). Two genetic loci, HDAC9 and RAP1GAP, were associated with abdominal aortic calcification at a genome-wide level (Pâ<â5.0âĂâ10-8). No SNPs were associated with thoracic aortic calcification at the genome-wide threshold. Increased expression of HDAC9 in human aortic smooth muscle cells promoted calcification and reduced contractility, while inhibition of HDAC9 in human aortic smooth muscle cells inhibited calcification and enhanced cell contractility. In matrix Gla protein-deficient mice, a model of human vascular calcification, mice lacking HDAC9 had a 40% reduction in aortic calcification and improved survival. This translational genomic study identifies the first genetic risk locus associated with calcification of the abdominal aorta and describes a previously unknown role for HDAC9 in the development of vascular calcification
A new neonatal BCG vaccination pathway in England: a mixed methods evaluation of its implementation.
INTRODUCTION: The introduction of a national evaluation of newborn screening for Severe Combined Immunodeficiency (SCID) in England triggered a change to the selective Bacillus Calmette-Guerin (BCG) vaccination programme delivery pathway, as this live attenuated vaccine is contraindicated in infants with SCID. The neonatal BCG vaccination programme is a targeted programme for infants at increased risk of tuberculosis and used to be offered shortly after birth. Since September 2021 the BCG vaccine is given to eligible infants within 28 days of birth, when the SCID screening outcome is available. We explore the experiences of those implementing the new pathway, and how they made sense of, engaged with, and appraised the change. METHODS: A mixed-methods evaluation was conducted between October 2022 and February 2023. This involved national online surveys with BCG commissioners and providers and qualitative semi-structured interviews with commissioners, providers, and Child Health Information System stakeholders in two urban areas. Survey data was analysed using descriptive statistics and interview data was analysed thematically. The data was triangulated using Normalization Process Theory as a guiding framework. RESULTS: Survey respondents (nâ=â65) and qualitative interviewees (nâ=â16) revealed that making sense of the new pathway was an iterative process. Some expressed a desire for more direction on how to implement the new pathway. The perceived value of the change varied from positive, ambivalent, to concerned. Some felt well-prepared and that improvements to data capture, eligibility screening, and accountably brought by the change were valuable. Others were concerned about the feasibility of the 28-day target, reductions in vaccination coverage, increased resource burden, and the outcome of the SCID evaluation. New collaborations and communities of practice were required to facilitate the change. Three main challenges in implementing the pathway and meeting the 28-day vaccination target were identified: appointment non-attendance; appointment and data systems; and staffing and resourcing. Feedback mechanisms were informal and took place in tandem with implementation. CONCLUSION: The new NHS neonatal BCG service specification has created an effective structure for monitoring and managing the BCG vaccination programme, but further work is required to support delivery of the 28-day vaccination target and improve uptake rates
Functional polymorphisms in the TERT promoter are associated with risk of serious ovarian and breast cancer
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