48 results on '"Melissa M. Kelley"'
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2. Delivering health messages using traditional and new media: Communication preferences of california residents during the 2009 H1N1 influenza outbreak.
- Author
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Melissa M. Kelley, Bindu Tharian, and Kimberley I. Shoaf
- Published
- 2011
3. A LigA three-domain region protects hamsters from lethal infection by Leptospira interrogans.
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Mariana L Coutinho, Henry A Choy, Melissa M Kelley, James Matsunaga, Jane T Babbitt, Michael S Lewis, Jose Antonio G Aleixo, and David A Haake
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Arctic medicine. Tropical medicine ,RC955-962 ,Public aspects of medicine ,RA1-1270 - Abstract
The leptospiral LigA protein consists of 13 bacterial immunoglobulin-like (Big) domains and is the only purified recombinant subunit vaccine that has been demonstrated to protect against lethal challenge by a clinical isolate of Leptospira interrogans in the hamster model of leptospirosis. We determined the minimum number and location of LigA domains required for immunoprotection. Immunization with domains 11 and 12 was found to be required but insufficient for protection. Inclusion of a third domain, either 10 or 13, was required for 100% survival after intraperitoneal challenge with Leptospira interrogans serovar Copenhageni strain Fiocruz L1-130. As in previous studies, survivors had renal colonization; here, we quantitated the leptospiral burden by qPCR to be 1.2×10(3) to 8×10(5) copies of leptospiral DNA per microgram of kidney DNA. Although renal histopathology in survivors revealed tubulointerstitial changes indicating an inflammatory response to the infection, blood chemistry analysis indicated that renal function was normal. These studies define the Big domains of LigA that account for its vaccine efficacy and highlight the need for additional strategies to achieve sterilizing immunity to protect the mammalian host from leptospiral infection and its consequences.
- Published
- 2011
- Full Text
- View/download PDF
4. The multifunctional LigB adhesin binds homeostatic proteins with potential roles in cutaneous infection by pathogenic Leptospira interrogans.
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Henry A Choy, Melissa M Kelley, Julio Croda, James Matsunaga, Jane T Babbitt, Albert I Ko, Mathieu Picardeau, and David A Haake
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Medicine ,Science - Abstract
Leptospirosis is a potentially fatal zoonotic disease in humans and animals caused by pathogenic spirochetes, such as Leptospira interrogans. The mode of transmission is commonly limited to the exposure of mucous membrane or damaged skin to water contaminated by leptospires shed in the urine of carriers, such as rats. Infection occurs during seasonal flooding of impoverished tropical urban habitats with large rat populations, but also during recreational activity in open water, suggesting it is very efficient. LigA and LigB are surface localized proteins in pathogenic Leptospira strains with properties that could facilitate the infection of damaged skin. Their expression is rapidly induced by the increase in osmolarity encountered by leptospires upon transition from water to host. In addition, the immunoglobulin-like repeats of the Lig proteins bind proteins that mediate attachment to host tissue, such as fibronectin, fibrinogen, collagens, laminin, and elastin, some of which are important in cutaneous wound healing and repair. Hemostasis is critical in a fresh injury, where fibrinogen from damaged vasculature mediates coagulation. We show that fibrinogen binding by recombinant LigB inhibits fibrin formation, which could aid leptospiral entry into the circulation, dissemination, and further infection by impairing healing. LigB also binds fibroblast fibronectin and type III collagen, two proteins prevalent in wound repair, thus potentially enhancing leptospiral adhesion to skin openings. LigA or LigB expression by transformation of a nonpathogenic saprophyte, L. biflexa, enhances bacterial adhesion to fibrinogen. Our results suggest that by binding homeostatic proteins found in cutaneous wounds, LigB could facilitate leptospirosis transmission. Both fibronectin and fibrinogen binding have been mapped to an overlapping domain in LigB comprising repeats 9-11, with repeat 11 possibly enhancing binding by a conformational effect. Leptospirosis patient antibodies react with the LigB domain, suggesting applications in diagnosis and vaccines that are currently limited by the strain-specific leptospiral lipopolysaccharide coats.
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- 2011
- Full Text
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5. Author Response to Reviews of Grief: Contemporary Theory and the Practice of Ministry
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Melissa M. Kelley
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Psychoanalysis ,Sociology and Political Science ,Social Psychology ,media_common.quotation_subject ,Religious studies ,Contemporary theory ,Injustice ,Cross-cultural psychology ,Pastoral Psychology ,Multiculturalism ,Christian ministry ,Grief ,Sociology ,Applied Psychology ,media_common - Abstract
The purpose of this article is to respond to three reviews in Pastoral Psychology of the author’s text, Grief: Contemporary Theory and the Practice of Ministry (Kelley 2010). This article considers in particular the grief born of injustice, the need for pastoral caregivers to cultivate skills and sensitivities for grief ministry in multicultural and multireligious settings, and the centrality for many of a secure relationship with the Divine as a primary source of hope after loss.
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- 2013
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6. An Examination of the Effect of Perceived Risk on Preparedness Behavior
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Rotrease Regan, Michele M. Wood, Dennis S. Mileti, Linda B. Bourque, Melissa M. Kelley, and Megumi Kano
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Risk perception ,Preparedness ,Sample (statistics) ,Psychology ,Practical implications ,Social psychology ,Full sample ,General Environmental Science - Abstract
This article explores and specifies the impact of risk perception on household preparedness for terrorism based on a representative sample of households in the United States. This was done by constructing a path model, which included factors that both predict risk perception and others that mediate its effect on preparedness behaviors. An unweighted sample of the nation was randomly split to allow a path model to be developed on a calibration sample, confirmed on a cross-validation sample, and rerun on the full sample using Mplus. Analyses were conducted on the unweighted samples. Results led to the conclusion that risk perception does not have a significant direct effect on preparedness behavior and that its effect is largely meditated by knowledge, perceived efficacy, and milling behavior. The theoretical and practical implications of these findings are discussed and recommendations are offered for future research.
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- 2012
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7. Communicating Actionable Risk for Terrorism and Other Hazards⋆
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Melissa M. Kelley, Michele M. Wood, Rotrease Regan, Dennis S. Mileti, Megumi Kano, and Linda B. Bourque
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Engineering ,business.industry ,Poison control ,Human factors and ergonomics ,Public relations ,Computer security ,computer.software_genre ,Suicide prevention ,Diffusion of innovations ,Physiology (medical) ,Preparedness ,Injury prevention ,Terrorism ,Safety, Risk, Reliability and Quality ,business ,computer ,Risk management - Abstract
We propose a shift in emphasis when communicating to people when the objective is to motivate household disaster preparedness actions. This shift is to emphasize the communication of preparedness actions (what to do about risk) rather than risk itself. We have called this perspective "communicating actionable risk," and it is grounded in diffusion of innovations and communication theories. A representative sample of households in the nation was analyzed using a path analytic framework. Preparedness information variables (including content, density, and observation), preparedness mediating variables (knowledge, perceived effectiveness, and milling), and preparedness actions taken were modeled. Clear results emerged that provide a strong basis for communicating actionable risk, and for the conclusion both that information observed (seeing preparedness actions that other have taken) and information received (receiving recommendations about what preparedness actions to take) play key, although different, roles in motivating preparedness actions among the people in our nation.
- Published
- 2011
- Full Text
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8. The Grace of Teaching Mistakes
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Melissa M. Kelley
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Social Psychology ,Perspective (graphical) ,Pastoral theology ,Religious studies ,Mistake ,Space (commercial competition) ,Self perception ,Epistemology ,Self-awareness ,Data_FILES ,ComputingMilieux_COMPUTERSANDEDUCATION ,Self-consciousness ,Psychological counseling ,Psychology ,Social Sciences (miscellaneous) ,Applied Psychology - Abstract
Teaching mistakes are often unwelcome intruders in our courses, and we may think they are best avoided altogether. In contrast to this perspective, this article proposes that teaching mistakes may be occasions of grace both for us and for our students. Teaching mistakes may be gifts of grace in four particular ways. Teaching about our mistakes in pedagogically intentional ways may also create a space for God's gracious activity in our lives and in those of our students. These points are illustrated by the story of the author's most powerful teaching mistake.
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- 2009
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9. Loss Through the Lens of Attachment to God
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Melissa M. Kelley
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Psychoanalysis ,Social Psychology ,Spirituality ,Religious studies ,Attachment theory ,Case vignette ,Psychology ,Social Sciences (miscellaneous) ,Applied Psychology ,Through-the-lens metering - Abstract
This article explores the experience of loss in part through the lens of “attachment to God.” While attachment theory is a familiar frame for understanding loss, the area of attachment to God is still largely neglected. After an overview of attachment theory and a summary of contemporary work done on attachment to God, this article presents two case vignettes in order to highlight possible spiritual implications of an “attachment to God” framework for working with those who have experienced significant loss.
