• ASPP proteins discriminate between PP1 catalytic subunits through their SH3 domain and the PP1 C-tail

  Bertran, M Teresa; Mouilleron, Stéphane; Zhou, Yanxiang; Bajaj, Rakhi; Uliana, Federico; Kumar, Ganesan Senthil; van Drogen, Audrey; Lee, Rebecca; Banerjee, Jennifer J; Hauri, Simon; O'Reilly, Nicola; Gstaiger, Matthias; Page, Rebecca; Peti, Wolfgang; Tapon, Nicolas; Univ Arizona, Dept Chem & Biochem (NATURE PUBLISHING GROUP, 2019-02-15)

  Serine/threonine phosphatases such as PP1 lack substrate specificity and associate with a large array of targeting subunits to achieve the requisite selectivity. The tumour suppressor ASPP (apoptosis-stimulating protein of p53) proteins associate with PP1 catalytic subunits and are implicated in multiple functions from transcriptional regulation to cell junction remodelling. Here we show that Drosophila ASPP is part of a multiprotein PP1 complex and that PP1 association is necessary for several in vivo functions of Drosophila ASPP. We solve the crystal structure of the human ASPP2/PP1 complex and show that ASPP2 recruits PP1 using both its canonical RVxF motif, which binds the PP1 catalytic domain, and its SH3 domain, which engages the PP1 C-terminal tail. The ASPP2 SH3 domain can discriminate between PP1 isoforms using an acidic specificity pocket in the n-Src domain, providing an exquisite mechanism where multiple motifs are used combinatorially to tune binding affinity to PP1.
• Association study in African-admixed populations across the Americas recapitulates asthma risk loci in non-African populations

  Daya, Michelle; Rafaels, Nicholas; Brunetti, Tonya M; Chavan, Sameer; Levin, Albert M; Shetty, Aniket; Gignoux, Christopher R; Boorgula, Meher Preethi; Wojcik, Genevieve; Campbell, Monica; Vergara, Candelaria; Torgerson, Dara G; Ortega, Victor E; Doumatey, Ayo; Johnston, Henry Richard; Acevedo, Nathalie; Araujo, Maria Ilma; Avila, Pedro C; Belbin, Gillian; Bleecker, Eugene; Bustamante, Carlos; Caraballo, Luis; Cruz, Alvaro; Dunston, Georgia M; Eng, Celeste; Faruque, Mezbah U; Ferguson, Trevor S; Figueiredo, Camila; Ford, Jean G; Gan, Weiniu; Gourraud, Pierre-Antoine; Hansel, Nadia N; Hernandez, Ryan D; Herrera-Paz, Edwin Francisco; Jiménez, Silvia; Kenny, Eimear E; Knight-Madden, Jennifer; Kumar, Rajesh; Lange, Leslie A; Lange, Ethan M; Lizee, Antoine; Maul, Pissamai; Maul, Trevor; Mayorga, Alvaro; Meyers, Deborah; Nicolae, Dan L; O'Connor, Timothy D; Oliveira, Ricardo Riccio; Olopade, Christopher O; Olopade, Olufunmilayo; Qin, Zhaohui S; Rotimi, Charles; Vince, Nicolas; Watson, Harold; Wilks, Rainford J; Wilson, James G; Salzberg, Steven; Ober, Carole; Burchard, Esteban G; Williams, L Keoki; Beaty, Terri H; Taub, Margaret A; Ruczinski, Ingo; Mathias, Rasika A; Barnes, Kathleen C; Univ Arizona, Dept Med, Coll Med (NATURE PUBLISHING GROUP, 2019-02-20)

  Asthma is a complex disease with striking disparities across racial and ethnic groups. Despite its relatively high burden, representation of individuals of African ancestry in asthma genome-wide association studies (GWAS) has been inadequate, and true associations in these underrepresented minority groups have been inconclusive. We report the results of a genome-wide meta-analysis from the Consortium on Asthma among African Ancestry Populations (CAAPA; 7009 asthma cases, 7645 controls). We find strong evidence for association at four previously reported asthma loci whose discovery was driven largely by non-African populations, including the chromosome 17q12-q21 locus and the chr12q13 region, a novel (and not previously replicated) asthma locus recently identified by the Trans-National Asthma Genetic Consortium (TAGC). An additional seven loci reported by TAGC show marginal evidence for association in CAAPA. We also identify two novel loci (8p23 and 8q24) that may be specific to asthma risk in African ancestry populations.
• Hits Close to Home: Repeated Persecution of King Cobras (Ophiophagus hannah) in Northeastern Thailand

  Marshall, Benjamin M.; Strine, Colin T.; Jones, Max D.; Theodorou, Alexandros; Amber, Evan; Waengsothorn, Surachit; Suwanwaree, Pongthep; Goode, Matt; Univ Arizona, Sch Nat Resources & Environm (SAGE PUBLICATIONS INC, 2018-12-19)

