Constitutively active transforming growth factor β receptor 1 in the mouse ovary promotes tumorigenesis

Despite the well-established tumor suppressive role of TGFβ proteins, depletion of key TGFβ signaling components in the mouse ovary does not induce a growth advantage. To define the role of TGFβ signaling in ovarian tumorigenesis, we created a mouse model expressing a constitutively active TGFβ receptor 1 (TGFBR1) in ovarian somatic cells using conditional gain-of-function approach. Remarkably, these mice developed ovarian sex cord-stromal tumors with complete penetrance, leading to reproductive failure and mortality. The tumors expressed multiple granulosa cell markers and caused elevated serum inhibin and estradiol levels, reminiscent of granulosa cell tumors. Consistent with the tumorigenic effect, overactivation of TGFBR1 altered tumor microenvironment by promoting angiogenesis and enhanced ovarian cell proliferation, accompanied by impaired cell differentiation and dysregulated expression of critical genes in ovarian function. By further exploiting complementary genetic models, we substantiated our finding that constitutively active TGFBR1 is a potent oncogenic switch in mouse granulosa cells. In summary, overactivation of TGFBR1 drives gonadal tumor development. The TGFBR1 constitutively active mouse model phenocopies a number of morphological, hormonal, and molecular features of human granulosa cell tumors and are potentially valuable for preclinical testing of targeted therapies to treat granulosa cell tumors, a class of poorly defined ovarian malignancies

Soft Polydimethylsiloxane-Supported Lipid Bilayers for Studying T Cell Interactions.

Much of what we know about the early stages of T cell activation has been obtained from studies of T cells interacting with glass-supported lipid bilayers that favor imaging but are orders of magnitude stiffer than typical cells. We developed a method for attaching lipid bilayers to polydimethylsiloxane polymer supports, producing "soft bilayers" with physiological levels of mechanical resistance (Young's modulus of 4 kPa). Comparisons of T cell behavior on soft and glass-supported bilayers revealed that whereas late stages of T cell activation are thought to be substrate-stiffness dependent, early calcium signaling was unaffected by substrate rigidity, implying that early steps in T cell receptor triggering are not mechanosensitive. The exclusion of large receptor-type phosphatases was observed on the soft bilayers, however, even though it is yet to be demonstrated at authentic cell-cell contacts. This work sets the stage for an imaging-based exploration of receptor signaling under conditions closely mimicking physiological cell-cell contact.Royal Societ

Monitoring investments in Oregon's Federal Forest Restoration Program, 2019-2021 biennium

36 pagesThe Federal Forest Restoration Program (FFR Program) is a partnership between the state of Oregon, federal forest managers, and public lands stakeholders to increase forest restoration and economic opportunity on federal forest lands across Oregon. The purpose of this working paper is to provide an update for the investments made by the FFR Program for the 2019–2021 state funding biennium as well as an assessment of the tangible and intangible impacts of those investments over the same period. Previous findings for Oregon state fiscal years (FY) 2014–2019, including a cumulative report, are reported elsewhere. This report presents: 1) FFR Program expenditures, 2) economic impacts of FFR Program expenditures, 3) on-the-ground accomplishments of FFR Program expenditures, and 4) stakeholders’ perspectives about FFR Program successes and current and future challenges.Funding for this study was provided by the Oregon Department of Forestry to the University of Oregon (M0177, Task order #2), Oregon State University (Task order #191-677-3), and the USDA Forest Service (#20-CO-11261979-021)

Stakeholder perspectives of a pilot multicomponent delirium prevention intervention for adult patients with advanced cancer in palliative care units: A behaviour change theory-based qualitative study

