Dynamics of seeded Aβ40-fibril growth from atomistic molecular dynamics simulations: kinetic trapping and reduced water mobility in the locking step

Filamentous β-amyloid aggregates are crucial for the pathology of Alzheimer's disease. Despite the tremendous biomedical importance, the molecular pathway of growth propagation is not completely understood and remains challenging to investigate by simulations due to the long time scales involved. Here, we apply extensive all-atom molecular dynamics simulations in explicit water to obtain free energy profiles and kinetic information from position-dependent diffusion profiles for three different Aβ9-40-growth processes: fibril elongation by single monomers at the structurally unequal filament tips and association of larger filament fragments. Our approach provides insight into the molecular steps of the kinetic pathway and allows close agreement with experimental binding free energies and macroscopic growth rates. Water plays a decisive role, and solvent entropy is identified as the main driving force for assembly. Fibril growth is disfavored energetically due to cancellation of direct peptide-peptide interactions and solvation effects. The kinetics of growth is consistent with the characteristic dock/lock mechanism, and docking is at least 2 orders of magnitude faster. During initial docking, interactions are mediated by transient non-native hydrogen bonds, which efficiently catch the incoming monomer or fragment already at separations of about 3 nm. In subsequent locking, the dynamics is much slower due to formation of kinetically trapped conformations caused by long-lived non-native hydrogen bonds. Fibril growth additionally requires collective motion of water molecules to create a dry binding interface. Fibril growth is further retarded due to reduced mobility of the involved hydration water, evident from a 2-fold reduction of the diffusion coefficient

Art-Making During a Global Pandemic: A Collaborative Autoethnography

Between March 11, 2020 and May of 2021, the World Health Organization (WHO) counted over 100 million cases of COVID-19, resulting in three million deaths worldwide (WHO, 2021). In order to examine the effects of art-making on social and psychological well-being, seven graduate students from the Marital and Family Art Therapy Program at LMU conducted the following study utilizing a qualitative, arts-based research approach through collaborative autoethnography (CAE). The research question — What are the effects of personal art-making on well-being during the COVID-19 pandemic? — was posed by the seven graduate student authors. The data revealed that pandemic-time art-making impacted well-being through three primary avenues: by acting as a means to cope, to adapt, and to process. Each of our emerging themes highlighted the use of art-making as a tool, and each theme described this phenomenon in a unique and pointed way. First, our art-making impacted our well-being during the pandemic by serving as a tool to cope with the stressors of the pandemic by minimizing, banishing, or making them tolerable. Going one step further than coping, art-making also served as a tool for adapting. It acted as the mediating force between the pandemic’s external impacts and our ensuing internal experiences. Finally, art-making impacted well-being throughout the pandemic by serving as a tool to process corporeal experiences, emotional experiences, and other personal realities. In order to build upon our findings, we propose future research on the impacts of personal art-making on wellness through collaborative autoethnography by participant-researchers representing diverse cultures within their social and environmental contexts

Provider reported implementation of nutrition-related practices in childcare centers and family childcare homes in rural and urban Nebraska

Approximately 15 million children under age 6 are in childcare settings, offering childcare providers an opportunity to influence children’s dietary intake. Childcare settings vary in organizational structure – childcare centers (CCCs) vs. family childcare homes (FCCHs) – and in geographical location – urban vs. rural. Research on the nutrition-related best practices across these childcare settings is scarce. The objective of this study is to compare nutrition-related best practices of CCCs and FCCHs that participate in the Child and Adult Care Food Program (CACFP) in rural and urban Nebraska. Nebraska providers (urban n = 591; rural n = 579) reported implementation level, implementation difficulty and barriers to implementing evidence-informed food served and mealtime practices. Chi-square tests comparing CCCs and FCCHs in urban Nebraska and CCCs and FCCHs in rural Nebraska showed sub-optimal implementation for some practices across all groups, including limiting fried meats and high sugar/ high fat foods, using healthier foods or non-food treats for celebrations and serving meals family style. Significant differences (p \u3c .05) between CCCs and FCCHs also emerged, especially with regard to perceived barriers to implementing best practices. For example, CCCs reported not having enough money to cover the cost of meals for providers, lack of control over foods served and storage problems, whereas FCCHs reported lack of time to prepare healthier foods and sit with children during mealtimes. Findings suggest that policy and public health interventions may need to be targeted to address the unique challenges of implementing evidence-informed practices within different organizational structures and geographic locations

Psychometric Properties of the Hoarding Rating Scale-Interview

The present study tested the psychometric properties of an expanded version of the Hoarding Rating Scale (HRS-I), a semistructured interview for hoarding disorder (HD). Eighty-seven adults with HD and 44 healthy control (HC) participants were assessed using the HRS-I and completed a battery of self-report measures of HD severity, negative affect, and functional impairment. All interviews were audio recorded. From the HD participants, 21 were randomly selected for inter-rater reliability (IRR) analysis and 11 for test-retest reliability (TRR) analysis. The HRS-I showed excellent internal consistency (α = 0.87). IRR and TRR in the HD sample were good (intra-class coefficients = 0.81 and 0.85, respectively). HRS-I scores correlated strongly with scores on the self-report Saving Inventory-Revised (SI-R); partial correlations indicated that the HRS-I clutter, difficulty discarding, and acquiring items correlated significantly and at least moderately with corresponding SI-R subscales, when controlling for the other SI-R subscales. The HD group scored significantly higher on all items than did the HC group, with large effect sizes (d = 1.28–6.58). ROC analysis showed excellent sensitivity (1.00) and specificity (1.00) for distinguishing the HD and HC groups with a cutoff score of 11. Results and limitations are discussed in light of prior research

