Skp, Cullin, F-box (SCF)-Met30 and SCF-Cdc4-Mediated Proteolysis of CENP-A Prevents Mislocalization of CENP-A for Chromosomal Stability in Budding Yeast

Restricting the localization of the histone H3 variant CENP-A (Cse4 in yeast, CID in flies) tocentromeres is essential for faithful chromosome segregation. Mislocalization of CENP-Aleads to chromosomal instability (CIN) in yeast, fly and human cells. Overexpression andmislocalization of CENP-A has been observed in many cancers and this correlates withincreased invasiveness and poor prognosis. Yet genes that regulate CENP-A levels andlocalization under physiological conditions have not been defined. In this study we used agenome-wide genetic screen to identify essential genes required for Cse4 homeostasis toprevent its mislocalization for chromosomal stability. We show that two Skp, Cullin, Fbox(SCF) ubiquitin ligases with the evolutionarily conserved F-box proteins Met30 andCdc4 interact and cooperatively regulate proteolysis of endogenous Cse4 and prevent itsmislocalization for faithful chromosome segregation under physiological conditions. Theinteraction of Met30 with Cdc4 is independent of the D domain, which is essential for theirhomodimerization and ubiquitination of other substrates. The requirement for both Cdc4and Met30 for ubiquitination is specifc for Cse4; and a common substrate for Cdc4 andMet30 has not previously been described. Met30 is necessary for the interaction betweenCdc4 and Cse4, and defects in this interaction lead to stabilization and mislocalization ofCse4, which in turn contributes to CIN. We provide the first direct link between Cse4 mislocalizationto defects in kinetochore structure and show that SCF-mediated proteolysis ofPLOS Genetics Cse4 is a major mechanism that prevents stable maintenance of Cse4 at non-centromericregions, thus ensuring faithful chromosome segregation. In summary, we have identifiedessential pathways that regulate cellular levels of endogenous Cse4 and shown that proteolysisof Cse4 by SCF-Met30/Cdc4 prevents mislocalization and CIN in unperturbed cells.Fil: Au, Wei-Chun. National Institutes of Health; Estados UnidosFil: Zhang, Tianyi. National Institutes of Health; Estados UnidosFil: Mishra, Prashant K.. National Institutes of Health; Estados UnidosFil: Eisenstatt, Jessica R.. National Institutes of Health; Estados UnidosFil: Walker, Robert L.. National Institutes of Health; Estados UnidosFil: Ocampo, Josefina. National Institutes of Health; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Dawson, Anthony. National Institutes of Health; Estados UnidosFil: Warren, Jack. National Institutes of Health; Estados UnidosFil: Costanzo, Michael. University of Toronto; CanadáFil: Baryshnikova, Anastasia. California Life Company; Estados UnidosFil: Flick, Karin. University of California; Estados UnidosFil: Clark, David J.. National Institutes of Health; Estados UnidosFil: Meltzer, Paul S.. National Institutes of Health; Estados UnidosFil: Baker, Richard E.. University of Massachussets; Estados UnidosFil: Myers, Chad. University of Minnesota; Estados UnidosFil: Boone, Charles. University of Toronto; CanadáFil: Kaiser, Peter. University of California; Estados UnidosFil: Basrai, Munira A.. National Institutes of Health; Estados Unido

Perioperative pain management and opioid-reduction in head and neck endocrine surgery: An American Head and Neck Society Endocrine Surgery Section consensus statement

BACKGROUND: This American Head and Neck Society (AHNS) consensus statement focuses on evidence-based comprehensive pain management practices for thyroid and parathyroid surgery. Overutilization of opioids for postoperative pain management is a major contributing factor to the opioid addiction epidemic however evidence-based guidelines for pain management after routine head and neck endocrine procedures are lacking. METHODS: An expert panel was convened from the membership of the AHNS, its Endocrine Surgical Section, and ThyCa. An extensive literature review was performed, and recommendations addressing several pain management subtopics were constructed based on best available evidence. A modified Delphi survey was then utilized to evaluate group consensus of these statements. CONCLUSIONS: This expert consensus provides evidence-based recommendations for effective postoperative pain management following head and neck endocrine procedures with a focus on limiting unnecessary use of opioid analgesics

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

A Controlled Investigation of Optimal Internal Medicine Ward Team Structure at a Teaching Hospital

BACKGROUND: The optimal structure of an internal medicine ward team at a teaching hospital is unknown. We hypothesized that increasing the ratio of attendings to housestaff would result in an enhanced perceived educational experience for residents. METHODS: Harbor-UCLA Medical Center (HUMC) is a tertiary care, public hospital in Los Angeles County. Standard ward teams at HUMC, with a housestaff∶attending ratio of 5:1, were split by adding one attending and then dividing the teams into two experimental teams containing ratios of 3:1 and 2:1. Web-based Likert satisfaction surveys were completed by housestaff and attending physicians on the experimental and control teams at the end of their rotations, and objective healthcare outcomes (e.g., length of stay, hospital readmission, mortality) were compared. RESULTS: Nine hundred and ninety patients were admitted to the standard control teams and 184 were admitted to the experimental teams (81 to the one-intern team and 103 to the two-intern team). Patients admitted to the experimental and control teams had similar age and disease severity. Residents and attending physicians consistently indicated that the quality of the educational experience, time spent teaching, time devoted to patient care, and quality of life were superior on the experimental teams. Objective healthcare outcomes did not differ between experimental and control teams. CONCLUSIONS: Altering internal medicine ward team structure to reduce the ratio of housestaff to attending physicians improved the perceived educational experience without altering objective healthcare outcomes

