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1.  World Congress Integrative Medicine & Health 2017: Part one 
Brinkhaus, Benno | Falkenberg, Torkel | Haramati, Aviad | Willich, Stefan N. | Briggs, Josephine P. | Willcox, Merlin | Linde, Klaus | Theorell, Töres | Wong, Lisa M. | Dusek, Jeffrey | Wu, Darong | Eisenberg, David | Haramati, Aviad | Berger, Bettina | Kemper, Kathi | Stock-Schröer, Beate | Sützl-Klein, Hedda | Ferreri, Rosaria | Kaplan, Gary | Matthes, Harald | Rotter, Gabriele | Schiff, Elad | Arnon, Zahi | Hahn, Eckhard | Luberto, Christina M. | Martin, David | Schwarz, Silke | Tauschel, Diethard | Flower, Andrew | Gramminger, Harsha | Gupta, Hedwig H. | Gupta, S. N. | Kerckhoff, Annette | Kessler, Christian S. | Michalsen, Andreas | Kessler, Christian S. | Kim, Eun S. | Jang, Eun H. | Kim, Rana | Jan, Sae B. | Mittwede, Martin | Mohme, Wiebke | Ben-Arye, Eran | Bonucci, Massimo | Saad, Bashar | Breitkreuz, Thomas | Rossi, Elio | Kebudi, Rejin | Daher, Michel | Razaq, Samaher | Gafer, Nahla | Nimri, Omar | Hablas, Mohamed | Kienle, Gunver Sophia | Samuels, Noah | Silbermann, Michael | Bandelin, Lena | Lang, Anna-Lena | Wartner, Eva | Holtermann, Christoph | Binstock, Maxwell | Riebau, Robert | Mujkanovic, Edin | Cramer, Holger | Lauche, Romy | Michalsen, Andres | Ward, Lesley | Cramer, Holger | Irnich, Dominik | Stör, Wolfram | Burnstock, Geoffrey | Schaible, Hans-Georg | Ots, Thomas | Langhorst, Jost | Lauche, Romy | Sundberg, Tobias | Falkenberg, Torkel | Amarell, Catherina | Amarell, Catherina | Anheyer, Melanie | Eckert, Marion | Eckert, Marion | Ogal, Mercedes | Eckert, Marion | Amarell, Catherina | Schönauer, Annette | Reisenberger, Birgit | Brand, Bernhard | Anheyer, Dennis | Dobos, Gustav | Kroez, Matthias | Martin, David | Matthes, Harald | Ammendola, Aldo | Mao, Jun J. | Witt, Claudia | Yang, Yufei | Dobos, Gustav | Oritz, Miriam | Horneber, Markus | Voiß, Petra | Reisenberger, Birgit | von Rosenstiel, Alexandra | Eckert, Marion | Ogal, Mercedes | Amarell, Catharina | Anheyer, Melanie | Schad, Friedemann | Schläppi, Marc | Kröz, Matthias | Büssing, Arndt | Bar-Sela, Gil | Matthes, Harald | Schiff, Elad | Ben-Arye, Eran | Arnon, Zahi | Avshalomov, David | Attias, Samuel | Schönauer, Annette | Haramati, Aviad | Witt, Claudia | Brinkhaus, Benno | Cotton, Sian | Jong, Miek | Jong, Mats | Scheffer, Christian | Haramati, Aviad | Tauschel, Diethard | Edelhäuser, Friedrich | AlBedah, Abdullah | Lee, Myeong Soo | Khalil, Mohamed | Ogawa, Keiko | Motoo, Yoshiharu | Arimitsu, Junsuke | Ogawa, Masao | Shimizu, Genki | Stange, Rainer | Kraft, Karin | Kuchta, Kenny | Watanabe, Kenji | Bonin, D | Büssing, Arndt | Gruber, Harald | Koch, Sabine | Gruber, Harald | Pohlmann, Urs | Caldwell, Christine | Krantz, Barbara | Kortum, Ria | Martin, Lily | Wieland, Lisa S. | Kligler, Ben | Gould-Fogerite, Susan | Zhang, Yuqing | Wieland, Lisa S. | Riva, John J. | Lumpkin, Michael | Ratner, Emily | Ping, Liu | Jian, Pei | Hamme, Gesa-Meyer | Mao, Xiaosong | Chouping, Han | Schröder, Sven | Hummelsberger, Josef | Wullinger, Michael | Brodzky, Marc | Zalpour, Christoff | Langley, Julia | Weber, Wendy | Mudd, Lanay M. | Wayne, Peter | Witt, Clauda | Weidenhammer, Wolfgang | Fønnebø, Vinjar | Boon, Heather | Steel, Amie | Bugarcic, Andrea | Rangitakatu, Melisa | Steel, Amie | Adams, Jon | Sibbritt, David | Wardle, Jon | Leach, Matthew | Schloss, Janet | Dieze, Helene | Boon, Heather | Ijaz, Nadine | Willcox, Merlin | Heinrich, Michael | Lewith, George | Flower, Andrew | Graz, Bertrand | Adam, Daniela | Grabenhenrich, Linus | Ortiz, Miriam | Binting, Sylvia | Reinhold, Thomas | Brinkhaus, Benno | Andermo, Susanne | Sundberg, Tobias | Falkenberg, Torkel | Nordberg, Johanna Hök | Arman, Maria | Bhasin, Manoj | Fan, Xueyi | Libermann, Towia | Fricchione, Gregory | Denninger, John | Benson, Herbert | Berger, Bettina | Stange, Rainer | Michalsen, Andreas | Martin, David D. | Boers, Inge | Vlieger, Arine | Jong, Miek | Brinkhaus, Benno | Teut, Michael | Ullmann, Alexander | Ortiz, Miriam | Rotter, Gabriele | Binting, Sylvia | Lotz, Fabian | Roll, Stephanie | Canella, Claudia | Mikolasek, Michael | Rostock, Matthias | Beyer, Jörg | Guckenberger, Matthias | Jenewein, Josef | Linka, Esther | Six, Claudia | Stoll, Sarah | Stupp, Roger | Witt, Claudia M. | Chuang, Elisabeth | Kligler, Ben | McKee, Melissa D. | Cramer, Holger | Lauche, Romy | Klose, Petra | Lange, Silke | Langhorst, Jost | Dobos, Gustav | Chung, Vincent C. H. | Wong, Hoi L. C. | Wu, Xin Y. | Wen, Grace Y. G. | Ho, Robin S. T. | Ching, Jessica Y. L. | Wu, Justin C. Y. | Coakley, Amanda | Flanagan, Jane | Annese, Christine | Empoliti, Joanne | Gao, Zishan | Liu, Xugang | Yu, Shuguang | Yan, Xianzhong | Liang, Fanrong | Hohmann, Christoph D. | Steckhan, Nico | Ostermann, Thomas | Paetow, Arion | Hoff, Evelyn | Michalsen, Andreas | Hu, Xiao-Yang | Wu, Ruo-Han | Logue, Martin | Blonde, Clara | Lai, Lily Y. | Stuart, Beth | Flower, Andrew | Fei, Yu-Tong | Moore, Michael | Liu, Jian-Ping | Lewith, George | Hu, Xiao-Yang | Wu, Ruo-Han | Logue, Martin | Blonde, Clara | Lai, Lily Y. | Stuart, Beth | Flower, Andrew | Fei, Yu-Tong | Moore, Michael | Liu, Jian-Ping | Lewith, George | Jeitler, Michael | Zillgen, Hannah | Högl, Manuel | Steckhan, Nico | Stöckigt, Barbara | Seifert, Georg | Michalsen, Andreas | Kessler, Christian | Khadivzadeh, Talat | Bashtian, Maryam Hassanzadeh | Aval, Shapour Badiee | Esmaily, Habibollah | Kim, Jihye | Kim, Keun H. | Klocke, Carina | Joos, Stefanie | Koshak, Abdulrahman | Wie, Li | Koshak, Emad | Wali, Siraj | Alamoudi, Omer | Demerdash, Abdulrahman | Qutub, Majdy | Pushparaj, Peter | Heinrich, Michael | Kruse, Sigrid | Fischer, Isabell | Tremel, Nadine | Rosenecker, Joseph | Leung, Brenda | Takeda, Wendy | Liang, Ning | Feng, Xue | Liu, Jian-ping | Cao, Hui-juan | Luberto, Christina M. | Shinday, Nina | Philpotts, Lisa | Park, Elyse | Fricchione, Gregory L. | Yeh, Gloria | Munk, Niki | Zakeresfahani, Arash | