Hsp90-binding immunophilins link p53 to dynein during p53 transport to the nucleus

The tumor suppressor protein p53 is known to be transported to the nucleus along microtubular tracks by cytoplasmic dynein. However, the connection between p53 and the dynein motor protein complex has not been established. Here, we show that hsp90.binding immunophilins link p53.hsp90 complexes to dynein and that prevention of that linkage in vivo inhibits the nuclear movement of p53. First, we show that p53.hsp90 heterocomplexes from DLD-1 human colon cancer cells contain an immunophilin (FKBP52, CyP-40, or PP5) as well as dynein. p53.hsp90.immunophilin.dynein complexes can be formed by incubating immunopurified p53 with rabbit reticulocyte lysate, and we show by peptide competition that the immunophilins link via their tetratricopeptide repeat domains to p53-bound hsp90 and by means of their PPIase domains to the dynein complex. The linkage of immunophilins to the dynein motor is indirect by means of the dynamitin component of the dynein-associated dynactin complex, and we show that purified FKBP52 binds directly by means of its PPIase domain to purified dynamitin. By using a temperature-sensitive mutant of p53 where cytoplasmic-nuclear movement occurs by shift to permissive temperature, we show that p53 movement is impeded when p53 binding to hsp90 is inhibited by the hsp90 inhibitor radicicol. Also, nuclear movement of p53 is inhibited when immunophilin binding to dynein is competed for by expression of a PPIase domain fragment in the same manner as when dynein linkage to cargo is dissociated by expression of dynamitin. This is the first demonstration of the linkage between an hsp90-chaperoned transcription factor and the system for its retrograde movement to the nucleus both in vitro and in vivo.Fil: Galigniana, Mario Daniel. University of Michigan; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; ArgentinaFil: Harrell, Jennifer M.. University of Michigan; Estados UnidosFil: O´Hagen, Heather M.. University of Michigan; Estados UnidosFil: Ljungman, Mats. University of Michigan; Estados UnidosFil: Pratt, William B.. University of Michigan; Estados Unido

Gender, Sexual Orientation, Ethnicity and Socioeconomic Factors Influence How Wildland Firefighters Communicate their Work Experiences

As Climates Change, Natural Resource Professionals Are Often Working on the Frontlines of Intensifying Environmental Disasters, Acting in Both Scientific and Emergency Response Roles. One Subset of This Group, Wildland Firefighters Often Engage in Multifaceted Careers that Incorporate Elements of Resource Planning, Conservation Management, Community Disaster Relief, and Operational Management. Despite These STEM Roles and Nearly Half (48%) of Them Having Earned at Least a bachelor\u27s degree, usually in a STEM Field, Wildland Firefighters Are Almost Exclusively Lumped with Emergency Responders in the Scientific Literature. We Surveyed 708 Wildland Firefighters with 9 Open Response Questions as Part of a Larger Survey Asking About Experiences and Attitudes in the United States Federal Workplace. from their Responses and Voluntarily Provided Demographic Data, We Extracted Information About Response Length, Use of Hedges, Tag Questions and Imperatives, Use of Personal Language, Use of Expletives and Derogatory Language, Use of Apologetic Language, and the Types of Responses Provided. We Then Analyzed Whether Certain Demographic and Socioeconomic Factors Were Statistical Predictors of Language Use in Wildland Firefighter Survey Responses with the Goal of Ultimately Providing a Framework for Differentiating and Identifying Factors that May Influence Employee Retention, Attitudes, Morale, and Experiences among Wildland Firefighter Sub-Demographics. We Found that Different Demographic Groups Varied in their Responses to Questions: Minority Groups Used Fewer Words and Were More Likely to Relate Personal Experiences Than Majority Groups

Pifithrin-alpha inhibits p53 signaling after interaction of the tumor suppressor protein with hsp90 and its nuclear translocation

