M-CSF and GM-CSF Regulation of STAT5 Activation and DNA Binding in Myeloid Cell Differentiation is Disrupted in Nonobese Diabetic Mice

Defects in macrophage colony-stimulating factor (M-CSF) signaling disrupt myeloid cell differentiation in nonobese diabetic (NOD) mice, blocking myeloid maturation into tolerogenic antigen-presenting cells (APCs). In the absence of M-CSF signaling, NOD myeloid cells have abnormally high granulocyte macrophage colony-stimulating factor (GM-CSF) expression, and as a result, persistent activation of signal transducer/activator of transcription 5 (STAT5). Persistent STAT5 phosphorylation found in NOD macrophages is not affected by inhibiting GM-CSF. However, STAT5 phosphorylation in NOD bone marrow cells is diminished if GM-CSF signaling is blocked. Moreover, if M-CSF signaling is inhibited, GM-CSF stimulation in vitro can promote STAT5 phosphorylation in nonautoimmune C57BL/6 mouse bone marrow cultures to levels seen in the NOD. These findings suggest that excessive GM-CSF production in the NOD bone marrow may interfere with the temporal sequence of GM-CSF and M-CSF signaling needed to mediate normal STAT5 function in myeloid cell differentiation gene regulation

HDAC-mediated control of ERK- and PI3K-dependent TGF-β-induced extracellular matrix-regulating genes

Histone deacetylases (HDACs) regulate the acetylation of histones in the control of gene expression. Many non-histone proteins are also targeted for acetylation, including TGF-ß signalling pathway components such as Smad2, Smad3 and Smad7. Our studies in mouse C3H10T1/2 fibroblasts suggested that a number of TGF-ß-induced genes that regulate matrix turnover are selectively regulated by HDACs. Blockade of HDAC activity with trichostatin A (TSA) abrogated the induction of a disintegrin and metalloproteinase 12 (Adam12) and tissue inhibitor of metalloproteinases-1 (Timp-1) genes by TGF-ß, whereas plasminogen activator inhibitor-1 (Pai-1) expression was unaffected. Analysis of the activation of cell signalling pathways demonstrated that TGF-ß induced robust ERK and PI3K activation with delayed kinetics compared to the phosphorylation of Smads. The TGF-ß induction of Adam12 and Timp-1 was dependent on such non-Smad signalling pathways and, importantly, HDAC inhibitors completely blocked their activation without affecting Smad signalling. Analysis of TGF-ß-induced Adam12 and Timp-1 expression and ERK/PI3K signalling in the presence of semi-selective HDAC inhibitors valproic acid, MS-275 and apicidin implicated a role for class I HDACs. Furthermore, depletion of HDAC3 by RNA interference significantly down-regulated TGF-ß-induced Adam12 and Timp-1 expression without modulating Pai-1 expression. Correlating with the effect of HDAC inhibitors, depletion of HDAC3 also blocked the activation of ERK and PI3K by TGF-ß. Collectively, these data confirm that HDACs, and in particular HDAC3, are required for activation of the ERK and PI3K signalling pathways by TGF-ß and for the subsequent gene induction dependent on these signalling pathways

Impact of COVID-19 on ‘living well’ with mild-to-moderate dementia in the community: findings from the IDEAL cohort

Economic and Social Research Council (ESRC) grant ES/V004964/1; Economic and Social Research Council (ESRC) and National Institute for Health Research (NIHR) joint grant ES/L001853/2; Alzheimer’s Society, grant number 348, AS-PR2-16-001; NIHR Applied Research Collaboration South-West Peninsula

Minimal Impact of COVID-19 Pandemic on the Mental Health and Wellbeing of People Living With Dementia: Analysis of Matched Longitudinal Data From the IDEAL Study