Provider reported implementation of nutrition-related practices in childcare centers and family childcare homes in rural and urban Nebraska

Approximately 15 million children under age 6 are in childcare settings, offering childcare providers an opportunity to influence children’s dietary intake. Childcare settings vary in organizational structure – childcare centers (CCCs) vs. family childcare homes (FCCHs) – and in geographical location – urban vs. rural. Research on the nutrition-related best practices across these childcare settings is scarce. The objective of this study is to compare nutrition-related best practices of CCCs and FCCHs that participate in the Child and Adult Care Food Program (CACFP) in rural and urban Nebraska. Nebraska providers (urban n = 591; rural n = 579) reported implementation level, implementation difficulty and barriers to implementing evidence-informed food served and mealtime practices. Chi-square tests comparing CCCs and FCCHs in urban Nebraska and CCCs and FCCHs in rural Nebraska showed sub-optimal implementation for some practices across all groups, including limiting fried meats and high sugar/ high fat foods, using healthier foods or non-food treats for celebrations and serving meals family style. Significant differences (p \u3c .05) between CCCs and FCCHs also emerged, especially with regard to perceived barriers to implementing best practices. For example, CCCs reported not having enough money to cover the cost of meals for providers, lack of control over foods served and storage problems, whereas FCCHs reported lack of time to prepare healthier foods and sit with children during mealtimes. Findings suggest that policy and public health interventions may need to be targeted to address the unique challenges of implementing evidence-informed practices within different organizational structures and geographic locations

British Gynaecological Cancer Society recommendations and guidance on patient-initiated follow-up (PIFU)

The National Cancer Survivorship Initiative through the National Health Service (NHS) improvement in the UK started the implementation of stratified pathways of patient-initiated follow-up (PIFU) across various tumor types. Now the initiative is continued through the Living With and Beyond Cancer program by NHS England. Evidence from non-randomized studies and systematic reviews does not demonstrate a survival advantage to the long-established practice of hospital-based follow-up regimens, traditionally over 5 years. Evidence shows that patient needs are inadequately met under the traditional follow-up programs and there is therefore an urgent need to adapt pathways to the needs of patients. The assumption that hospital-based follow-up is able to detect cancer recurrences early and hence improve patient prognosis has not been validated. A recent survey demonstrates that follow-up practice across the UK varies widely, with telephone follow-up clinics, nurse-led clinics and PIFU becoming increasingly common. There are currently no completed randomized controlled trials in PIFU in gynecological malignancies, although there is a drive towards implementing PIFU. PIFU aims to individualize patient care, based on risk of recurrence and holistic needs, and optimizing resources. The British Gynaecological Cancer Society wishes to provide the gynecological oncology community with guidance and a recommendations statement regarding the value, indications, and limitations of PIFU in endometrial, cervical, ovarian, and vulvar cancers in an effort to standardize practice and improve patient care. [Abstract copyright: © IGCS and ESGO 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Prenatal and Postnatal Cardiac Development in Offspring of Hypertensive Pregnancies.

Background Pregnancy complications such as preterm birth and fetal growth restriction are associated with altered prenatal and postnatal cardiac development. We studied whether there were changes related specifically to pregnancy hypertension. Methods and Results Left and right ventricular volumes, mass, and function were assessed at birth and 3 months of age by echocardiography in 134 term-born infants. Fifty-four had been born to mothers who had normotensive pregnancy and 80 had a diagnosis of preeclampsia or pregnancy-induced hypertension. Differences between groups were interpreted, taking into account severity of pregnancy disorder, sex, body size, and blood pressure. Left and right ventricular mass indexed to body surface area (LVMI and RVMI) were similar in both groups at birth (LVMI 20.9±3.7 versus 20.6±4.0 g/m2, P=0.64, RVMI 17.5±3.7 versus 18.1±4.7 g/m2, P=0.57). However, right ventricular end diastolic volume index was significantly smaller in those born to hypertensive pregnancy (16.8±5.3 versus 12.7±4.7 mL/m2, P=0.001), persisting at 3 months of age (16.4±3.2 versus 14.4±4.8 mL/m2, P=0.04). By 3 months of age these infants also had significantly greater LVMI and RVMI (LVMI 24.9±4.6 versus 26.8±4.9 g/m2, P=0.04; RVMI 17.1±4.2 versus 21.1±3.9 g/m2, P<0.001). Differences in RVMI and right ventricular end diastolic volume index at 3 months, but not left ventricular measures, correlated with severity of the hypertensive disorder. No differences in systolic or diastolic function were evident. Conclusions Infants born at term to a hypertensive pregnancy have evidence of both prenatal and postnatal differences in cardiac development, with right ventricular changes proportional to the severity of the pregnancy disorder. Whether differences persist long term as well as their underlying cause and relationship to increased cardiovascular risk requires further study