Background: Theory-based and qualitative evaluations in pilot trials of complex clinical interventions help to understand quantitative results, as well as inform the feasibility and design of subsequent effectiveness and implementation trials. Aim: To explore patient, family, clinician and volunteer (‘stakeholder’) perspectives of the feasibility and acceptability of a multicomponent non-pharmacological delirium prevention intervention for adult patients with advanced cancer in four Australian palliative care units that participated in a phase II trial, the ‘PRESERVE pilot study’. Design: A trial-embedded qualitative study via semi-structured interviews and directed content analysis using Michie’s Behaviour Change Wheel and the Theoretical Domains Framework. Setting/participants: Thirty-nine people involved in the trial: nurses (n = 17), physicians (n = 6), patients (n = 6), family caregivers (n = 4), physiotherapists (n = 3), a social worker, a pastoral care worker and a volunteer. Results: Participants’ perspectives aligned with the ‘capability’, ‘opportunity’ and ‘motivation’ domains of the applied frameworks. Of seven themes, three were around the alignment of the delirium prevention intervention with palliative care (intervention was considered routine care; intervention aligned with the compassionate and collaborative culture of palliative care; and differing views of palliative care priorities influenced perspectives of the intervention) and four were about study processes more directly related to adherence to the intervention (shared knowledge increased engagement with the intervention; impact of the intervention checklist on attention, delivery and documentation of the delirium prevention strategies; clinical roles and responsibilities; and addressing environmental barriers to delirium prevention). Conclusion: This theory-informed qualitative study identified multiple influences on the delivery and documentation of a pilot multicomponent non-pharmacological delirium prevention intervention in four palliative care units. Findings inform future definitive studies of delirium prevention in palliative care

Monitoring investments in Oregon's Federal Forest Restoration Program, 2021-2023 biennium

35 pagesThe Federal Forest Restoration (FFR) Program is a joint effort among the Oregon Department of Forestry (ODF), federal forest managers, and public lands stakeholders to increase the pace, scale, and quality of federal forest restoration across Oregon. The program supports management for forest resilience on federal lands as well as economic opportunities for surrounding communities. This working paper provides an update on FFR Program investments and outcomes for the 2021-2023 biennium. Reports from the previous biennium (2019-2021) can be found elsewhere. Here we report: 1) FFR Program expenditures, 2) economic activity from timber sales and the FFR grant investments, 3) on-the-ground accomplishments of the FFR Program, and 4) stakeholders’ perspectives on the FFR Program’s successes and challenges.Funding for this study was provided by the Oregon Department of Forestry to the University of Oregon’s Ecosystem Workforce Program (Agreement number M0177, Task order #5)

Intracranial EEG structure-function coupling predicts surgical outcomes in focal epilepsy

Alterations to structural and functional brain networks have been reported across many neurological conditions. However, the relationship between structure and function -- their coupling -- is relatively unexplored, particularly in the context of an intervention. Epilepsy surgery alters the brain structure and networks to control the functional abnormality of seizures. Given that surgery is a structural modification aiming to alter the function, we hypothesized that stronger structure-function coupling preoperatively is associated with a greater chance of post-operative seizure control. We constructed structural and functional brain networks in 39 subjects with medication-resistant focal epilepsy using data from intracranial EEG (pre-surgery), structural MRI (pre-and post-surgery), and diffusion MRI (pre-surgery). We investigated pre-operative structure-function coupling at two spatial scales a) at the global iEEG network level and b) at the resolution of individual iEEG electrode contacts using virtual surgeries. At global network level, seizure-free individuals had stronger structure-function coupling pre-operatively than those that were not seizure-free regardless of the choice of interictal segment or frequency band. At the resolution of individual iEEG contacts, the virtual surgery approach provided complementary information to localize epileptogenic tissues. In predicting seizure outcomes, structure-function coupling measures were more important than clinical attributes, and together they predicted seizure outcomes with an accuracy of 85% and sensitivity of 87%. The underlying assumption that the structural changes induced by surgery translate to the functional level to control seizures is valid when the structure-functional coupling is strong. Mapping the regions that contribute to structure-functional coupling using virtual surgeries may help aid surgical planning