This is the final version. Available on open access from Frontiers Media via the DOI in this recordData Availability Statement: The datasets presented in this article are not readily available because IDEAL data were deposited with the UK data archive in April 2020 and will be available to access from April 2023. Details of how the data can be accessed after that date can be found at: http://reshare.ukdataservice.ac.uk/854293/. INCLUDE data will be archived in connection with the IDEAL dataset in March 2022. Requests to access the datasets should be directed to http://reshare.ukdataservice.ac.uk/854293/ or Linda Clare [email protected]: Research suggests a decline in the mental health and wellbeing of people with dementia (PwD) during the COVID-19 pandemic; however few studies have compared data collected pre-pandemic and during the pandemic. Moreover, none have compared this change with what would be expected due to dementia progression. We explored whether PwD experienced changes in mental health and wellbeing by comparing pre-pandemic and pandemic data, and drew comparisons with another group of PwD questioned on two occasions prior to the pandemic. Methods: Community-dwelling PwD enrolled in the IDEAL programme were split into two groups matched for age group, sex, dementia diagnosis, and time since diagnosis. Although each group was assessed twice, one was assessed prior to and during the pandemic (pandemic group; n = 115) whereas the other was assessed prior to the pandemic (pre-pandemic group; n = 230). PwD completed measures of mood, sense of self, wellbeing, optimism, quality of life, and life satisfaction. Results: Compared to the pre-pandemic group, the pandemic group were less likely to report mood problems, or be pessimistic, but more likely to become dissatisfied with their lives. There were no changes in continuity in sense of self, wellbeing, and quality of life. Discussion: Results suggest the pandemic had little effect on the mental health and wellbeing of PwD, with any changes observed likely to be consistent with expected rates of decline due to dementia. Although personal accounts attest to the challenges experienced, PwD appear to have been resilient to the impact of lockdown and social restrictions during the pandemic.Economic and Social Research Council (ESRC)National Institute for Health Research (NIHR)Alzheimer’s Societ

A Comparison of Well-Being of Carers of People with Dementia and Their Ability to Manage Before and During the COVID-19 Pandemic: Findings from the IDEAL Study

Data Access: IDEAL data were deposited with the UK data archive in April 2020 and will be available to access from April 2023. Details of how the data can be accessed after that date can be found here: https://reshare.ukdataservice.ac.uk/854293/ INCLUDE data will be deposited with the UK data archive in June 2022 and will be available to access from June 2023.IDEAL study...TB

A comparison of well-being of carers of people with dementia and their ability to manage before and during the COVID-19 pandemic: findings from the IDEAL study

YesBackground: Social restriction measures imposed to curb the spread of COVID-19 in the United Kingdom impacted on carers of people with dementia, limiting access to support services and increasing perceived burden of caring. Few studies have compared data collected both during and before the pandemic to examine the effect of these changes. Objective: To explore whether the COVID-19 pandemic affected the well-being of carers of people with dementia living in the community, and their ability to cope with their caring responsibilities. Methods: Analysis was conducted on two groups of carers who were enrolled in the IDEAL programme; the ‘pre-pandemic group’ (n = 312), assessed at two time points prior to the pandemic, and the ‘pandemic group’, assessed prior to and several months into the pandemic (n = 156). For the pre-pandemic group, carers were matched 2:1 to carers in the pandemic group on certain characteristics. Differences in change over time between the two groups on self-reported well-being, quality of life, coping, perceived competence, and role captivity, were investigated using mixed effect modelling. Results: Compared to the pre-pandemic group, those in the pandemic group appeared to cope better and had more stable self-rated competency and role captivity. They did not differ in terms of well-being or quality of life. Conclusion: Despite reports of negative impacts on carers early in the pandemic, the findings suggest the pandemic had little negative longer-term impact on carers of people with dementia, and in fact they appeared to have a more positive attitude towards coping several months into the pandemic.We acknowledge the support of NIHR Dementias and Neurodegeneration Specialty (DeNDRoN) and Health and Care Research Wales with IDEAL cohort recruitment and data collection. We gratefully acknowledge the local principal investigators and researchers involved in participant recruitment and assessment within these networks. We are grateful to the IDEAL study participants for their participation in the IDEAL and INCLUDE studies, to the wider group of IDEAL programme researchers, and to members of the ALWAYs group and the Project Advisory Group for their support. ‘Identifying and mitigating the individual and dyadic impact of COVID19 and life under physical distancing on people with dementia and carers (INCLUDE)’ was funded by the Economic and Social Research Council (ESRC) through grant ES/V004964/1. Investigators: L. Clare, C. Victor, F.E. Matthews, C. Quinn, A. Hillman, A. Burns, L. Allan, R. Litherland, A. Martyr, R. Collins, & C. Pentecost. ESRC is part of UK Research and Innovation (UKRI). ‘Improving the experience of Dementia and Enhancing Active Life: living well with dementia. The IDEAL study’ was funded jointly by the Economic and Social Research Council (ESRC) and the National Institute for Health Research (NIHR) through grant ES/L001853/2. Investigators: L. Clare, I.R. Jones, C. Victor, J.V. Hindle, R.W. Jones, M. Knapp, M. Kopelman, R. Litherland, A. Martyr, F.E. Matthews, R.G. Morris, S.M. Nelis, J.A. Pickett, C. Quinn, J. Rusted, J. Thom. ‘Improving the experience of Dementia and Enhancing Active Life: a longitudinal perspective on living well with dementia. The IDEAL-2 study’ is funded by Alzheimer’s Society, grant number 348, AS-PR2-16-001. Investigators: L. Clare, I.R. Jones, C. Victor, C. Ballard, A. Hillman, J.V. Hindle, J. Hughes, R.W. Jones, M. Knapp, R. Litherland, A. Martyr, F.E. Matthews, R.G. Morris, S.M. Nelis, C. Quinn, J. Rusted. L. Clare and L. Allan acknowledge support from the NIHR Applied Research Collaboration SouthWest Peninsula. This report is independent research supported by the National Institute for Health and Care Research Applied Research Collaboration South West Peninsula. The views expressed in this publication are those of the author(s) and not necessarily those of the ESRC, UKRI, NIHR, the Department of Health and Social Care, the National Health Service, or Alzheimer’s Society. The support of ESRC, NIHR and Alzheimer’s Society is gratefully acknowledged. Authors’ disclosures available online (https:// www.j-alz.com/manuscript-disclosures/22-0221r1)