Pifithrin-alpha (PFTalpha) was originally thought to be a specific inhibitor of signaling by the tumor suppressor protein p53. However, the laboratory that discovered pifithrin recently reported that the compound also inhibits heat shock and glucocorticoid receptor (GR) signaling, and they suggested that PFTalpha targets a factor common to all three signal transduction pathways, such as the hsp90/hsp70-based chaperone machinery (Komarova, E. A., Neznanov, N., Komarov, P. G., Chernov, M. V., Wang, K., and Gudkov, A. V. (2003) J. Biol. Chem. 278, 15465-15468). Because it is important for the mechanistic study of this machinery to identify unique inhibitors of chaperone action, we have examined the effect of PFTalpha on transcriptional activation, the hsp90 heterocomplex assembly, and hsp90-dependent nuclear translocation for both p53 and the GR. At concentrations where PFTalpha blocks p53-mediated induction of p21/Waf-1 in human embryonic kidney cells, we observed no inhibition of GR-mediated induction of a chloramphenicol acetyl transferase reporter in LMCAT cells. PFTalpha did, however, cause a left shift in the dexamethasone dose response curve by increasing intracellular dexamethasone concentration, apparently by competing for dexamethasone efflux from the cell. The assembly of p53 or GR heterocomplexes with hsp90 and immunophilins was not affected by PFTalpha either in vivo or in vitro and did not affect the nuclear translocation of either transcription factor. Thus, we conclude that PFTalpha does not inhibit GR-mediated induction or the function of the chaperone machinery, and, as originally thought, it may specifically inhibit p53 signaling by acting at a stage after p53 translocation to the nucleus.Fil: Murphy, Patrick J.. University of Michigan; Estados UnidosFil: Galigniana, Mario Daniel. University of Michigan; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Morishima, Yoshihiro. University of Michigan; Estados UnidosFil: Harrell, Jennifer M.. University of Michigan; Estados UnidosFil: Kwok, Roland P.. University of Michigan; Estados UnidosFil: Ljungman, Mats. University of Michigan; Estados UnidosFil: Pratt, William B.. University of Michigan; Estados Unido

The impact of adolescent exposure to medical marijuana laws on high school completion, college enrollment and college degree completion

Background: There is concern that medical marijuana laws (MMLs) could negatively affect adolescents. To better understand these policies, we assess how adolescent exposure to MMLs is related to educational attainment. Methods: Data from the 2000 Census and 2001-2014 American Community Surveys were restricted to individuals who were of high school age (14-18) between 1990 and 2012 (n = 5,483,715). MML exposure was coded as: (i) a dichotomous any MML indicator, and (ii) number of years of high school age exposure. We used logistic regression to model whether MMLs affected: (a) completing high school by age 19; (b) beginning college, irrespective of completion; and (c) obtaining any degree after beginning college. A similar dataset based on the Youth Risk Behavior Survey (YRBS) was also constructed for confirmatory analyses assessing marijuana use. Results: MMLs were associated with a 0.40 percentage point increase in the probability of not earning a high school diploma or GED after completing the 12th grade (from 3.99% to 4.39%). High school MML exposure was also associated with a 1.84 and 0.85 percentage point increase in the probability of college non-enrollment and degree non-completion, respectively (from 31.12% to 32.96% and 45.30% to 46.15%, respectively). Years of MML exposure exhibited a consistent dose response relationship for all outcomes. MMLs were also associated with 0.85 percentage point increase in daily marijuana use among 12th graders (up from 1.26%). Conclusions: Medical marijuana law exposure between age 14 to 18 likely has a delayed effect on use and education that persists over time. (C) 2016 Elsevier Ireland Ltd. All rights reserved

Report of the 2016-2017 Student Affairs Standing Committee

The 2016-2017 AACP Student Affairs Standing Committee addressed charges related to recruitment to the profession of pharmacy and a national awareness campaign for pharmacy careers, as well as promotion of student wellness and stress management. The Committee report provides six recommendations to the American Association of Colleges of Pharmacy (AACP) and one proposed policy statement for the AACP House of Delegates related to recruitment to the pharmacy profession. The Committee report also provides three recommendations to AACP and one proposed policy statement for the AACP House of Delegates related to student wellness and stress management. In addition, this report provides recommendations for future AACP Student Affairs Standing Committee work

Postoperative Cavity Stereotactic Radiosurgery for Brain Metastases

During the past decade, tumor bed stereotactic radiosurgery (SRS) after surgical resection has been increasingly utilized in the management of brain metastases. SRS has risen as an alternative to adjuvant whole brain radiation therapy (WBRT), which has been shown in several studies to be associated with increased neurotoxicity. Multiple recent articles have shown favorable local control rates compared to those of WBRT. Specifically, improvements in local control can be achieved by adding a 2 mm margin around the resection cavity. Risk factors that have been established as increasing the risk of local recurrence after resection include: subtotal resection, larger treatment volume, lower margin dose, and a long delay between surgery and SRS (>3 weeks). Moreover, consensus among experts in the field have established the importance of (a) fusion of the pre-operative magnetic resonance imaging scan to aid in volume delineation (b) contouring the entire surgical tract and (c) expanding the target to include possible microscopic disease that may extend to meningeal or venous sinus territory. These strategies can minimize the risks of symptomatic radiation-induced injury and leptomeningeal dissemination after postoperative SRS. Emerging data has arisen suggesting that multifraction postoperative SRS, or alternatively, preoperative SRS could provide decreased rates of radiation necrosis and leptomeningeal disease. Future prospective randomized clinical trials comparing outcomes between these techniques are necessary in order to improve outcomes in these patients

