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"Pollard, M"
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Archaeological chemistry
\"The use of chemistry in archaeology can help archaeologists answer questions about the nature and origin of the many organic and inorganic finds recovered through excavation, providing valuable information about the social history of humankind. This textbook tackles the fundamental issues in chemical studies of archaeological materials.
Book
Gender differences in walking (for leisure, transport and in total) across adult life: a systematic review
Background
The aim of this systematic review was to examine gender differences in walking for leisure, transport and in total in adults living in high-income countries, and to assess whether gender differences in walking practices change across the life-course.
Methods
A systematic literature search was conducted of publications dated 1995 to 2015. Papers providing quantitative data on participation in walking of both men and women aged at least 18 years in a high-income country were screened for the quality of the data on gender differences in walking. Data were extracted and results were synthesised using forest plots and narrative summary.
Results
Thirty-six studies were included in the review: 18 reported on walking for leisure, 16 on walking for transport (in total, or for particular purposes), and 14 on total walking. Most (33) studies provided data comparing the proportion of men and women who walked (at all or for a minimum duration) over a defined period, usually one week. There was consistent evidence that more women than men walk for leisure, although effect sizes were small. However, this effect varies by age: more younger women than younger men walk for leisure, but the gender difference diminishes with age and appears to reverse in the oldest age groups. Taking all ages together, there was no consistent gender difference in walking for transport or in total walking, although the small number of studies reporting on walking to undertake errands suggested that more women than men walk for this purpose.
Conclusions
While there is little evidence that levels of total walking consistently vary by gender, our findings suggest that there are consistent gender differences in participation in walking for some purposes, including for leisure, and that there are gender differences in the impact of age on walking. We conclude that more research is needed to improve our understanding of how walking fits into the lives of women and men across the life-course, especially in relation to gender differences in the impact of aging on walking.
Prospero registration
PROSPERO registration number:
CRD42015025961
.
Journal Article
Social prescribing during the COVID-19 pandemic: a qualitative study of service providers’ and clients’ experiences
Background
COVID-19 public health restrictions, such as social distancing and self-isolation, have been particularly challenging for vulnerable people with health conditions and/or complex social needs. Link worker social prescribing is widespread in the UK and elsewhere and is regarded as having the potential to provide support to vulnerable people during the pandemic. This qualitative study explores accounts of how an existing social prescribing service adapted to meet clients’ needs in the first wave of the pandemic, and of how clients experienced these changes.
Methods
Data were collected in a deprived urban area of North East England via remote interviews with clients (
n
= 44), link workers (
n
= 5) and service provider managerial staff (
n
= 8) from May–September 2020. Thematic data analysis was conducted.
Results
The research found that service providers quickly adapted to remote intervention delivery aiming to serve existing clients and other vulnerable groups. Service providers experienced improved access to some existing clients via telephone in the first months of remote delivery and in some cases were able to engage clients who had previously not attended appointments at GP surgeries. However, link workers also experienced challenges in building rapport with clients, engaging clients with the aims of the intervention and providing a service to digitally excluded people. Limited link worker capacity meant clients experienced variable contact with link workers with only some experiencing consistent support that was highly valued for helping to manage their conditions and mental wellbeing. Limited access to linked services also adversely affected clients. Clients living in less affluent circumstances and/or with worse health were more likely to experience negative impacts on their long-term condition. Some found their health and progress with social prescribing was ‘on hold’ or ‘going backwards’, which sometimes negatively affected their health.
Conclusions
Social prescribing offered valued support to some during the pandemic, but remote support sometimes had limited impact for clients and findings highlight the vulnerability of social prescribing’s success when linked services are disrupted. Findings also show the need for more to be done in the upscaling of social prescribing to provide support to digitally excluded populations.
Journal Article
Cohesin-mediated interactions organize chromosomal domain architecture
To ensure proper gene regulation within constrained nuclear space, chromosomes facilitate access to transcribed regions, while compactly packaging all other information. Recent studies revealed that chromosomes are organized into megabase‐scale domains that demarcate active and inactive genetic elements, suggesting that compartmentalization is important for genome function. Here, we show that very specific long‐range interactions are anchored by cohesin/CTCF sites, but not cohesin‐only or CTCF‐only sites, to form a hierarchy of chromosomal loops. These loops demarcate topological domains and form intricate internal structures within them. Post‐mitotic nuclei deficient for functional cohesin exhibit global architectural changes associated with loss of cohesin/CTCF contacts and relaxation of topological domains. Transcriptional analysis shows that this cohesin‐dependent perturbation of domain organization leads to widespread gene deregulation of both cohesin‐bound and non‐bound genes. Our data thereby support a role for cohesin in the global organization of domain structure and suggest that domains function to stabilize the transcriptional programmes within them.