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- 2009
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10. Genomewide Clonal Analysis of Lethal Mutations in the Drosophila melanogaster Eye: Comparison of the X Chromosome and Autosomes
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Christopher Lee, Thanh Luu, Maurine Tong, Cheryl Chan, Thomas Walsh, Mabel Chin, Jiong Chen, Jacob Makshanoff, Diane Vo, Yuli Chang, John M. Olson, Tony Hung, Yuki Yamauchi, Manyak Saakyan, Renata P. Lerner, Elizabeth Evers, Latiffe Amado, Nick Garrone, Carol Salame, Jesse M. Zaretsky, Eric Paul, Winston Wu, Trinh Tran, David Kohanchi, James Z. Hui, Neetika Srivastava, Allison M. Yabroff, Aria Hong, Daniel Solomin, Preethi Poulose, Brian Kirkpatrick, Katherine Wu, Eunha Kim, Abbas Anwar, Diane Tan, Nneka Orjiakor, Utpal Banerjee, Lindsay Hovestreydt, Riju Gupta, Michael Hsieh, Jian-ya Lin, Jennifer Leighn. Sta.Ana, Alex Pavlenko, Ardy Davarifar, Stephanie S. Latterman, Shekhar S. Pai, Qing Xu, Phyllis Gayda, Amir Yavari, Allen Bookatz, Kathy T. Ngo, Paul D. Picard, Srpouhi Gasparyan, ToHang S. Lee, Emily Skinner, Sanjit Datta, Jennifer D. Trinh, Sarah Brewer, Courtney Gonzalez, Matteo Pellegrini, Desiree Rosselli, Gerald B. Call, Gemma Lewis, Kosha Soneji, Quynh-Minh Tran, Amy W. Ku, Farzin Farshidi, Cynthia Nguyen, Vivek Singh, Tanya Minasian, Mara Pavel-Dinu, Chad Goffstein, Bryon C. Lim, So-Youn Lee, Stephanie S. Lauw, Long H. Nguyen, Kevin Yackle, Will Yarosh, Santino Laxamana, Chelsea E. Taber, Sarah Kim, Tiffany Liu, Stacy Chan, Armonde Baghdanian, Kelly Trangsrud, Robert Kwak, Gelsey L. Goodstein, Farnaz Shadpour, Mariam Guirguis, Wah-Yung Tsang, Jayantha Thiyanaratnam, Edwin Paz, Chloe Knudsen-Robbins, Tatiana Moroz, Arlene J. Formanes, Mei L. Iao, Latifat Alli, Shawn S. Badal, Kathleen Lin, PhuongThao Tran, Jamie L. Marshall, Regan S. Wong, Akanksha Chhabra, Ran X. Zhu, Amanda Abramson, Sarah Min, Amit Misra, Vanessa Soma, Blake E. Haas, Eddie Garcia, Ndidi Onugha, Divi Ramola, Ya-Whey Wu, Bogdana Kovshilovskaya, Crystal P. Y. Lui, Kai C. Lei, Jeyling Chou, Yasaman Moshfegh, Sohrab Sidhu, Mark E. L. Landig, Michael G. Yeranosian, James S. Yu, Laura Yee, Lydia S-H. Kim, Katrina Fischer, Angela Y. Kim, Junia J. Song, Melissa M. Kelley, Sheila Lezcano, Jingwen Tan, Vincent Luong, Jennifer J. Zhou, Christopher N.H. Bui, Jenny Chan, Sophia D. Jin, Natalie Buu, Emily Weiss, Amanda O'Donahue, Christian Sanchez, Andrew Folick, Nkau X. V. Yang, Christie Sun, Lephong Pham, Stephanie Calvillo, Charles Hu, Yein Kim, Aileen Chang, George Yen, Joy Wu, Poonam Desai, Linda Kao, Emily G. Travis, Mary Unkovic, Damien Wood, Miriam Segura, Marc Uemura, Henry Lin, Maggie Wells, Miles Morimoto, Sumit Datta, Kha Nguyen, Jessica Wickland, Christina C. Seifert, Leo Thai, Bhavin Padhiar, Hei J. Chan, Yibing Chen, Abhishek Shah, Julie Hong, Cheng R. Huang, Sara A. Baumann, Xibin A. Cheng, Russell Powell, Shawn J. Cokus, Sonia Arevalo, Anna L. Abrams, Mark Engeln, Minh-Tu Do, Joseph Cao, JiEun Lee, Brenda Hermogeno, Bassel Rifai, Preethika S Ekanayake, Alison S. Teruya, Carlyn Crisostomo, Lesley L. Leung, Toni Lee, Megan King, Amy Chan, William R. Marrs, Ryan Hassid, Elena Bibikova, Adam D. Langenbacher, Francie Diep, Jun Gong, Joann S. Lee, Manish Pandya, Emil Kohan, Daniel S. Lee, Jenny Anderson, Kristin Spivey, Devon M Huff, Yulee Kim, Thomas Kho, Alma Rangel, Janet Lee, Aneet Toor, Pamela Saarikoski, Nikki Villarasa, Julie Luu, Vivian N. Becerra, Yara A. Mikhaeil, Shahbaz Farnad, Vida Chitsazzadeh, Q. Angela Fang, Ju An, Leena Tekchandani, Tharani Prasad, Elsa Beyer, Christopher M. Allen, Fleurette Chong, Eric Lee, Meghann Ribbens, Sherrylene Go, Amrita K. Cheema, Jordan Fabrikant, Michael Safaee, An-Chi Mei, Peter Lin, Jessica Murray, Nina Sanchez, Katherine Fu, Sacha L. Prashad, Artemis Deravanesian, Erin Marsh, Robyn Tikia, Raymond W. Kung, Sarah Phaklides, Oganes H. Shilgevorkyan, Peter Dang, Aadit R. Patel, Erika Stageberg, Helena Minye, Alexander N. Patananan, Albert Cespedes, Kasey Topp, Vicky Hahm, Keenan Bashour, Joo Choi, Daniel Chang, Majid Moarefi, William Kim, Farid Jamshidian, Inderroop Singh, Aileen E. Chang, Miguel Meza, Edward Kuoy, Danny Ayoub, Aya Pusic, Daniel Sitz, Marina Stavchanskiy, Sophia Wu, Emily Vollmer, Angela Delosreyes, James Jen, Ernesto Nodado, Aram Shemmassian, Kirsten Regalia, Ramnik Singh, Arthur H. Baghdanian, Steve Tovar, H-C. Angela Liu, and Katrin Kahen
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Genetics Education ,Genetics ,Mutation ,Genes, Essential ,X Chromosome ,Autosome ,Genome, Insect ,Genes, Insect ,Biology ,Eye ,biology.organism_classification ,medicine.disease_cause ,Clonal analysis ,Clone Cells ,Drosophila melanogaster ,medicine ,Eye development ,Animals ,Genes, Lethal ,Drosophila (subgenus) ,Gene ,X chromosome - Abstract
Using a large consortium of undergraduate students in an organized program at the University of California, Los Angeles (UCLA), we have undertaken a functional genomic screen in the Drosophila eye. In addition to the educational value of discovery-based learning, this article presents the first comprehensive genomewide analysis of essential genes involved in eye development. The data reveal the surprising result that the X chromosome has almost twice the frequency of essential genes involved in eye development as that found on the autosomes.
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- 2007
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11. Physiological Osmotic Induction of Leptospira interrogans Adhesion: LigA and LigB Bind Extracellular Matrix Proteins and Fibrinogen
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Henry A. Choy, Melissa M. Kelley, Tammy L. Chen, Annette K. Møller, David A. Haake, and James Matsunaga
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Immunology ,Plasma protein binding ,Microbiology ,Bacterial Adhesion ,law.invention ,Extracellular matrix ,law ,Laminin ,Cricetinae ,Animals ,Humans ,Adhesins, Bacterial ,Antigens, Bacterial ,Extracellular Matrix Proteins ,Mesocricetus ,biology ,Osmolar Concentration ,Fibrinogen ,Gene Expression Regulation, Bacterial ,biology.organism_classification ,Molecular Pathogenesis ,Blood proteins ,Bacterial adhesin ,Fibronectin ,Infectious Diseases ,biology.protein ,Recombinant DNA ,Parasitology ,Leptospira interrogans ,Protein Binding - Abstract
Transmission of leptospirosis occurs through contact of mucous membranes and abraded skin with freshwater contaminated by pathogenic Leptospira spp. Exposure to physiological osmolarity induces leptospires to express high levels of the Lig surface proteins containing imperfect immunoglobulin-like repeats that are shared or differ between LigA and LigB. We report that osmotic induction of Lig is accompanied by 1.6- to 2.5-fold increases in leptospiral adhesion to immobilized extracellular matrix and plasma proteins, including collagens I and IV, laminin, and especially fibronectin and fibrinogen. Recombinant LigA-unique and LigB-unique repeat proteins bind to these same host ligands. We found that the avidity of LigB in binding fibronectin is comparable to that of the Staphylococcus aureus FnBPA D repeats. Both LigA- and LigB-unique repeats interact with the amino-terminal fibrin- and gelatin-binding domains of fibronectin, which are also recognized by fibronectin-binding proteins mediating the adhesion of other microbial pathogens. In contrast, repeats common to both LigA and LigB do not bind these host proteins, and nonrepeat sequences in the carboxy-terminal domain of LigB show only weak interaction with fibronectin and fibrinogen. A functional role for the binding activity of LigA and LigB is suggested by the ability of the recombinants to inhibit leptospiral adhesion to fibronectin by 28% and 21%, respectively. The binding of LigA and LigB to multiple ligands present in different tissues suggests that these adhesins may be involved in the initial colonization and dissemination stages of leptospirosis. The characterization of the Lig adhesin function should aid the design of Lig-based vaccines and serodiagnostic tests.
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- 2007
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12. Enhancing emergency preparedness and response systems: correlates of collaboration between local health departments and school districts
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Kimberley Shoaf, Katharine D. Arrington, Michael L. Prelip, Melissa M. Kelley, and Kaitlin A. O'Keefe
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medicine.medical_specialty ,Civil defense ,Policy and Administration ,MEDLINE ,Disaster Planning ,Nursing ,Sustainable Cities and Communities ,Clinical Research ,Surveys and Questionnaires ,Medicine ,Humans ,Cooperative Behavior ,Community resilience ,Local Government ,Schools ,Emergency management ,business.industry ,Public health ,Public Health, Environmental and Occupational Health ,Civil Defense ,Expanding Partnerships ,Health Services ,Public relations ,Los Angeles ,Local government ,Public Health and Health Services ,Public Health ,Cooperative behavior ,business ,Public Health Administration ,Disaster planning - Abstract
Objective.Collaboration between existing components of the public health system is important for protecting public health and promoting community resilience. We describe the factors that promote collaborative emergency preparedness and response activities between local health departments (LHDs) and school systems.Methods.We gathered data from a multistage, stratified random sample of 750 LHDs nationwide. Utilizing a mailed invitation, we recruited respondents to participate in an online questionnaire. We calculated descriptive and inferential statistics.Results.The majority of LHDs collaborated with school systems for emergency preparedness and response activities and most indicated they were likely to collaborate in the future. Characteristics of the jurisdiction, general experience and perceptions of collaboration, and characteristics of the preparedness collaboration itself predicted future collaboration.Conclusion.Our results help us understand the nature of collaborations between LHDs and school systems on emergency preparedness and response activities, which can be used to identify priority areas for developing successful and sustainable joint efforts in the future. By focusing on the perceived value of collaboration and building on existing non-preparedness partnering, communities can increase the likelihood of ongoing successful LHD-school system emergency preparedness collaborations.
- Published
- 2014
13. Assessing the role of attachment to God, meaning, and religious coping as mediators in the grief experience
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Melissa M. Kelley and Keith Chan
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Adult ,Male ,Religion and Psychology ,Coping (psychology) ,Adolescent ,Sense of Coherence ,media_common.quotation_subject ,Structural equation modeling ,Young Adult ,Arts and Humanities (miscellaneous) ,Adaptation, Psychological ,Developmental and Educational Psychology ,Attachment theory ,Humans ,media_common ,Aged ,Depressive Disorder ,Middle Aged ,Resilience, Psychological ,Object Attachment ,humanities ,Clinical Psychology ,Massachusetts ,Grief ,Female ,Psychology ,Social psychology - Abstract
Research has examined the relationship of styles of attachment to others and meaning with grief and the stress-related growth process. Less has been written on styles of attachment to God and patterns of religious coping and how these constructs may impact adjustment in persons dealing with loss. This study examines the roles of attachment to God, meaning, and religious coping as mediators in the grief experience for a sample of 93 individuals who experienced a significant death in the prior year. Results suggest that a more secure style of attachment to God was directly and indirectly associated with lower depression and grief and increased stress-related growth for this sample. Meaning, defined as a sense of purpose and coherence, also emerged as an important construct in this process. Overall goodness-of fit statistics were examined for competing models using structural equation modeling. Secure attachment to God, meaning, and positive religious coping were found to have significant direct and indirect effects on grief and stress-related growth. For some individuals, attachment to God may be an important construct in the experience of meaning following a significant death and may have tremendous potential in its direct and indirect effects on overall outcomes.
- Published
- 2014
14. Communicating actionable risk for terrorism and other hazards
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Michele M, Wood, Dennis S, Mileti, Megumi, Kano, Melissa M, Kelley, Rotrease, Regan, and Linda B, Bourque
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Risk ,Risk Management ,Risk-Taking ,Communication ,Humans ,Disaster Planning ,Terrorism ,Models, Theoretical ,United States - Abstract
We propose a shift in emphasis when communicating to people when the objective is to motivate household disaster preparedness actions. This shift is to emphasize the communication of preparedness actions (what to do about risk) rather than risk itself. We have called this perspective "communicating actionable risk," and it is grounded in diffusion of innovations and communication theories. A representative sample of households in the nation was analyzed using a path analytic framework. Preparedness information variables (including content, density, and observation), preparedness mediating variables (knowledge, perceived effectiveness, and milling), and preparedness actions taken were modeled. Clear results emerged that provide a strong basis for communicating actionable risk, and for the conclusion both that information observed (seeing preparedness actions that other have taken) and information received (receiving recommendations about what preparedness actions to take) play key, although different, roles in motivating preparedness actions among the people in our nation.
- Published
- 2011
15. Book Review: Stations of the Heart: Parting with a Son. By Richard Lischer
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Melissa M. Kelley
- Subjects
Religious studies - Published
- 2014
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16. Grief Transition and Loss : Contemporary Theory And The Practice Of Ministry
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Melissa M. Kelley and Melissa M. Kelley
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- Grief--Religious aspects--Christianity, Church work with bereaved persons
- Abstract
The experience of grief has been a source of intrigue and curiosity throughout history, and it continues to stimulate thought and theory in various fields of study. Unfortunately, these fields tend to function in isolation from each other. The result is a substantial disconnect between grief research, theory, and care—which has evolved greatly over the last two decades—and ministerial practice. Using a metaphor of grief as a mosaic, Melissa Kelley presents contemporary grief theory and research, integrated with important theological, religious, and ministerial perspectives. Written in an accessible way for ministers, ministers-in-training, and all pastoral and spiritual caregivers, this book provides the most up-to-date theory and research in grief to help inform their care of others. Through exploration of critical topics including attachment to God, meaning making, and religious coping in grief, readers are brought right to the heart of a contemporary understanding of grief.
- Published
- 2010
17. Molecular evolution and mosaicism of leptospiral outer membrane proteins involves horizontal DNA transfer
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Manjula Dundoo, Richard L. Zuerner, Melissa M. Kelley, Marc A. Suchard, David P. Alt, and David A. Haake
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Nonsynonymous substitution ,Genetics ,DNA, Bacterial ,Leptospira ,Molecular Biology of Pathogens ,Phylogenetic tree ,Gene Transfer, Horizontal ,Sequence analysis ,Molecular Sequence Data ,Biology ,Microbiology ,Conserved sequence ,Evolution, Molecular ,Phylogenetics ,Molecular evolution ,RNA, Ribosomal, 16S ,Horizontal gene transfer ,Amino Acid Sequence ,Molecular Biology ,Gene ,Conserved Sequence ,Phylogeny ,Bacterial Outer Membrane Proteins - Abstract
Leptospires belong to a genus of parasitic bacterial spirochetes that have adapted to a broad range of mammalian hosts. Mechanisms of leptospiral molecular evolution were explored by sequence analysis of four genes shared by 38 strains belonging to the core group of pathogenic Leptospira species: L. interrogans , L. kirschneri , L. noguchii , L. borgpetersenii , L. santarosai , and L. weilii . The 16S rRNA and lipL32 genes were highly conserved, and the lipL41 and ompL1 genes were significantly more variable. Synonymous substitutions are distributed throughout the ompL1 gene, whereas nonsynonymous substitutions are clustered in four variable regions encoding surface loops. While phylogenetic trees for the 16S, lipL32 , and lipL41 genes were relatively stable, 8 of 38 (20%) ompL1 sequences had mosaic compositions consistent with horizontal transfer of DNA between related bacterial species. A novel Bayesian multiple change point model was used to identify the most likely sites of recombination and to determine the phylogenetic relatedness of the segments of the mosaic ompL1 genes. Segments of the mosaic ompL1 genes encoding two of the surface-exposed loops were likely acquired by horizontal transfer from a peregrine allele of unknown ancestry. Identification of the most likely sites of recombination with the Bayesian multiple change point model, an approach which has not previously been applied to prokaryotic gene sequence analysis, serves as a model for future studies of recombination in molecular evolution of genes.
- Published
- 2004
18. Local emergency evacuation planning in California, USA: a comparison with the hurricane states
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Michelle Hashemi, Melissa M. Kelley, and Megumi Kano
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Emergency management ,business.industry ,Special needs ,Crisis management ,medicine.disease ,Preparedness ,Emergency evacuation ,Local planning ,Emergency Medicine ,medicine ,Emergency planning ,Medical emergency ,Business ,Hurricane evacuation ,Environmental planning - Abstract
Many of the losses due to wildfires, floods, and other hazards can be avoided with proper evacuation planning. This study examined local emergency evacuation readiness in the State of California of the USA. Emergency planning documents were obtained from 41 of the 58 California counties; only 8 of those were free-standing emergency evacuation plans eligible for evaluation. The plans were evaluated using a tool previously developed for a congressional study of hurricane evacuation plans. The California plans scored relatively well in the areas of decision making and communications but scored poorly on other issues including planning for alternative transportation modes and evacuating special needs populations. Overall, the California evacuation plans did not measure up to those developed in the hurricane states. This study highlights the need to strengthen and standardise evacuation planning in at-risk areas and to improve knowledge about local evacuation preparedness.
- Published
- 2011
- Full Text
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19. Discovery-based science education: functional genomic dissection in Drosophila by undergraduate researchers
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Kristin Spivey, Aneet Toor, Gerald B. Call, Brenda Hermogeno, Pamela Saarikoski, Qing Xu, Sheryllene Go, Vivek Singh, Brian Kirkpatrick, Bhavin Padhiar, Aram Shemmassian, Ramnik Singh, Steve Tovar, Sophia Wu, James Jen, Katrin Kahen, Courtney Gonzalez, Grant Alkin, Bassel Rifai, Poonam Desai, Damien Wood, Robert Kwak, Mariam Guirguis, Jayantha Thiyanaratnam, Preethi Poulose, Yuli Chang, Maggie Wells, Jamie L. Marshall, Aya Pusic, Marina Stavchanskiy, Thomas Kho, Nick Garrone, Jeyling Chou, Stephanie Calvillo, Charles Hu, Emily Vollmer, Winston Wu, Henry Lin, Sumit Datta, Leo Thai, Sheila Lezcano, Devon M Huff, Santino Laxamana, Meghann Ribbens, Mara Pavel-Dinu, Yein Kim, Yibing Chen, Eunha Kim, Nneka Orjiakor, Sarah Kim, Allison Milchanowski, Edwin Paz, Manyak Saakyan, Erin Marsh, Linda Kao, Russell Powell, Christopher N.H. Bui, Nikki Villarasa, Joy Wu, Eric Paul, Artemis Deravanesian, Aria Hong, Kha Nguyen, Akanksha Chhabra, Leena Tekchandani, Toni Lee, Utpal Banerjee, William R. Marrs, Elena Bibikova, Eric Lee, Lindsay Hovestreydt, Anna L. Abrams, Jordan Fabrikant, Joseph Cao, Chad Goffstein, So-Youn Lee, Daniel Chang, Will Yarosh, Peter Lin, Kosha Soneji, Christopher Lee, Thanh Luu, Katherine Fu, Maurine Tong, Amanda O'Donahue, Amanda Abramson, Desiree Rosselli, Gemma Lewis, Farid Jamshidian, George Yen, Jiong Chen, Amir Yavari, Yasaman Moshfegh, Amit Misra, Lephong Pham, Ernesto Nodado, Tanya Minasian, Ryan Hassid, Erika Stageberg, Stacy Chan, Cynthia Nguyen, Yuki Yamauchi, Marc Uemura, Janet Lee, Helena Minye, Aileen Chang, Alex Pavlenko, Kelly Trangsrud, Phyllis Gayda, Miles Morimoto, Kirsten Regalia, Jenny Chan, Ardy Davarifar, Shahbaz Farnad, Peter Dang, Daniel Solomin, Laura Yee, Jenny Anderson, Albert Cespedes, To Hang S Lee, Julie Luu, Jessica Murray, Allen Bookatz, Keenan Bashour, Joo Choi, Adam D. Langenbacher, Emil Kohan, Amy M. Chan, Sarah Min, Melissa M. Kelley, Miriam Segura, Elsa Beyer, Sarah Phaklides, Natalie Buu, Emily Weiss, Mary Unkovic, Julie Hong, Emily Skinner, Farnaz Shadpour, Wah-Yung Tsang, Eddie Garcia, Divi Ramola, Latiffe Amado, Srpouhi Gasparyan, Sarah Brewer, Kevin Yackle, and Ndidi Onugha
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Discovery science ,Genetics ,General Immunology and Microbiology ,QH301-705.5 ,General Neuroscience ,Genomics ,In vivo analysis ,Biology ,Development ,Genetics/Genomics/Gene Therapy ,Data science ,Science education ,Genome ,General Biochemistry, Genetics and Molecular Biology ,Community Page ,ComputingMilieux_COMPUTERSANDEDUCATION ,Identification (biology) ,Drosophila ,Biology (General) ,General Agricultural and Biological Sciences ,Curriculum ,Functional genomics - Abstract
The excitement of scientific research and discovery cannot be fully conveyed by didactic lectures alone. Several recent initiatives and proposals, therefore, have supported a more participatory, discovery-based instruction for undergraduate science education [1,2]. In functional genomics, we have found an ideal platform to simultaneously benefit students and contribute to scientific discovery. The sequencing of eukaryotic genomes has facilitated the identification of complete sets of genes in humans and model genetic organisms. This has allowed many forms of high-throughput analyses of transcriptional profiles, protein interactions, structural motifs, and even genome-wide knock-downs in cell lines or in selected organisms. However, one of the best tools to provide functional information about gene action— obtaining in vivo evidence about the phenotype resulting from heritable loss of function—is difficult and less amenable to high-throughput research. We were able to achieve a large-scale in vivo analysis with a significant number of undergraduate students at UCLA, called the UCLA Undergraduate Consortium for Functional Genomics. This work, a practical manifestation of policy positions proposing discoverybased education, is described in summary form here (and in Box 1) and in detail online at http://www.bruinfly.ucla.edu. This effort combines professional-quality research with a strategy for research-based undergraduate education.
20. Tyrosine transfer RNA levels and modifications during blood-feeding and vitellogenesis in the mosquito, Aedes aegypti.
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Kelley M, Holmes CJ, Herbert C, Rayhan A, Joves J, Uhran M, Klaus L, Frigard R, Singh K, Limbach PA, Addepalli B, and Benoit JB
- Subjects
- Animals, Female, Feeding Behavior, Fat Body metabolism, Vitellogenins metabolism, Vitellogenins genetics, Aedes genetics, Aedes metabolism, Vitellogenesis, RNA, Transfer metabolism, RNA, Transfer genetics
- Abstract
Mosquitoes such as Aedes aegypti must consume a blood meal for the nutrients necessary for egg production. Several transcriptome and proteome changes occur post-blood meal that likely corresponds with codon usage alterations. Transfer RNA (tRNA) is the adapter molecule that reads messenger RNA codons to add the appropriate amino acid during protein synthesis. Chemical modifications to tRNA enhance codon decoding, improving the accuracy and efficiency of protein synthesis. Here, we examined tRNA modifications and transcripts associated with the blood meal and subsequent periods of vitellogenesis in A. aegypti. More specifically, we assessed tRNA transcript abundance and modification levels in the fat body at critical times post blood-feeding. Based on a combination of alternative codon usage and identification of particular modifications, we discovered that increased transcription of tyrosine tRNAs is likely critical during the synthesis of egg yolk proteins in the fat body following a blood meal. Altogether, changes in both the abundance and modification of tRNA are essential factors in the process of vitellogenin production after blood-feeding in mosquitoes., (© 2024 The Author(s). Insect Molecular Biology published by John Wiley & Sons Ltd on behalf of Royal Entomological Society.)
- Published
- 2025
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21. Feasibility, validity, and normative data for the remote Uniform Data Set neuropsychological battery at the University of Pennsylvania Alzheimer's Disease Research Center.
- Author
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Hackett K, Shi Y, Schankel L, Oliveira N, Kelley M, McCoubrey H, Peskin SM, O'Brien K, Xie SX, Wolk D, and Mechanic-Hamilton D
- Abstract
Introduction: We investigated the feasibility and validity of the remotely-administered neuropsychological battery from the National Alzheimer's Coordinating Center Uniform Data Set (UDS T-Cog)., Methods: Two hundred twenty Penn Alzheimer's Disease Research Center participants with unimpaired cognition, mild cognitive impairment, and dementia completed the T-Cog during their annual UDS evaluation. We assessed administration feasibility and diagnostic group differences cross-sectionally across telephone versus videoconference modalities, and compared T-Cog to prior in-person UDS scores longitudinally., Results: Administration time averaged 54 min and 79% of participants who initiated a T-Cog completed all 12 subtests; completion time and rates differed by diagnostic group but not by modality. Performance varied expectedly across groups with moderate to strong associations between most T-Cog measures and in-person correlates, although select subtests demonstrated lower comparability., Discussion: The T-Cog is feasibly administered and shows preliminary validity in a cognitively heterogeneous cohort. Normative data from this cohort should be expanded to more diverse populations to enhance utility and generalizability., Highlights: This study examined the feasibility and validity of the remote Uniform Data Set (also known as the T-Cog) and contributes key normative data for widespread use.A remote neuropsychological battery was feasibly administered with high overall engagement and completion rates, adequate reliability compared to in-person testing, and evidence of validity across diagnostic groups.Typical barriers to administration included hearing impairment, technology issues, and distractions; hearing difficulties were particularly common among cognitively impaired groups.Certain tests were less closely related to their in-person correlates and should be used with caution., Competing Interests: The authors declare no conflicts of interest. Author disclosures are available in the supporting information., (© 2024 The Author(s). Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)
- Published
- 2024
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22. Impaired humidity sensing reduces tick survival by preventing water homeostasis.
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Uhran MR, Onyeagba K, Sanderson SM, Hoque SF, Kelley M, Smith ES, Oyen K, Benton-Anderson A, Arya T, Ledezma A, Almatar H, Kennedy J, Frigard R, Holmes CJ, Chen SC, Olafson PU, Gaff HD, and Benoit JB
- Abstract
Off-host periods are critical for ticks, representing a period when environmental stress, particularly dehydration, can impact tick survival. To prevent dehydration, ticks must be able to detect and move into high humidity areas to allow for water vapor uptake. Ionotropic receptor 93a (Ir93a), which is highly expressed in the front forelegs (location of Haller
, s organ), increases expression following dehydration, suggesting a role in humidity detection. Although the Haller, s organ is suggested as the site of humidity detection in ticks, humidity detection has not been extensively examined. Here, we assessed the ability of American dog ticks, Dermacentor variabilis , to sense humidity and how altered humidity detection impacts tick survival by manipulating the Haller, s organ. Permanent (cutting or heat ablation) or temporary blocking (silicone covering) of the Haller, s organ impairs the ability of the American dog tick, Dermacentor variabilis, to rest in areas necessary to maintain hydration. Impaired detection of humidity did not impact tick survival when individuals were held under stable optimal conditions. Still, variable conditions (low and high humidity gradient) reduced survival through dehydration stress and decreased energy reserves, as chronic water vapor uptake is energetically expensive. Field validation of these studies in D. variabilis confirmed that humidity detection is critical to tick survival. Lastly, modeling indicates impaired humidity detection will reduce questing tick populations, specifically in the adult stages. These studies confirm that the Haller, s organ is critical for humidity sensing in ticks. Without this ability, tick survival will be impaired by potential dehydration or more rapid depletion of energy reserves.- Published
- 2024
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23. Developmental stage and level of submersion in water impact the viability of lone star and winter tick eggs.
- Author
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Alhawsawi MRI, Lewis DA, Frigard RA, Smith EM, Sivakumar J, Sharma AM, Nantz AR, Sabile CEG, Kennedy J, Loni R, LeFevre G, Vaka A, Leanza Q, Kelley M, Stacey CL, Santhosh RA, Catlett N, Cady TL, Rizvi RS, Wagner Z, Olafson PU, and Benoit JB
- Abstract
Female ticks deposit large egg clusters that range in size from hundreds to thousands. These egg clusters are restricted to a deposition site as they are stationary, usually under leaf litter and other debris. In some habitats, these sites can be exposed to periodic flooding. When the clusters of tick eggs are disturbed, they may float to the surface or remain underneath organic debris entirely submerged underwater. Here, we examined the viability of egg clusters from winter ticks, Dermacentor albipictus, and lone star ticks, Amblyomma americanum, when partially or fully submerged in water and in relation to the developmental stages of the eggs under lab conditions. In general, egg clusters that were older and partially submerged had a higher viability than fully submerged, younger eggs. Of the two species, A. americanum was more resistant to water exposure. These studies highlight that egg clusters for certain tick species can remain viable when exposed to water for at least two weeks. These results also suggest that distribution by flooding of egg clusters could occur for some species and water submersion will differentially impact tick egg survival based on the specific developmental stage of exposure and species., (© The Author(s) 2024. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
- Published
- 2024
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24. Developmental stage and level of submersion in water impact the viability of lone star and winter tick eggs during flooding.
- Author
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Alhawsawi MRI, Lewis DA, Frigard RA, Smith EM, Sivakumar J, Sharma AM, Nantz AR, Sabile C, Kennedy J, Loni R, LeFefevre G, Vaka A, Leanza Q, Kelley M, Stacey CL, Santosh RA, Catlett N, Cady TL, Rizvi RS, Wagner Z, Olafson PU, and Benoit JB
- Abstract
Female ticks deposit large egg clusters that range in size from hundreds to thousands. These clusters are restricted to a deposition site, usually under leaf litter and other debris. These sites can be exposed to periodic flooding, where the cluster of tick eggs can float to the surface or remain underneath organic debris entirely underwater. Here, we examined the viability of egg clusters from winter ticks, Dermacentor albipictus , and lone star ticks, Amblyomma americanum , when partially submerged or fully submerged in water in relation to the developmental stages of the eggs. In general, egg clusters that were older and partially submerged had a higher viability than fully submerged, young eggs in water. A. americanum was much more resistant to water exposure between the two species. These studies highlight that egg clusters for specific tick species can remain viable when exposed to water for at least two weeks, where eggs float on the surface. These studies also suggest that water-based distribution of egg clusters could occur for some species, and flooding will differentially impact tick egg survival based on the specific developmental stage of exposure and species.
- Published
- 2024
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25. The chromosome-scale genome assembly for the West Nile vector Culex quinquefasciatus uncovers patterns of genome evolution in mosquitoes.
- Author
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Ryazansky SS, Chen C, Potters M, Naumenko AN, Lukyanchikova V, Masri RA, Brusentsov II, Karagodin DA, Yurchenko AA, Dos Anjos VL, Haba Y, Rose NH, Hoffman J, Guo R, Menna T, Kelley M, Ferrill E, Schultz KE, Qi Y, Sharma A, Deschamps S, Llaca V, Mao C, Murphy TD, Baricheva EM, Emrich S, Fritz ML, Benoit JB, Sharakhov IV, McBride CS, Tu Z, and Sharakhova MV
- Subjects
- Animals, Humans, Male, Phylogeny, DNA Transposable Elements genetics, Mosquito Vectors genetics, Chromosomes, Evolution, Molecular, Culex genetics, Aedes genetics
- Abstract
Background: Understanding genome organization and evolution is important for species involved in transmission of human diseases, such as mosquitoes. Anophelinae and Culicinae subfamilies of mosquitoes show striking differences in genome sizes, sex chromosome arrangements, behavior, and ability to transmit pathogens. However, the genomic basis of these differences is not fully understood., Methods: In this study, we used a combination of advanced genome technologies such as Oxford Nanopore Technology sequencing, Hi-C scaffolding, Bionano, and cytogenetic mapping to develop an improved chromosome-scale genome assembly for the West Nile vector Culex quinquefasciatus., Results: We then used this assembly to annotate odorant receptors, odorant binding proteins, and transposable elements. A genomic region containing male-specific sequences on chromosome 1 and a polymorphic inversion on chromosome 3 were identified in the Cx. quinquefasciatus genome. In addition, the genome of Cx. quinquefasciatus was compared with the genomes of other mosquitoes such as malaria vectors An. coluzzi and An. albimanus, and the vector of arboviruses Ae. aegypti. Our work confirms significant expansion of the two chemosensory gene families in Cx. quinquefasciatus, as well as a significant increase and relocation of the transposable elements in both Cx. quinquefasciatus and Ae. aegypti relative to the Anophelines. Phylogenetic analysis clarifies the divergence time between the mosquito species. Our study provides new insights into chromosomal evolution in mosquitoes and finds that the X chromosome of Anophelinae and the sex-determining chromosome 1 of Culicinae have a significantly higher rate of evolution than autosomes., Conclusion: The improved Cx. quinquefasciatus genome assembly uncovered new details of mosquito genome evolution and has the potential to speed up the development of novel vector control strategies., (© 2024. The Author(s).)