Development and testing of the BONES physical activity survey for young children

<p>Abstract</p> <p>Background</p> <p>Weight-bearing and high intensity physical activities are particularly beneficial for stimulating bone growth in children given that bone responds favorably to mechanical load. While it is important to assess the contribution and impact of weight-bearing physical activity on health outcomes, measurement tools that quantify and provide information on these activities separately from overall physical activity are limited. This study describes the development and evaluation of a pictorial physical activity survey (PAS) that measures children's participation and knowledge of high-intensity, weight-bearing ("bone smart") physical activity.</p> <p>Methods</p> <p>To test reliability, two identical sets of the PAS were administered on the same day to 41 children (mean age 7.1 ± 0.8 years; 63% female) and compared. To test validity, accelerometry data from 40 children (mean age 7.7 ± 0.8 years; 50% female) were compared to data provided by the PAS. Agreements between categorical and ordinal items were assessed with Kappa statistics; agreements between continuous indices were assessed with Spearman's correlation tests.</p> <p>Results</p> <p>The subjects produced reliable results in all 10 physical activity participation items (κ range: 0.36-0.73, all p < 0.05), but less reliable in answering if the physical activities were "bone smart" (κ range: -0.04-0.66). Physical activity indices, including metabolic equivalent time and weight-bearing factors, were significant in test-retest analyses (Spearman's <it>r </it>range: 0.57-0.74, all p < 0.001). Minutes of very vigorous activity from the accelerometer were associated with the self-reported weight-bearing activity, moderate-high, and high activity scores from the PAS (Spearman's <it>r </it>range: 0.47-0.48, all p < 0.01). However, accelerometer counts, counts per minute, and minutes of moderate-vigorous and vigorous activity were not associated with the PAS scores.</p> <p>Conclusions</p> <p>Together, the results of these studies suggest that the PAS has acceptable test-retest reliability, but limited validity for early elementary school children. This survey demonstrates a first step towards developing a questionnaire that measures high intensity, weight-bearing activity in schoolchildren.</p

American Head and Neck Society Endocrine Section clinical consensus statement: North American quality statements and evidence‐based multidisciplinary workflow algorithms for the evaluation and management of thyroid nodules

BackgroundCare for patients with thyroid nodules is complex and multidisciplinary, and research demonstrates variation in care. The objective was to develop clinical guidelines and quality metrics to reduce unwarranted variation and improve quality.MethodsMultidisciplinary expert consensus and modified Delphi approach. Source documents were workflow algorithms from Kaiser Permanente Northern California and Cancer Care of Ontario based on the 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer.ResultsA consensus‐based, unified preoperative, perioperative, and postoperative workflow was developed for North American use. Twenty‐one panelists achieved consensus on 16 statements about workflow‐embedded process and outcomes metrics addressing safety, access, appropriateness, efficiency, effectiveness, and patient centeredness of care.ConclusionA panel of Canadian and United States experts achieved consensus on workflows and quality metric statements to help reduce unwarranted variation in care, improving overall quality of care for patients diagnosed with thyroid nodules.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148340/1/hed25526_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148340/2/hed25526.pd

Estrategia para conservar las poblaciones de buitres del viejo mundo utilizando el enfoque de una salud