Chromosomal compartmentalization has been recognized as important for genome function. High‐resolution techniques such as Hi‐C, ChIP‐ and 4C‐seq offer novel insights into cohesin's dynamic role in shaping the nuclear architecture.
Journal Article
The white matter is a pro-differentiative niche for glioblastoma
Glioblastomas are hierarchically organised tumours driven by glioma stem cells that retain partial differentiation potential. Glioma stem cells are maintained in specialised microenvironments, but whether, or how, they undergo lineage progression outside of these niches remains unclear. Here we identify the white matter as a differentiative niche for glioblastomas with oligodendrocyte lineage competency. Tumour cells in contact with white matter acquire pre-oligodendrocyte fate, resulting in decreased proliferation and invasion. Differentiation is a response to white matter injury, which is caused by tumour infiltration itself in a tumoursuppressive feedback loop. Mechanistically, tumour cell differentiation is driven by selective white matter upregulation of SOX10, a master regulator of normal oligodendrogenesis. SOX10 overexpression or treatment with myelination-promoting agents that upregulate endogenous SOX10, mimic this response, leading to niche-independent pre-oligodendrocyte differentiation and tumour suppression in vivo. Thus, glioblastoma recapitulates an injury response and exploiting this latent programme may offer treatment opportunities for a subset of patients.
Glioma stem cells (GSCs) retain the ability to partially differentiate, but it is unclear how the brain microenvironment may influence this response. Here the authors show that glioblastoma cells infiltrating into the white matter acquire pre-oligodendrocyte-like fate in a process that mimics myelin repair and results in tumour suppression
Journal Article
Associations of sedentary time and self-reported television time during pregnancy with incident gestational diabetes and plasma glucose levels in women at risk of gestational diabetes in the UK
Background
Sedentary time is associated with increased risk of type 2 diabetes, but the association between objectively measured sedentary time and incident gestational diabetes mellitus (GDM) has not been tested. The purpose of this paper is to test associations between objectively measured sedentary time and self-reported television time during pregnancy with incident GDM and plasma glucose levels among women at high risk for GDM.
Methods
At 20 weeks’ gestation, pregnant women (
n
= 188) in the North East of England with a risk factor for GDM wore an activPAL accelerometer and reported their usual television time. Participants underwent a standard oral glucose tolerance test at 24–28 weeks’ gestation. Regression analyses were used to test for associations of total and prolonged sedentary time, breaks in sedentary time, and television time with GDM and fasting and 2-h glucose levels. Interaction terms were applied to examine whether the association between each indicator of sedentary time and glucose levels differed by GDM status.
Results
Total sedentary time (hours/day) was not associated with incident GDM (OR 1.00 (95%CI 1.00, 1.01)). The association between total sedentary time and glucose levels depended on GDM status: sedentary time was associated with fasting (β = 0.16 (95%CI 0.01, 0.31)) and 2-h (β = 0.15 (95%CI 0.01, 0.30)) glucose levels for those without GDM, while breaks in sedentary time were associated with lower fasting (β
= −
0.55 (95%CI – 0.92, − 0.17)) and 2-h (β = − 0.40 (95%CI - 0.77, − 0.03)) glucose levels for those with GDM. Prolonged sedentary time was associated with higher fasting glucose levels regardless of GDM status (β 0.15 (0.01, 0.30)). Television time was associated with development of GDM (OR 3.03 (95%CI 1.21, 7.96)) but not with plasma glucose levels.
Conclusions
This is the first study to test associations between posture-based measures of sedentary time during pregnancy and GDM and glucose levels. The findings presented here suggest the possible importance of minimizing or breaking up sedentary time for the management of glucose levels during pregnancy, at least among women at high risk of GDM. Further research is needed to understand the different roles of total sedentary time and television time in the development of GDM.