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- 2024
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26. Tyrosine transfer RNA levels and modifications during blood-feeding and vitellogenesis in the mosquito, Aedes aegypti .
- Author
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Kelley M, Holmes CJ, Herbert C, Rayhan A, Joves J, Uhran M, Frigard R, Singh K, Limbach PA, Addepalli B, and Benoit JB
- Abstract
Mosquitoes such as Aedes aegypti must consume a blood meal for the nutrients necessary for egg production. Several transcriptome and proteome changes occur post blood meal that likely corresponds with codon usage alterations. Transfer RNA (tRNA) is the adapter molecule that reads messenger RNA (mRNA) codons to add the appropriate amino acid during protein synthesis. Chemical modifications to tRNA enhance codons' decoding, improving the accuracy and efficiency of protein synthesis. Here, we examined tRNA modifications and transcripts associated with the blood meal and subsequent periods of vitellogenesis in A. aegypti . More specifically, we assessed tRNA transcript abundance and modification levels in the fat body at critical times post blood-feeding. Based on a combination of alternative codon usage and identification of particular modifications, we identified that increased transcription of tyrosine tRNAs is likely critical during the synthesis of egg yolk proteins in the fat body following a blood meal. Altogether, changes in both the abundance and modification of tRNA are essential factors in the process of vitellogenin production after blood-feeding in mosquitoes.
- Published
- 2023
- Full Text
- View/download PDF
27. Aging and Alzheimer's disease have dissociable effects on local and regional medial temporal lobe connectivity.
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Hrybouski S, Das SR, Xie L, Wisse LEM, Kelley M, Lane J, Sherin M, DiCalogero M, Nasrallah I, Detre J, Yushkevich PA, and Wolk DA
- Abstract
Functional disruption of the medial temporal lobe-dependent networks is thought to underlie episodic memory deficits in aging and Alzheimer's disease. Previous studies revealed that the anterior medial temporal lobe is more vulnerable to pathological and neurodegenerative processes in Alzheimer's disease. In contrast, cognitive and structural imaging literature indicates posterior, as opposed to anterior, medial temporal lobe vulnerability in normal aging. However, the extent to which Alzheimer's and aging-related pathological processes relate to functional disruption of the medial temporal lobe-dependent brain networks is poorly understood. To address this knowledge gap, we examined functional connectivity alterations in the medial temporal lobe and its immediate functional neighbourhood-the Anterior-Temporal and Posterior-Medial brain networks-in normal agers, individuals with preclinical Alzheimer's disease and patients with Mild Cognitive Impairment or mild dementia due to Alzheimer's disease. In the Anterior-Temporal network and in the perirhinal cortex, in particular, we observed an inverted 'U-shaped' relationship between functional connectivity and Alzheimer's stage. According to our results, the preclinical phase of Alzheimer's disease is characterized by increased functional connectivity between the perirhinal cortex and other regions of the medial temporal lobe, as well as between the anterior medial temporal lobe and its one-hop neighbours in the Anterior-Temporal system. This effect is no longer present in symptomatic Alzheimer's disease. Instead, patients with symptomatic Alzheimer's disease displayed reduced hippocampal connectivity within the medial temporal lobe as well as hypoconnectivity within the Posterior-Medial system. For normal aging, our results led to three main conclusions: (i) intra-network connectivity of both the Anterior-Temporal and Posterior-Medial networks declines with age; (ii) the anterior and posterior segments of the medial temporal lobe become increasingly decoupled from each other with advancing age; and (iii) the posterior subregions of the medial temporal lobe, especially the parahippocampal cortex, are more vulnerable to age-associated loss of function than their anterior counterparts. Together, the current results highlight evolving medial temporal lobe dysfunction in Alzheimer's disease and indicate different neurobiological mechanisms of the medial temporal lobe network disruption in aging versus Alzheimer's disease., Competing Interests: D.A.W. has served as a paid consultant to Eli Lilly, GE Healthcare and Qynapse. He serves on a DSMB for Functional Neuromodulation. He receives research support paid to his institution from Biogen. I.N. serves on the Scientific Advisory Board for Eisai and does educational speaking for Biogen. All other authors report no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)
- Published
- 2023
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28. Reduced male fertility of an Antarctic mite following extreme heat stress could prompt localized population declines.
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Benoit JB, Finch G, Ankrum AL, Niemantsverdriet J, Paul B, Kelley M, Gantz JD, Matter SF, Lee RE Jr, and Denlinger DL
- Subjects
- Female, Animals, Male, Antarctic Regions, Fertility, Heat-Shock Response, Mites, Extreme Heat
- Abstract
Climate change is leading to substantial global thermal changes, which are particularly pronounced in polar regions. Therefore, it is important to examine the impact of heat stress on the reproduction of polar terrestrial arthropods, specifically, how brief extreme events may alter survival. We observed that sublethal heat stress reduces male fecundity in an Antarctic mite, yielding females that produced fewer viable eggs. Females and males collected from microhabitats with high temperatures showed a similar reduction in fertility. This impact is temporary, as indicated by recovery of male fecundity following return to cooler, stable conditions. The diminished fecundity is likely due to a drastic reduction in the expression of male-associated factors that occur in tandem with a substantial increase in the expression of heat shock proteins. Cross-mating between mites from different sites confirmed that heat-exposed populations have impaired male fertility. However, the negative impacts are transient as the effect on fertility declines with recovery time under less stressful conditions. Modeling indicated that heat stress is likely to reduce population growth and that short bouts of non-lethal heat stress could have substantial reproductive effects on local populations of Antarctic arthropods., (© 2023. The Author(s), under exclusive licence to Cell Stress Society International.)
- Published
- 2023
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29. Additive Effects of Cyclic Peptide [R4W4] When Added Alongside Azithromycin and Rifampicin against Mycobacterium avium Infection.
- Author
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Kelley M, Sasaninia K, Abnousian A, Badaoui A, Owens J, Beever A, Kachour N, Tiwari RK, and Venketaraman V
- Abstract
Mycobacterium avium ( M. avium ), a type of nontuberculous mycobacteria (NTM), poses a risk for pulmonary infections and disseminated infections in immunocompromised individuals. Conventional treatment consists of a 12-month regimen of the first-line antibiotics rifampicin and azithromycin. However, the treatment duration and low antibiotic tolerability present challenges in the treatment of M. avium infection. Furthermore, the emergence of multidrug-resistant mycobacterium strains prompts a need for novel treatments against M. avium infection. This study aims to test the efficacy of a novel antimicrobial peptide, cyclic [R4W4], alongside the first-line antibiotics azithromycin and rifampicin in reducing M. avium survival. Colony-forming unit (CFU) counts were assessed after treating M. avium cultures with varying concentrations of cyclic [R4W4] alone or in conjunction with azithromycin or rifampicin 3 h and 4 days post-treatment. M. avium growth was significantly reduced 4 days after cyclic [R4W4] single treatment. Additionally, cyclic [R4W4]-azithromycin and cyclic [R4W4]-rifampicin combination treatments at specific concentrations significantly reduced M. avium survival 3 h and 4 days post-treatment compared with single antibiotic treatment alone. These findings demonstrate cyclic [R4W4] as a potent treatment method against M. avium and provide insight into novel therapeutic approaches against mycobacterium infections.
- Published
- 2023
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30. Effectors of anterior morphogenesis in C. elegans embryos.
- Author
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Balasubramaniam B, Topalidou I, Kelley M, Meadows SM, Funk O, Ailion M, and Fay DS
- Subjects
- Animals, Morphogenesis genetics, Extracellular Matrix metabolism, Embryonic Development genetics, Caenorhabditis elegans metabolism, Caenorhabditis elegans Proteins genetics, Caenorhabditis elegans Proteins metabolism
- Abstract
During embryogenesis the nascent Caenorhabditis elegans epidermis secretes an apical extracellular matrix (aECM) that serves as an external stabilizer, preventing deformation of the epidermis by mechanical forces exerted during morphogenesis. At present, the factors that contribute to aECM function are mostly unknown, including the aECM components themselves, their posttranslational regulators, and the pathways required for their secretion. Here we showed that two proteins previously linked to aECM function, SYM-3/FAM102A and SYM-4/WDR44, colocalize to intracellular and membrane-associated puncta and likely function in a complex. Proteomics experiments also suggested potential roles for SYM-3/FAM102A and SYM-4/WDR44 family proteins in intracellular trafficking. Nonetheless, we found no evidence to support a critical function for SYM-3 or SYM-4 in the apical deposition of two aECM components, NOAH-1 and FBN-1. Moreover, loss of a key splicing regulator of fbn-1, MEC-8/RBPMS2, had surprisingly little effect on the abundance or deposition of FBN-1. Using a focused screening approach, we identified 32 additional proteins that likely contribute to the structure and function of the embryonic aECM. We also characterized morphogenesis defects in embryos lacking mir-51 microRNA family members, which display a similar phenotype to mec-8; sym double mutants. Collectively, these findings add to our knowledge of factors controlling embryonic morphogenesis., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)
- Published
- 2023
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31. Liposomal Glutathione Supplementation Mitigates Extrapulmonary Tuberculosis in the Liver and Spleen.
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Sasaninia K, Kelley M, Abnousian A, Owens J, Yoon S, Beever A, Kachour N, Yegiazaryan A, Kolloli A, Kumar R, Ramasamy S, Subbian S, and Venketaraman V
- Subjects
- Animals, Mice, Liver, Cytokines, Glutathione, Dietary Supplements, Spleen, Tuberculosis, Extrapulmonary
- Abstract
Background: Extrapulmonary tuberculosis (EPTB) accounts for a fifth of all Mycobacterium tuberculosis ( M. tb ) infections worldwide. The rise of multidrug resistance in M. tb alongside the hepatotoxicity associated with antibiotics presents challenges in managing and treating tuberculosis (TB), thereby prompting a need for new therapeutic approaches. Administration of liposomal glutathione (L-GSH) has previously been shown to lower oxidative stress, enhance a granulomatous response, and reduce the burden of M. tb in the lungs of M. tb -infected mice. However, the effects of L-GSH supplementation during active EPTB in the liver and spleen have yet to be explored., Methods: In this study, we evaluated hepatic glutathione (GSH) and malondialdehyde (MDA) levels, and the cytokine profiles of untreated and L-GSH-treated M. tb -infected wild type (WT) mice. Additionally, the hepatic and splenic M. tb burdens and tissue pathologies were also assessed., Results: L-GSH supplementation increased total hepatic levels and reduced GSH. A decrease in the levels of MDA, oxidized GSH, and interleukin (IL)-6 was also detected following L-GSH treatment. Furthermore, L-GSH supplementation was observed to increase interferon-gamma (IFN-γ) and tumor necrosis factor (TNF)-α production and decrease IL-10 levels. M. tb survival was significantly reduced in the liver and spleen following L-GSH supplementation. L-GSH treatment also provided a host-protective effect in the liver and spleen of M. tb -infected mice., Conclusions: Overall, L-GSH supplementation elevated the levels of total and reduced forms of GSH in the liver and reduced the burden of M. tb by decreasing oxidative stress, enhancing the production of immunosupportive cytokines, and reducing the levels of immunosuppressive cytokines. These observed benefits highlight the potential of L-GSH supplementation during active EPTB and provide insight into novel therapeutic interventions against M. tb infections., Competing Interests: The authors declare no conflict of interest., (© 2023 The Author(s). Published by IMR Press.)