One Health brings the powerful interrelationship between human and wildlife health together with ecosystem health. The initial concept of One Health was formulated decades ago and focused on disease transfer from wildlife to human populations. More recently, the concept has been used to associate resilience to disease with the health of the ecosystem and resilience to environmental stressors. The need for a One Health approach is particularly evident in the plight of Old World vultures, which are facing a conservation crisis due to drastic reductions in populations across their entire range. Moreover, vulture conservation exemplifies many contemporary tenets of One Health; vultures are critical to a sustainable and resilient ecosystem, which in turn is essential for the socio-ecological health of human communities. In this review, we examine the complex factors contributing to the demise of Old World vulture populations, using the lens of One Health to conceptualize the primary drivers impacting the health and sustainability of these populations. The One Health concept provides the basis for the development of a framework that incorporates a multidimensional approach and includes human health, wildlife health, environmental and disease-related stressors, disease incidences, societal pressures, and environmental contaminants. Integrating societal needs with management aimed at maintaining healthy vulture populations is key for successfully using a One Health framework to optimize the health of human and wildlife populations and ensure ecosystem health.El enfoque ‘‘Una Salud’’ promueve una poderosa interrelacio´n entre la salud de los humanos y de la fauna salvaje asociados a la salud de los ecosistemas. El concepto inicial de Una Salud fue formulado de´cadas atra´s y se enfocaba en la transferencia de enfermedades de la fauna salvaje a las poblaciones humanas. Ma´s recientemente, el concepto ha sido usado para asociar la resiliencia a las enfermedades con la salud de los ecosistemas y la resiliencia a factores de estre´s ambiental. La necesidad de utilizar el enfoque de Una Salud es particularmente evidente ante la dif´ıcil situacio´n de los buitres del Viejo Mundo, los cuales se enfrentan a una situacio´n de crisis de conservacio´n debido a la reduccio´n dra´stica en sus poblaciones a lo largo de toda su a´rea de distribucio´n. Adema´s, la conservacio´n de los buitres ejemplifica mucho de los principios contempora´neos de Una Salud; los buitres son cr´ıticos para un ecosistema sostenible y resiliente, lo que a su vez es esencial para la salud socio-ecolo´gica de las comunidades humanas. En esta revisio´n, examinamos los factores complejos que contribuyen al descenso de las poblaciones de buitres del Viejo Mundo, usando el enfoque de Una Salud para conceptualizar los factores principales que impactan en la salud y la sostenibilidad de estas poblaciones. El concepto de Una Salud proporciona las bases para el desarrollo de un marco de referencia que incorpora un enfoque multidimensional, incluyendo la salud humana y de la vida silvestre, factores estresantes ambientales y de enfermedades, incidencia de enfermedades, presiones sociales y qu´ımicos ambientales. Integrar las necesidades de la sociedad con la gestio´n destinada a mantener poblaciones saludables de buitres es clave para usar exitosamente el marco de referencia de Una Salud y as´ı optimizar la salud de las poblaciones humanas y de la fauna salvaje asegurando la salud del ecosistema.The National Science Foundationhttps://bioone.org/journals/journal-of-raptor-researcham2022Zoology and Entomolog

Determinants of emergency response willingness in the local public health workforce by jurisdictional and scenario patterns: a cross-sectional survey

<p>Abstract</p> <p>Background</p> <p>The all-hazards willingness to respond (WTR) of local public health personnel is critical to emergency preparedness. This study applied a threat-and efficacy-centered framework to characterize these workers' scenario and jurisdictional response willingness patterns toward a range of naturally-occurring and terrorism-related emergency scenarios.</p> <p>Methods</p> <p>Eight geographically diverse local health department (LHD) clusters (four urban and four rural) across the U.S. were recruited and administered an online survey about response willingness and related attitudes/beliefs toward four different public health emergency scenarios between April 2009 and June 2010 (66% response rate). Responses were dichotomized and analyzed using generalized linear multilevel mixed model analyses that also account for within-cluster and within-LHD correlations.</p> <p>Results</p> <p>Comparisons of rural to urban LHD workers showed statistically significant odds ratios (ORs) for WTR context across scenarios ranging from 1.5 to 2.4. When employees over 40 years old were compared to their younger counterparts, the ORs of WTR ranged from 1.27 to 1.58, and when females were compared to males, the ORs of WTR ranged from 0.57 to 0.61. Across the eight clusters, the percentage of workers indicating they would be unwilling to respond regardless of severity ranged from 14-28% for a weather event; 9-27% for pandemic influenza; 30-56% for a radiological 'dirty' bomb event; and 22-48% for an inhalational anthrax bioterrorism event. Efficacy was consistently identified as an important independent predictor of WTR.</p> <p>Conclusions</p> <p>Response willingness deficits in the local public health workforce pose a threat to all-hazards response capacity and health security. Local public health agencies and their stakeholders may incorporate key findings, including identified scenario-based willingness gaps and the importance of efficacy, as targets of preparedness curriculum development efforts and policies for enhancing response willingness. Reasons for an increased willingness in rural cohorts compared to urban cohorts should be further investigated in order to understand and develop methods for improving their overall response.</p