Plasma Membrane Subdomain Compartmentalization Contributes to Distinct Mechanisms of Ceramide Action on Insulin Signaling

International audienc

Tectonic evolution of the southern margin of the Amazonian craton in the late Mesoproterozoic based on field relationships and zircon U-Pb geochronology

New U-Pb zircon geochronological data integrated with field relationships and an airborne geophysical survey suggest that the Nova Brasilândia and Aguapeí belts are part of the same monocyclic, metaigneous and metasedimentary belt formed in the late Mesoproterozoic (1150 Ma-1110 Ma). This geological history is very similar to the within-plate origin of the Sunsás belt, in eastern Bolivia. Thus, we propose that the Nova Brasilândia, Aguapeí and Sunsás belts represent a unique geotectonic unit (here termed the Western Amazon belt) that became amalgamated at the end of the Mesoproterozoic and originated through the reactivation of a paleo-suture (Guaporé suture zone) in an intracontinental rift environment. Therefore, its geological history involves a short, complete Wilson cycle of ca. 40 Ma. Globally, this tectonic evolution may be related with the final breakup of the supercontinent Columbia. Mafic rocks and trondhjemites in the northernmost portion of the belt yielded U-Pb zircon ages ca. 1110 Ma, which dates the high-grade metamorphism and the closure of the rift. This indicates that the breakup of supercontinent Columbia was followed in short sequence by the assembly of supercontinent Rodinia at ca. 1.1-1.0 Ga and that the Western Amazon belt was formed during the accretion of the Arequipa-Antofalla basement to the Amazonian craton

'The nourishing soil of the soul': The role of horticultural therapy in promoting well-being in community-dwelling people with dementia.

Two-thirds of people with dementia reside in their own homes; however, support for community-dwelling people with dementia to continue to participate in everyday activities is often lacking, resulting in feelings of depression and isolation among people living with the condition. Engagement in outdoor activities such as gardening can potentially counteract these negative experiences by enabling people with dementia to interact with nature, helping to improve their physical and psychological well-being. Additionally, the collaborative nature of community gardening may encourage the development of a sense of community, thereby enhancing social integration. Despite increasing evidence supporting its therapeutic value for people with dementia in residential care, the benefits of horticultural therapy have yet to be transposed into a community setting. This paper will examine the theoretical support for the application of horticultural therapy in dementia care, before exploring the potential of horticultural therapy as a means of facilitating improved physical and psychological well-being and social integration for people living with dementia within the community