  Protected areas are often promoted as an important solution to preserving biodiversity. However, permeable edges can undermine the effectiveness of preserves because animals may move into adjacent human-dominated unprotected areas. We investigated attitudes toward, and sources of mortality of, a far-ranging apex predator, the king cobra (Ophiophagus hannah; Cantor 1836), in a biosphere reserve in northeastern Thailand. Our questionnaire revealed marked fear of snakes and hostility toward king cobras. Using radiotelemetry, we followed 23 king cobras over a 4-year period, during which time we documented the mortality of 14 individuals. We considered 10 of the deaths to be anthropogenic in origin, including road mortality, pollution, fish traps, and direct persecution; these deaths disproportionately occurred in unprotected areas. Our results highlight how dangerous human-dominated landscapes are for king cobras. Because king cobras move long distances and maintain large home ranges, it is likely that successful conservation of the species cannot be satisfactorily met by protected areas alone; a more holistic, education-focused conservation strategy is required. We stress the importance of a human dimensions approach that leads toward greater understanding of human attitudes toward king cobras, and snakes in general, combined with ecological research for more effective conservation.
• Characteristics of Lawyers Who Are Subject to Complaints and Misconduct Findings

  Sklar, Tara; Taouk, Yamna; Studdert, David; Spittal, Matthew; Paterson, Ron; Bismark, Marie; Univ Arizona, James E Rogers Coll Law, Hlth Law (WILEY, 2019-06)

  Regulators of the legal profession are charged with protecting the public by ensuring lawyers are fit to practice law. However, their approach tends to be reactive and case based, focusing on the resolution of individual complaints. Regulators generally do not seek to identify patterns and trends across their broader caseloads and the legal profession as a whole. Using administrative data routinely collected by the main regulator of the legal profession in Victoria, Australia, we characterized complaints lodged between 2005 and 2015 and the lawyers against whom they were made. We also analyzed risk factors for complaints and misconduct findings. We found that the odds of being subject to a complaint were higher among lawyers who were male, older, had trust account authority, and whose legal practices were smaller, in nonurban locations, and incorporated. A deeper understanding of these risk factors could support efforts to improve professional standards and reform regulatory practices.
• Disparities in outcomes of patients admitted with diabetic foot infections

  Tan, Tze-Woei; Shih, Chia-Ding; Concha-Moore, Kirsten C; Diri, Muhanad M; Hu, Bo; Marrero, David; Zhou, Wei; Armstrong, David G; Univ Arizona, Coll Med (PUBLIC LIBRARY SCIENCE, 2019-02-04)

  Objective The purpose of this study was to evaluate the disparities in the outcomes of White, African American (AA) and non-AA minority (Hispanics and Native Americans (NA)), patients admitted in the hospitals with diabetic foot infections (DFIs). Research design and methods The HCUP-Nationwide Inpatient Sample (2002 to 2015) was queried to identify patients who were admitted to the hospital for management of DFI using ICD-9 codes. Outcomes evaluated included minor and major amputations, open or endovascular revascularization, and hospital length of stay (LOS). Incidence for amputation and open or endovascular revascularization were evaluated over the study period. Multivariable regression analyses were performed to assess the association between race/ethnicity and outcomes. Results There were 150,701 admissions for DFI, including 98,361 Whites, 24,583 AAs, 24,472 Hispanics, and 1,654 Native Americans (NAs) in the study cohort. Overall, 45,278 (30%) underwent a minor amputation, 9,039 (6%) underwent a major amputation, 3,151 underwent an open bypass, and 8,689 had an endovascular procedure. There was a decreasing incidence in major amputations and an increasing incidence of minor amputations over the study period (P <.05). The risks for major amputation were significantly higher (all p<0.05) for AA (OR 1.4, 95%Cl 1.4,1.5), Hispanic (OR 1.3, 95%Cl 1.3,1.4), and NA (OR 1.5, 95%Cl 1.2,1.8) patients with DFIs compared to White patients. Hispanics (OR 1.3, 95%Cl 1.2,1.5) and AAs (OR 1.2, 95%Cl 1.1,1.4) were more likely to receive endovascular intervention or open bypass than Whites (all p<0.05). NA patients with DFI were less likely to receive a revascularization procedure (OR 0.6, 95%Cl 0.3, 0.9, p = 0.03) than Whites. The mean hospital length of stay (LOS) was significantly longer for AAs (9.2 days) and Hispanics (8.6 days) with DFIs compared to Whites (8.1 days, p<0.001). Conclusion Despite a consistent incidence reduction of amputation over the past decade, racial and ethnic minorities including African American, Hispanic, and Native American patients admitted to hospitals with DFIs have a consistently significantly higher risk of major amputation and longer hospital length of stay than their White counterparts. Native Americans were less likely to receive revascularization procedures compared to other minorities despite exhibiting an elevated risk of an amputation. Further study is required to address and limit racial and ethnic disparities and to further promote equity in the treatment and outcomes of these at-risk patients.

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