Fiction Fix 09

https://digitalcommons.unf.edu/fiction_fix/1003/thumbnail.jp

Social Health and Change in Cognitive Capability among Older Adults: Findings from Four European Longitudinal Studies

INTRODUCTION: In this study we examine whether social health markers measured at baseline are associated with differences in cognitive capability and in the rate of cognitive decline over an 11-to-18-year period among older adults and compare results across studies. METHODS: We applied an integrated data analysis approach to 16,858 participants (mean age 65 years; 56% female) from the National Survey for Health and Development (NSHD), the English Longitudinal Study of Aging (ELSA), the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), and the Rotterdam Study. We used multilevel models to examine social health in relation to cognitive capability and the rate of cognitive decline. RESULTS: Pooled estimates show distinct relationships between markers of social health and cognitive domains e.g., a large network size (≥6 people vs none) was associated with higher executive function (0.17 SD[95%CI:0.0, 0.34], I2=27%) but not with memory (0.08 SD[95%CI: -0.02, 0.18], I2=19%). We also observed pooled associations between being married or cohabiting, having a large network size and participating in social activities with slower decline in cognitive capability, however estimates were close to zero e.g., 0.01SD/year [95%CI: 0.01 to 0.02] I2=19% for marital status and executive function. There were clear study-specific differences: results for average processing speed were the most homogenous and results for average memory were the most heterogenous. CONCLUSION: Overall, markers of good social health have a positive association with cognitive capability. However, we found differential associations between specific markers of social health and cognitive domains and differences between studies. These findings highlight the importance of examining between study differences and considering context specificity of findings in developing and deploying any interventions

Social health and subsequent cognitive functioning in people aged 50 years and older:examining the mediating roles of depressive symptoms and inflammatory biomarkers in two European longitudinal studies

Background: Social health markers, including marital status, contact frequency, network size, and social support, have been shown to be associated with cognition. However, the mechanisms underlying these associations remain poorly understood. We investigated whether depressive symptoms and inflammation mediated associations between social health and subsequent cognition. Methods: In the English Longitudinal Study of Ageing (ELSA), a nationally representative longitudinal study in England, UK, we sampled 7136 individuals aged 50 years or older living in private households without dementia at baseline or at the intermediate mediator assessment timepoint, who had recorded information on at least one social health marker and potential mediator. We used four-way decomposition to examine to what extent depressive symptoms, C-reactive protein, and fibrinogen mediated associations between social health and subsequent standardised cognition (verbal fluency and delayed and immediate recall), including cognitive change, with slopes derived from multilevel models (12-year slope). We examined whether findings were replicated in the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), a population-based longitudinal study in Sweden, in a sample of 2604 individuals aged 60 years or older living at home or in institutions in Kungsholmen (central Stockholm) without dementia at baseline or at the intermediate mediator assessment timepoint (6-year slope). Social health exposures were assessed at baseline, potential mediators were assessed at an intermediate timepoint (wave 2 in ELSA and 6-year follow-up in SNAC-K); cognitive outcomes were assessed at a single timepoint (wave 3 in ELSA and 12-year follow-up in SNAC-K), and cognitive change (between waves 3 and 9 in ELSA and between 6-year and 12-year follow-ups in SNAC-K). Findings: The study sample included 7136 participants from ELSA, of whom 3962 (55·5%) were women and 6934 (97·2%) were White; the mean baseline age was 63·8 years (SD 9·4). Replication analyses included 2604 participants from SNAC-K, of whom 1604 (61·6%) were women (SNAC-K did not collect ethnicity data); the mean baseline age was 72·3 years (SD 10·1). In ELSA, we found indirect effects via depressive symptoms of network size, positive support, and less negative support on subsequent verbal fluency, and of positive support on subsequent immediate recall (pure indirect effect [PIE] 0·002 [95% CI 0·001–0·003]). Depressive symptoms also partially mediated associations between less negative support and slower decline in immediate recall (PIE 0·001 [0·000–0·002]) and in delayed recall (PIE 0·001 [0·000–0·002]), and between positive support and slower decline in immediate recall (PIE 0·001 [0·000–0·001]). We did not observe mediation by inflammatory biomarkers. Findings of mediation by depressive symptoms in the association between positive support and verbal fluency and between positive support and change in immediate recall were replicated in SNAC-K. Interpretation: The findings of this study provide new insights into mechanisms linking social health with cognition, suggesting that associations between interactional aspects of social health, especially social support, and cognition are partly underpinned by depressive symptoms. Funding: EU Joint Programme—Neurodegenerative Disease Research (JPND) and Alzheimer's Society. Translation: For the Swedish translation of the abstract see Supplementary Materials section.</p