The role of microRNA-155/liver X receptor pathway in experimental and idiopathic pulmonary fibrosis

Background: Idiopathic Pulmonary Fibrosis (IPF) is progressive and rapidly fatal. Improved understanding of pathogenesis is required to prosper novel therapeutics. Epigenetic changes contribute to IPF therefore microRNAs may reveal novel pathogenic pathways. Objectives: To determine the regulatory role of microRNA(miR)-155 in the pro-fibrotic function of murine lung macrophages and fibroblasts, IPF lung fibroblasts and its contribution to experimental pulmonary fibrosis. Methods: Bleomycin-induced lung fibrosis in wild-type and miR-155-/- mice was analyzed by histology, collagen and pro-fibrotic gene expression. Mechanisms were identified by in silico and molecular approaches; validated in mouse lung fibroblasts and macrophages, and in IPF lung fibroblasts, using loss-and-gain of function assays, and in vivo using specific inhibitors. Results: miR-155-/- mice developed exacerbated lung fibrosis, increased collagen deposition, collagen 1 and 3 mRNA expression, TGFβ production, and activation of alternatively-activated macrophages, contributed by deregulation of the microRNA-155 target gene the liver X receptor (LXR)α in lung fibroblasts and macrophages. Inhibition of LXRα in experimental lung fibrosis and in IPF lung fibroblasts reduced the exacerbated fibrotic response. Similarly, enforced expression of miR-155 reduced the pro-fibrotic phenotype of IPF and miR-155-/- fibroblasts. Conclusion: We describe herein a molecular pathway comprising miR-155 and its epigenetic LXRα target that when deregulated enables pathogenic pulmonary fibrosis. Manipulation of the miR-155/LXR pathway may have therapeutic potential for IPF

Optimal Sovereign Debt: An Analytical Approach

This paper develops a model of sovereign debt where governments are myopic. Instead of focusing on the incentives to repay, as in most of the theoretical literature on the topic (which assumes implicitly that governments have long-term objectives), I therefore consider that governments always repay when they can, but also borrow as much as possible. without paying attention to the burden of future repayments. The pattern of debt is then only determined by the willingness of international investors to lend to the country. I characterize the Rational Expectations Equilibria of the credit market. These equilibria behave like rational bubbles: international investors lend a lot because they anticipate that other investors will lend again in the future. Capital flows are procyclical: the government borrows a fixed proportion of its income until a sudden stop occurs, generating default and an economic crisis. I suggest possible remedies to the high volatility of public expenditures that is generated by such borrowing patterns

Genome-wide Association Study Identifies Two Susceptibility Loci for Osteosarcoma

Osteosarcoma is the most common primary bone malignancy of adolescents and young adults. In order to better understand the genetic etiology of osteosarcoma, we performed a multi-stage genome-wide association study (GWAS) consisting of 941 cases and 3,291 cancer-free adult controls of European ancestry. Two loci achieved genome-wide significance: rs1906953 at 6p21.3, in the glutamate receptor metabotropic 4 [GRM4] gene (P = 8.1 ×10-9), and rs7591996 and rs10208273 in a gene desert on 2p25.2 (P = 1.0 ×10-8 and 2.9 ×10-7). These two susceptibility loci warrant further exploration to uncover the biological mechanisms underlying susceptibility to osteosarcoma

Ebola: translational science considerations

We are currently in the midst of the most aggressive and fulminating outbreak of Ebola-related disease, commonly referred to as “Ebola”, ever recorded. In less than a year, the Ebola virus (EBOV, Zaire ebolavirus species) has infected over 10,000 people, indiscriminately of gender or age, with a fatality rate of about 50%. Whereas at its onset this Ebola outbreak was limited to three countries in West Africa (Guinea, where it was first reported in late March 2014, Liberia, where it has been most rampant in its capital city, Monrovia and other metropolitan cities, and Sierra Leone), cases were later reported in Nigeria, Mali and Senegal, as well as in Western Europe (i.e., Madrid, Spain) and the US (i.e., Dallas, Texas; New York City) by late October 2014. World and US health agencies declared that the current Ebola virus disease (EVD) outbreak has a strong likelihood of growing exponentially across the world before an effective vaccine, treatment or cure can be developed, tested, validated and distributed widely. In the meantime, the spread of the disease may rapidly evolve from an epidemics to a full-blown pandemic. The scientific and healthcare communities actively research and define an emerging kaleidoscope of knowledge about critical translational research parameters, including the virology of EBOV, the molecular biomarkers of the pathological manifestations of EVD, putative central nervous system involvement in EVD, and the cellular immune surveillance to EBOV, patient-centered anthropological and societal parameters of EVD, as well as translational effectiveness about novel putative patient-targeted vaccine and pharmaceutical interventions, which hold strong promise, if not hope, to curb this and future Ebola outbreaks. This work reviews and discusses the principal known facts about EBOV and EVD, and certain among the most interesting ongoing or future avenues of research in the field, including vaccination programs for the wild animal vectors of the virus and the disease from global translational science perspective