- Published
- 2023
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32. Topical Absorption of Glutathione-Cyclodextrin Nanoparticle Complex in Healthy Human Subjects Improves Immune Response against Mycobacterium avium Infection.
- Author
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Sasaninia K, Kelley M, Abnousian A, Badaoui A, Alexander L, Sheren N, Owens J, Rajurkar S, Razo-Botello B, Chorbajian A, Yoon S, Dhama S, Avitia E, Ochoa C, Yutani R, and Venketaraman V
- Abstract
Glutathione (GSH) is an important intracellular antioxidant responsible for neutralizing reactive oxygen species (ROS). Our laboratory previously demonstrated that the oral administration of liposomal GSH improves immune function against mycobacterium infections in healthy patients along with patients with HIV and Type 2 diabetes. We aim to determine if the topical application of a glutathione-cyclodextrin nanoparticle complex (GSH-CD) confers a therapeutic effect against mycobacterium infections. In our study, healthy participants received either topical GSH-CD (n = 15) or placebo (n = 15) treatment. Subjects were sprayed four times twice a day for three days topically on the abdomen. Blood draws were collected prior to application, and at 1, 4, and 72 h post-initial topical application. GSH, malondialdehyde (MDA), and cytokine levels were assessed in the processed blood samples of study participants. Additionally, whole blood cultures from study participants were challenged with Mycobacterium avium (M. avium) infection in vitro to assess mycobacterium survival post-treatment. Topical GSH-CD treatment was observed to elevate GSH levels in peripheral blood mononuclear cells (PBMCs) and red blood cells and decrease MDA levels in PBMCs 72 h post-treatment. An increase in plasma IL-2, IFN-γ, IL-12p70, and TNF-α was observed at 72 h post-topical GSH-CD treatment. Enhanced mycobacterium clearance was observed at 4 h and 72 h post-topical GSH-CD treatment. Overall, topical GSH-CD treatment was associated with improved immune function against M. avium infection. The findings of this pilot study suggest GSH-cyclodextrin complex formulation can be used topically as a safe alternative mode of GSH delivery in the peripheral blood.
- Published
- 2023
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33. Glutathione Modulates Efficacious Changes in the Immune Response against Tuberculosis.
- Author
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Abnousian A, Vasquez J, Sasaninia K, Kelley M, and Venketaraman V
- Abstract
Glutathione (GSH) is an antioxidant in human cells that is utilized to prevent damage occurred by reactive oxygen species, free radicals, peroxides, lipid peroxides, and heavy metals. Due to its immunological role in tuberculosis (TB), GSH is hypothesized to play an important part in the immune response against M. tb infection. In fact, one of the hallmark structures of TB is granuloma formation, which involves many types of immune cells. T cells, specifically, are a major component and are involved in the release of cytokines and activation of macrophages. GSH also serves an important function in macrophages, natural killer cells, and T cells in modulating their activation, their metabolism, proper cytokine release, proper redox activity, and free radical levels. For patients with increased susceptibility, such as those with HIV and type 2 diabetes, the demand for higher GSH levels is increased. GSH acts as an important immunomodulatory antioxidant by stabilizing redox activity, shifting of cytokine profile toward Th1 type response, and enhancing T lymphocytes. This review compiles reports showing the benefits of GSH in improving the immune responses against M. tb infection and the use of GSH as an adjunctive therapy for TB.
- Published
- 2023
- Full Text
- View/download PDF
34. Pathways that affect anterior morphogenesis in C. elegans embryos.
- Author
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Boopathi B, Topalidou I, Kelley M, Meadows SM, Funk O, Ailion M, and Fay DS
- Abstract
During embryogenesis the nascent Caenorhabditis elegans epidermis secretes an apical extracellular matrix (aECM) that serves as an external stabilizer, preventing deformation of the epidermis by mechanical forces exerted during morphogenesis. We showed that two conserved proteins linked to this process, SYM-3/FAM102A and SYM-4/WDR44, colocalize to intracellular and membrane-associated puncta and likely function together in a complex. Proteomics data also suggested potential roles for FAM102A and WDR44 family proteins in intracellular trafficking, consistent with their localization patterns. Nonetheless, we found no evidence to support a clear function for SYM-3 or SYM-4 in the apical deposition of two aECM components, FBN-1 and NOAH. Surprisingly, loss of MEC-8/RBPMS2, a conserved splicing factor and regulator of fbn-1 , had little effect on the abundance or deposition of FBN-1 to the aECM. Using a focused screening approach, we identified 32 additional proteins that likely contribute to the structure and function of the embryonic aECM. Lastly, we examined morphogenesis defects in embryos lacking mir-51 microRNA family members, which display a related embryonic phenotype to mec-8; sym double mutants. Collectively, our findings add to our knowledge of pathways controlling embryonic morphogenesis., Summary Statement: We identify new proteins in apical ECM biology in C. elegans and provide evidence that SYM-3/FAM102A and SYM-4/WDR44 function together in trafficking but do not regulate apical ECM protein deposition.
- Published
- 2023
- Full Text
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35. Aging and Alzheimer's Disease Have Dissociable Effects on Medial Temporal Lobe Connectivity.
- Author
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Hrybouski S, Das SR, Xie L, Wisse LEM, Kelley M, Lane J, Sherin M, DiCalogero M, Nasrallah I, Detre JA, Yushkevich PA, and Wolk DA
- Abstract
Functional disruption of the medial temporal lobe-dependent networks is thought to underlie episodic memory deficits in aging and Alzheimer's disease. Previous studies revealed that the anterior medial temporal lobe is more vulnerable to pathological and neurodegenerative processes in Alzheimer's disease. In contrast, cognitive and structural imaging literature indicates posterior, as opposed to anterior, medial temporal lobe vulnerability in normal aging. However, the extent to which Alzheimer's and aging-related pathological processes relate to functional disruption of the medial temporal lobe-dependent brain networks is poorly understood. To address this knowledge gap, we examined functional connectivity alterations in the medial temporal lobe and its immediate functional neighborhood - the Anterior-Temporal and Posterior-Medial brain networks - in normal agers, individuals with preclinical Alzheimer's disease, and patients with Mild Cognitive Impairment or mild dementia due to Alzheimer's disease. In the Anterior-Temporal network and in the perirhinal cortex, in particular, we observed an inverted 'U-shaped' relationship between functional connectivity and Alzheimer's stage. According to our results, the preclinical phase of Alzheimer's disease is characterized by increased functional connectivity between the perirhinal cortex and other regions of the medial temporal lobe, as well as between the anterior medial temporal lobe and its one-hop neighbors in the Anterior-Temporal system. This effect is no longer present in symptomatic Alzheimer's disease. Instead, patients with symptomatic Alzheimer's disease displayed reduced hippocampal connectivity within the medial temporal lobe as well as hypoconnectivity within the Posterior-Medial system. For normal aging, our results led to three main conclusions: (1) intra-network connectivity of both the Anterior-Temporal and Posterior-Medial networks declines with age; (2) the anterior and posterior segments of the medial temporal lobe become increasingly decoupled from each other with advancing age; and, (3) the posterior subregions of the medial temporal lobe, especially the parahippocampal cortex, are more vulnerable to age-associated loss of function than their anterior counterparts. Together, the current results highlight evolving medial temporal lobe dysfunction in Alzheimer's disease and indicate different neurobiological mechanisms of the medial temporal lobe network disruption in aging vs. Alzheimer's disease.
- Published
- 2023
- Full Text
- View/download PDF
36. Abundances of transfer RNA modifications and transcriptional levels of tRNA-modifying enzymes are sex-associated in mosquitoes.
- Author
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Kelley M, Uhran M, Herbert C, Yoshida G, Watts ER, Limbach PA, and Benoit JB
- Subjects
- Animals, Anticodon, Female, Male, Protein Biosynthesis, RNA Processing, Post-Transcriptional, RNA, Transfer chemistry, RNA, Transfer genetics, RNA, Transfer metabolism, Culicidae genetics, Culicidae metabolism
- Abstract
As carriers of multiple human diseases, understanding the mechanisms behind mosquito reproduction may have implications for remediation strategies. Transfer RNA (tRNA) acts as the adapter molecule of amino acids and are key components in protein synthesis. A critical factor in the function of tRNAs is chemical modifications which contribute to codon-anticodon interactions. Here, we provide an assessment of tRNA modifications between sexes for three mosquito species and examine the correlation of transcript levels underlying key proteins involved in tRNA modification. Thirty-three tRNA modifications were detected among mosquito species and most of these modifications are higher in females compared to males for three mosquito species. Analysis of previous male and female RNA-seq datasets indicated a similar increase in transcript levels of tRNA-modifying enzymes in females among six mosquito species, supporting our observed female enrichment of tRNA modifications. Tissues-specific expressional studies revealed higher transcript levels for tRNA-modifying enzymes in the ovaries for Aedes aegypti, but not male reproductive tissues. These studies suggest that tRNA modifications may be critical to reproduction in mosquitoes, representing a potential novel target for control through suppression of fecundity., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
- Published
- 2022
- Full Text
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37. Ionizing radiation and chemical oxidant exposure impacts on Cryptococcus neoformans transfer RNAs.