Social health and subsequent cognitive functioning in people aged 50 years and older:examining the mediating roles of depressive symptoms and inflammatory biomarkers in two European longitudinal studies

Background: Social health markers, including marital status, contact frequency, network size, and social support, have been shown to be associated with cognition. However, the mechanisms underlying these associations remain poorly understood. We investigated whether depressive symptoms and inflammation mediated associations between social health and subsequent cognition. Methods: In the English Longitudinal Study of Ageing (ELSA), a nationally representative longitudinal study in England, UK, we sampled 7136 individuals aged 50 years or older living in private households without dementia at baseline or at the intermediate mediator assessment timepoint, who had recorded information on at least one social health marker and potential mediator. We used four-way decomposition to examine to what extent depressive symptoms, C-reactive protein, and fibrinogen mediated associations between social health and subsequent standardised cognition (verbal fluency and delayed and immediate recall), including cognitive change, with slopes derived from multilevel models (12-year slope). We examined whether findings were replicated in the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), a population-based longitudinal study in Sweden, in a sample of 2604 individuals aged 60 years or older living at home or in institutions in Kungsholmen (central Stockholm) without dementia at baseline or at the intermediate mediator assessment timepoint (6-year slope). Social health exposures were assessed at baseline, potential mediators were assessed at an intermediate timepoint (wave 2 in ELSA and 6-year follow-up in SNAC-K); cognitive outcomes were assessed at a single timepoint (wave 3 in ELSA and 12-year follow-up in SNAC-K), and cognitive change (between waves 3 and 9 in ELSA and between 6-year and 12-year follow-ups in SNAC-K). Findings: The study sample included 7136 participants from ELSA, of whom 3962 (55·5%) were women and 6934 (97·2%) were White; the mean baseline age was 63·8 years (SD 9·4). Replication analyses included 2604 participants from SNAC-K, of whom 1604 (61·6%) were women (SNAC-K did not collect ethnicity data); the mean baseline age was 72·3 years (SD 10·1). In ELSA, we found indirect effects via depressive symptoms of network size, positive support, and less negative support on subsequent verbal fluency, and of positive support on subsequent immediate recall (pure indirect effect [PIE] 0·002 [95% CI 0·001–0·003]). Depressive symptoms also partially mediated associations between less negative support and slower decline in immediate recall (PIE 0·001 [0·000–0·002]) and in delayed recall (PIE 0·001 [0·000–0·002]), and between positive support and slower decline in immediate recall (PIE 0·001 [0·000–0·001]). We did not observe mediation by inflammatory biomarkers. Findings of mediation by depressive symptoms in the association between positive support and verbal fluency and between positive support and change in immediate recall were replicated in SNAC-K. Interpretation: The findings of this study provide new insights into mechanisms linking social health with cognition, suggesting that associations between interactional aspects of social health, especially social support, and cognition are partly underpinned by depressive symptoms. Funding: EU Joint Programme—Neurodegenerative Disease Research (JPND) and Alzheimer's Society. Translation: For the Swedish translation of the abstract see Supplementary Materials section.</p