Journal Article
LRIG1 is a gatekeeper to exit from quiescence in adult neural stem cells
Adult neural stem cells (NSCs) must tightly regulate quiescence and proliferation. Single-cell analysis has suggested a continuum of cell states as NSCs exit quiescence. Here we capture and characterize in vitro primed quiescent NSCs and identify LRIG1 as an important regulator. We show that BMP-4 signaling induces a dormant non-cycling quiescent state (d-qNSCs), whereas combined BMP-4/FGF-2 signaling induces a distinct primed quiescent state poised for cell cycle re-entry. Primed quiescent NSCs (p-qNSCs) are defined by high levels of LRIG1 and CD9, as well as an interferon response signature, and can efficiently engraft into the adult subventricular zone (SVZ) niche. Genetic disruption of
Lrig1
in vivo within the SVZ NSCs leads an enhanced proliferation. Mechanistically, LRIG1 primes quiescent NSCs for cell cycle re-entry and EGFR responsiveness by enabling EGFR protein levels to increase but limiting signaling activation. LRIG1 is therefore an important functional regulator of NSC exit from quiescence.
How neural stem cells can transition between states of proliferation and quiescence is unclear. Here, the authors identify Lrig1 as a specific marker for the primed quiescent state and demonstrate that Lrig1 maintains cells in a quiescent state via modulation of the EGFR pathway.
Journal Article
Simultaneous disruption of PRC2 and enhancer function underlies histone H3.3-K27M oncogenic activity in human hindbrain neural stem cells
Driver mutations in genes encoding histone H3 proteins resulting in p.Lys27Met substitutions (H3-K27M) are frequent in pediatric midline brain tumors. However, the precise mechanisms by which H3-K27M causes tumor initiation remain unclear. Here, we use human hindbrain neural stem cells to model the consequences of H3.3-K27M on the epigenomic landscape in a relevant developmental context. Genome-wide mapping of epitope-tagged histone H3.3 revealed that both the wild type and the K27M mutant incorporate abundantly at pre-existing active enhancers and promoters, and to a lesser extent at Polycomb repressive complex 2 (PRC2)-bound regions. At active enhancers, H3.3-K27M leads to focal H3K27ac loss, decreased chromatin accessibility and reduced transcriptional expression of nearby neurodevelopmental genes. In addition, H3.3-K27M deposition at a subset of PRC2 target genes leads to increased PRC2 and PRC1 binding and augmented transcriptional repression that can be partially reversed by PRC2 inhibitors. Our work suggests that, rather than imposing de novo transcriptional circuits, H3.3-K27M drives tumorigenesis by locking initiating cells in their pre-existing, immature epigenomic state, via disruption of PRC2 and enhancer functions.
The oncohistone H3.3-K27M decreases chromatin accessibility and H3K27ac at some active enhancers and downregulates nearby neurodevelopmental genes, while increasing transcriptional repression of a subset of PRC2-bound neurodevelopment genes.
Journal Article
The Dynamics of DNA Methylation Covariation Patterns in Carcinogenesis
Recently it has been observed that cancer tissue is characterised by an increased variability in DNA methylation patterns. However, how the correlative patterns in genome-wide DNA methylation change during the carcinogenic progress has not yet been explored. Here we study genome-wide inter-CpG correlations in DNA methylation, in addition to single site variability, during cervical carcinogenesis. We demonstrate how the study of changes in DNA methylation covariation patterns across normal, intra-epithelial neoplasia and invasive cancer allows the identification of CpG sites that indicate the risk of neoplastic transformation in stages prior to neoplasia. Importantly, we show that the covariation in DNA methylation at these risk CpG loci is maximal immediately prior to the onset of cancer, supporting the view that high epigenetic diversity in normal cells increases the risk of cancer. Consistent with this, we observe that invasive cancers exhibit increased covariation in DNA methylation at the risk CpG sites relative to normal tissue, but lower levels relative to pre-cancerous lesions. We further show that the identified risk CpG sites undergo preferential DNA methylation changes in relation to human papilloma virus infection and age. Results are validated in independent data including prospectively collected samples prior to neoplastic transformation. Our data are consistent with a phase transition model of carcinogenesis, in which epigenetic diversity is maximal prior to the onset of cancer. The model and algorithm proposed here may allow, in future, network biomarkers predicting the risk of neoplastic transformation to be identified.
Journal Article