- Author
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Kelley M, Paulines MJ, Yoshida G, Myers R, Jora M, Levoy JP, Addepalli B, Benoit JB, and Limbach PA
- Subjects
- Hydrogen Peroxide metabolism, Nucleosides metabolism, Oxidants metabolism, RNA, Transfer metabolism, Radiation, Ionizing, Reactive Oxygen Species metabolism, Cryptococcosis microbiology, Cryptococcus neoformans physiology
- Abstract
Cryptococcus neoformans is a fungus that is able to survive abnormally high levels of ionizing radiation (IR). The radiolysis of water by IR generates reactive oxygen species (ROS) such as H2O2 and OH-. C. neoformans withstands the damage caused by IR and ROS through antioxidant production and enzyme-catalyzed breakdown of ROS. Given these particular cellular protein needs, questions arise whether transfer ribonucleic acids molecules (tRNAs) undergo unique chemical modifications to maintain their structure, stability, and/or function under such environmental conditions. Here, we investigated the effects of IR and H2O2 exposure on tRNAs in C. neoformans. We experimentally identified the modified nucleosides present in C. neoformans tRNAs and quantified changes in those modifications upon exposure to oxidative conditions. To better understand these modified nucleoside results, we also evaluated tRNA pool composition in response to the oxidative conditions. We found that regardless of environmental conditions, tRNA modifications and transcripts were minimally affected. A rationale for the stability of the tRNA pool and its concomitant profile of modified nucleosides is proposed based on the lack of codon bias throughout the C. neoformans genome and in particular for oxidative response transcripts. Our findings suggest that C. neoformans can rapidly adapt to oxidative environments as mRNA translation/protein synthesis are minimally impacted by codon bias., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2022
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38. Chemical Amination/Imination of Carbonothiolated Nucleosides During RNA Hydrolysis.
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Jora M, Borland K, Abernathy S, Zhao R, Kelley M, Kellner S, Addepalli B, and Limbach PA
- Subjects
- Amination, Chromatography, High Pressure Liquid, Hydrolysis, Isotope Labeling, RNA metabolism, RNA, Transfer chemistry, RNA, Transfer metabolism, Saccharomyces cerevisiae genetics, Saccharomyces cerevisiae metabolism, Tandem Mass Spectrometry, Nucleosides chemistry, RNA analysis, Sulfhydryl Compounds chemistry
- Abstract
Liquid chromatography-tandem mass spectrometry (LC-MS/MS) has become the gold-standard technique to study RNA and its various modifications. While most research on RNA nucleosides has been focused on their biological roles, discovery of new modifications remains of interest. With state-of-the-art technology, the presence of artifacts can confound the identification of new modifications. Here, we report the characterization of a non-natural mcm
5 isoC ribonucleoside in S. cerevisiae total tRNA hydrolysate by higher-energy collisional dissociation (HCD)-based fingerprints and isotope labeling of RNA. Its discovery revealed a class of amino/imino ribonucleoside artifacts that are generated during RNA hydrolysis under ammonium-buffered mild basic conditions. We then identified digestion conditions that can reduce or eliminate their formation. These finding and method enhancements will improve the accurate detection of new RNA modifications., (© 2020 Wiley-VCH GmbH.)- Published
- 2021
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39. Colon Capsule Visualization Is Not Enhanced with Prucalopride: A Randomized Controlled Trial.
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Hookey L, Kelley M, Marchut K, Green J, and Bechara R
- Published
- 2018
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40. Wait Time for Curative Intent Radio Frequency Ablation is Associated with Increased Mortality in Patients with Early Stage Hepatocellular Carcinoma.
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Brahmania M, Ahmed O, Kelley M, Wong D, Kowgier M, Khalili K, Beecroft R, Renner EL, Shah H, Feld J, Janssen HLA, and Sherman M
- Subjects
- Aged, Carcinoma, Hepatocellular mortality, Carcinoma, Hepatocellular pathology, Catheter Ablation adverse effects, Chi-Square Distribution, Female, Humans, Kaplan-Meier Estimate, Liver Neoplasms mortality, Liver Neoplasms pathology, Male, Middle Aged, Multivariate Analysis, Neoplasm Staging, Ontario, Proportional Hazards Models, Quality Improvement, Quality Indicators, Health Care, Retrospective Studies, Risk Factors, Time Factors, Carcinoma, Hepatocellular surgery, Catheter Ablation mortality, Liver Neoplasms surgery, Time-to-Treatment, Waiting Lists mortality
- Abstract
Introduction: Radiofrequency ablation (RFA) is a recommended curative intent treatment option for patients with early stage hepatocellular carcinoma (HCC). We investigated if wait times for RFA were associated with residual tumor, tumor recurrence, need for liver transplantation, or death., Material and Methods: We conducted a retrospective study of patients diagnosed with HCC between January 2010 and December 2013 presenting to University Health Network (UHN) in Toronto, Canada. All patients receiving curative intent RFA for HCC were included. Multivariable Cox regression was used to determine if wait times were associated with clinical outcomes., Results: 219 patients were included in the study. 72.6% were male and the median age was 62.7 years (IQR 55.6-71). Median tumor size at diagnosis was 21.5 mm (IQR 17-26); median MELD was 8.7 (IQR 7.2-11.4) and 57.1% were Barcelona stage 0. The cause of liver disease was viral hepatitis in 73.5% (Hepatitis B and C). The median time from HCC diagnosis to RFA treatment was 96 days (IQR 75-139). In multivariate analysis, wait time was not associated with requiring liver transplant or tumor recurrence, however, each incremental 30-day wait time was associated with an increased risk of residual tumor (HR = 1.09; 95% CI 1.01-1.19; p = 0.033) as well as death (HR = 1.23; 95% CI 1.11-1.36; p ≤ 0.001)., Conclusion: Incremental 30-day wait times are associated with a 9% increased risk of residual tumor and a 23% increased risk of death. We have identified system gaps where quality improvement measures can be implemented to reduce wait times and allocate resources for future RFA treatment, which may improve both quality and efficiency of HCC care.
- Published
- 2017
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41. A Hepatitis C Educational Needs Assessment of Canadian Healthcare Providers.
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Naghdi R, Seto K, Klassen C, Emokpare D, Conway B, Kelley M, Yoshida E, and Shah HA
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- Adult, Canada, Female, Humans, Male, Surveys and Questionnaires, Health Knowledge, Attitudes, Practice, Health Personnel education, Hepatitis C diagnosis, Hepatitis C therapy, Needs Assessment
- Abstract
Background and Aim . Despite advances in the treatment of chronic hepatitis C infection (CHC), it remains a major public health problem in Canada and globally. The knowledge of healthcare providers (HCPs) is critical to improve the care of CHC in Canada. To assess the current knowledge and educational needs of healthcare providers (HCPs) in the area of CHC management a national online survey was conducted. Method . An interprofessional steering committee designed a 29-question survey distributed through various direct and electronic routes. The survey assessed several domains (e.g., participant and practice demographics, access to resources, knowledge of new treatments, and educational preferences). Results . A total of 163 HCPs responded to the survey. All hepatologists and 8% of primary care providers (PCPs) reported involvement in treatment of CHC. Physicians most frequently screened patients who had abnormal liver enzymes, while nurses tended to screen based on lifestyle factors. More than 70% of PCPs were not aware of new medications and their mechanisms. Conclusion . Overall, the needs assessment demonstrated that there was a need for further education, particularly for primary care physicians, to maximize the role that they can play in screening, testing, and treatment of hepatitis C in Canada.
- Published
- 2017
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42. KCNK9 imprinting syndrome-further delineation of a possible treatable disorder.
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Graham JM Jr, Zadeh N, Kelley M, Tan ES, Liew W, Tan V, Deardorff MA, Wilson GN, Sagi-Dain L, and Shalev SA
- Subjects
- Facies, Female, Genetic Diseases, Inborn therapy, Humans, Infant, Male, Mutation, Phenotype, Genetic Diseases, Inborn diagnosis, Genetic Diseases, Inborn genetics, Genomic Imprinting, Potassium Channels, Tandem Pore Domain genetics
- Abstract
Patients with KCNK9 imprinting syndrome demonstrate congenital hypotonia, variable cleft palate, normal MRIs and EEGs, delayed development, and feeding problems. Associated facial dysmorphic features include dolichocephaly with bitemporal narrowing, short philtrum, tented upper lip, palatal abnormalities, and small mandible. This disorder maps to chromosomal region 8q24, and it is caused by a specific missense mutation 770G>A in exon 2, replacing glycine at position 236 by arginine (G236R) in the maternal copy of KCNK9 within this locus. KCNK9 (also called TASK3) encodes a member of the two pore- domain potassium channel (K2P) subfamily. This gene is normally imprinted with paternal silencing, thus a mutation in the maternal copy of the gene will result in disease, whereas a mutation in the paternal copy will have no effect. Exome sequencing in four new patients with developmental delay and central hypotonia revealed de novo G236R mutations. Older members of a previously reported Arab-Israeli family have intellectual disability of variable severity, persistent feeding difficulties in infancy with dysphagia of liquids and dysphonia with a muffled voice in early adulthood, generalized hypotonia, weakness of proximal muscles, elongated face with narrow bitemporal diameter, and reduced facial movements. We describe the clinical features in four recently recognized younger patients and compare them with those found in members of the originally reported Arab-Israeli family and suggest this may be a treatable disorder. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)
- Published
- 2016
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43. The stress-induced heat shock protein 70.3 expression is regulated by a dual-component mechanism involving alternative polyadenylation and HuR.
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Kraynik SM, Gabanic A, Anthony SR, Kelley M, Paulding WR, Roessler A, McGuinness M, and Tranter M
- Subjects
- 3' Untranslated Regions, Animals, ELAV Proteins metabolism, Gene Expression Regulation, HSP70 Heat-Shock Proteins genetics, Heat-Shock Response genetics, Mice, MicroRNAs genetics, Protein Processing, Post-Translational genetics, RNA, Messenger biosynthesis, RNA, Messenger genetics, ELAV Proteins genetics, HSP70 Heat-Shock Proteins biosynthesis, Polyadenylation genetics, Protein Biosynthesis
- Abstract
Heat shock protein 70.3 (Hsp70.3) expression increases in response to cellular stress and plays a cytoprotective role. We have previously shown that Hsp70.3 expression is controlled through coordinated post-transcriptional regulation by miRNAs and alternative polyadenylation (APA), and APA-mediated shortening of the Hsp70.3 3'-UTR facilitates increased protein expression. A stress-induced increase in Hsp70.3 mRNA and protein expression is accompanied by alternative polyadenylation (APA)-mediated truncation of the 3'UTR of the Hsp70.3 mRNA transcript. However, the role that APA plays in stress-induced expression of Hsp70.3 remains unclear. Our results show that APA-mediated truncation of the Hsp70.3 3'UTR increases protein expression through enhanced polyribosome loading. Additionally, we demonstrate that the RNA binding protein HuR, which has been previously shown to play a role in mediating APA, is necessary for heat shock mediated increase in Hsp70.3 mRNA and protein. However, it is somewhat surprising to note that HuR does not play a role in APA of the Hsp70.3 mRNA, and these two regulatory events appear to be mutually exclusive regulators of Hsp70.3 expression. These results not only provide important insight to the regulation of stress response genes following heat shock, but also contribute an enhanced understanding of how alternative polyadenylation contributes to gene regulation., (Copyright © 2015 Elsevier B.V. All rights reserved.)
- Published
- 2015
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44. FBN-1, a fibrillin-related protein, is required for resistance of the epidermis to mechanical deformation during C. elegans embryogenesis.
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Kelley M, Yochem J, Krieg M, Calixto A, Heiman MG, Kuzmanov A, Meli V, Chalfie M, Goodman MB, Shaham S, Frand A, and Fay DS
- Subjects
- Animals, Biomechanical Phenomena, Caenorhabditis elegans genetics, Caenorhabditis elegans Proteins chemistry, Epidermis embryology, Epidermis metabolism, Exons genetics, Fibrillins, Fluorescence Resonance Energy Transfer, Genes, Helminth, Morphogenesis, Mutation genetics, Pharynx physiology, Phenotype, Protein Structure, Tertiary, RNA Splicing genetics, Vertebrates metabolism, Caenorhabditis elegans embryology, Caenorhabditis elegans physiology, Caenorhabditis elegans Proteins metabolism, Embryonic Development, Epidermis pathology, Microfilament Proteins metabolism, Stress, Mechanical
- Abstract
During development, biomechanical forces contour the body and provide shape to internal organs. Using genetic and molecular approaches in combination with a FRET-based tension sensor, we characterized a pulling force exerted by the elongating pharynx (foregut) on the anterior epidermis during C. elegans embryogenesis. Resistance of the epidermis to this force and to actomyosin-based circumferential constricting forces is mediated by FBN-1, a ZP domain protein related to vertebrate fibrillins. fbn-1 was required specifically within the epidermis and FBN-1 was expressed in epidermal cells and secreted to the apical surface as a putative component of the embryonic sheath. Tiling array studies indicated that fbn-1 mRNA processing requires the conserved alternative splicing factor MEC-8/RBPMS. The conserved SYM-3/FAM102A and SYM-4/WDR44 proteins, which are linked to protein trafficking, function as additional components of this network. Our studies demonstrate the importance of the apical extracellular matrix in preventing mechanical deformation of the epidermis during development.
- Published
- 2015
- Full Text
- View/download PDF
45. Increased fibrosis and progression to heart failure in MRL mice following ischemia/reperfusion injury.
- Author
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Smiley D, Smith MA, Carreira V, Jiang M, Koch SE, Kelley M, Rubinstein J, Jones WK, and Tranter M
- Subjects
- Animals, Cell Enlargement, Disease Progression, Fibrosis, Heart Failure etiology, Heart Failure physiopathology, Hypertrophy, Left Ventricular pathology, Male, Mice, Mice, Inbred C57BL, Mice, Inbred MRL lpr, Models, Cardiovascular, Myocardial Reperfusion Injury complications, Myocardial Reperfusion Injury physiopathology, Myocytes, Cardiac pathology, Regeneration, Stem Cells pathology, Ventricular Function, Left, Ventricular Remodeling, Heart Failure pathology, Myocardial Reperfusion Injury pathology
- Abstract
The cardiac regenerative capacity of MRL/MpJ mouse remains a controversy. Although the MRL mouse has been reported to exhibit minimal scarring and subsequent cardiac regeneration after cryoinjury of the right ventricle, multiple studies have been unable to replicate this cardiac regenerative capacity after both cryogenic and coronary ligation cardiac injury. Therefore, we evaluated the cardiac regenerative wound-healing response and functional recovery of MRL mice compared to C57 mice, in response to a clinically relevant left ventricular (LV) coronary ligation. Male MRL/MpJ+/+ and C57BL/6 mice underwent left coronary artery ligation followed by reperfusion. Cardiac function was evaluated by echocardiography [LV ejection fraction (LVEF), LV end-diastolic volume (LVEDV), LV mass, wall thickness] at 24 hours post-ischemia and weekly for 13 weeks thereafter. Hearts were also analyzed histologically for individual cardiomyocyte hypertrophy and cardiac fibrosis. Our results show that contrary to prior reports of cardiac regenerations, MRL mice progress to heart failure more rapidly following I/R injury as marked by a significant decrease in LVEF, increase in LVEDV, LV mass, individual myocyte size, and fibrosis in the post-ischemic myocardium. Therefore, we conclude that MRL mice do not exhibit regeneration of the LV or enhanced functional improvement in response to coronary ligation. However, unlike prior studies, we matched initial infarct size in MRL and C57 mice, used high frequency echocardiography, and histological analysis to reach this conclusion. The prospect of cardiac regeneration after ischemia in MRL mice seems to have attenuated interest, given the multiple negative studies and the promise of stem cell cardiac regeneration. However, our novel observation that MRL may possess an impaired compensated hypertrophy response makes the MRL mouse strain an interesting model in the study of cardiac hypertrophy., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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46. Iron overload is rare in patients homozygous for the H63D mutation.
- Author
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Kelley M, Joshi N, Xie Y, and Borgaonkar M
- Subjects
- Alanine Transaminase blood, Aspartate Aminotransferases blood, Female, Ferritins blood, Genetic Testing, Hemochromatosis Protein, Homozygote, Humans, Iron blood, Iron Overload diagnosis, Male, Middle Aged, Penetrance, Retrospective Studies, Transferrin metabolism, Histocompatibility Antigens Class I genetics, Iron Overload blood, Iron Overload genetics, Membrane Proteins genetics, Point Mutation
- Abstract
Background: Previous research has suggested that the H63D HFE mutation is associated with elevated iron indexes. However, the true penetrance of this mutation remains unclear., Objective: To assess the proportion of H63D homozygotes with laboratory abnormalities consistent with iron overload., Methods: The present study was a retrospective analysis of all individuals referred for HFE genotyping in Newfoundland and Labrador between 1999 and 2009, who were found to be homozygous for the H63D mutation. Using electronic health records, results of ferritin, transferrin saturation, aspartate aminotransferase and alanine aminotransferase testing performed closest to the time of genetic testing were recorded for each patient. Iron overload was classified using previously published definitions from the HealthIron study. SPSS version 17.0 (IBM Corporation, USA) was used for descriptive statistics and to compare means using one-way ANOVA., Results: Between 1999 and 2009, 170 individuals tested positive for H63D⁄H63D. At the time of genotyping, 28.8% had an elevated mean (± SD) ferritin level of 501±829 μg⁄L and 15.9% had an elevated transferrin saturation of 0.45±0.18. At genotyping, 94 individuals had sufficient data available to classify iron overload status. Only three (3.2%) had documented iron overload while the majority (85.1%) had no evidence of iron overload. Sixty individuals had follow-up data available and, of these, only four (6.7%) had documented iron overload, while 45 (75.0%) had no evidence of iron overload. Only one individual had evidence of iron overload-related disease at genotyping and at follow-up., Conclusions: H63D homozygosity was associated with an elevated mean ferritin level, but only 6.7% had documented iron overload at follow-up. The penetrance of the H63D mutation appeared to be low.
- Published
- 2014
- Full Text
- View/download PDF
47. Herc5, an interferon-induced HECT E3 enzyme, is required for conjugation of ISG15 in human cells.
- Author
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Dastur A, Beaudenon S, Kelley M, Krug RM, and Huibregtse JM
- Subjects
- Humans, Intracellular Signaling Peptides and Proteins chemistry, RNA, Small Interfering pharmacology, Ubiquitins metabolism, Cytokines metabolism, Interferon-beta pharmacology, Intracellular Signaling Peptides and Proteins physiology
- Abstract
ISG15 is an interferon (IFN)-alpha/beta-induced ubiquitin-like protein that is conjugated to cellular proteins during innate immune responses to viral and bacterial infections. A recent proteomics study identified 158 human proteins targeted for ISG15 conjugation, including the ISG15 E1 and E2 enzymes (Ube1L and UbcH8, respectively) and a HECT E3 enzyme, Herc5. Like the genes encoding Ube1L and UbcH8, expression of Herc5 was also induced by IFN-beta, suggesting that Herc5 might be a component of the ISG15 conjugation system. Consistent with this, small interfering RNAs targeting Herc5 had a dramatic effect on overall ISG15 conjugation in human cells, abrogating conjugation to the vast majority of ISG15 target proteins in vivo. In addition, co-transfection of plasmids expressing ISG15, Ube1L, UbcH8, and Herc5 resulted in robust ISG15 conjugation in non-IFN-treated cells, while the active-site cysteine mutant of Herc5 or a mutant lacking the RCC1 repeat region did not support ISG15 conjugation. These results demonstrate that Herc5 is required for conjugation of ISG15 to a broad spectrum of target proteins in human cells.
- Published
- 2006
- Full Text
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48. Discovery-based science education: functional genomic dissection in Drosophila by undergraduate researchers.
- Author
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Chen J, Call GB, Beyer E, Bui C, Cespedes A, Chan A, Chan J, Chan S, Chhabra A, Dang P, Deravanesian A, Hermogeno B, Jen J, Kim E, Lee E, Lewis G, Marshall J, Regalia K, Shadpour F, Shemmassian A, Spivey K, Wells M, Wu J, Yamauchi Y, Yavari A, Abrams A, Abramson A, Amado L, Anderson J, Bashour K, Bibikova E, Bookatz A, Brewer S, Buu N, Calvillo S, Cao J, Chang A, Chang D, Chang Y, Chen Y, Choi J, Chou J, Datta S, Davarifar A, Desai P, Fabrikant J, Farnad S, Fu K, Garcia E, Garrone N, Gasparyan S, Gayda P, Goffstein C, Gonzalez C, Guirguis M, Hassid R, Hong A, Hong J, Hovestreydt L, Hu C, Jamshidian F, Kahen K, Kao L, Kelley M, Kho T, Kim S, Kim Y, Kirkpatrick B, Kohan E, Kwak R, Langenbacher A, Laxamana S, Lee C, Lee J, Lee SY, Lee TH, Lee T, Lezcano S, Lin H, Lin P, Luu J, Luu T, Marrs W, Marsh E, Min S, Minasian T, Misra A, Morimoto M, Moshfegh Y, Murray J, Nguyen C, Nguyen K, Nodado E 2nd, O'Donahue A, Onugha N, Orjiakor N, Padhiar B, Pavel-Dinu M, Pavlenko A, Paz E, Phaklides S, Pham L, Poulose P, Powell R, Pusic A, Ramola D, Ribbens M, Rifai B, Rosselli D, Saakyan M, Saarikoski P, Segura M, Singh R, Singh V, Skinner E, Solomin D, Soneji K, Stageberg E, Stavchanskiy M, Tekchandani L, Thai L, Thiyanaratnam J, Tong M, Toor A, Tovar S, Trangsrud K, Tsang WY, Uemura M, Unkovic M, Vollmer E, Weiss E, Wood D, Wu S, Wu W, Xu Q, Yackle K, Yarosh W, Yee L, Yen G, Alkin G, Go S, Huff DM, Minye H, Paul E, Villarasa N, Milchanowski A, and Banerjee U
- Subjects
- Animals, Curriculum, Genomics, Humans, Students, Universities, Drosophila genetics, Genome, Molecular Biology education, Research
- Published
- 2005
- Full Text
- View/download PDF
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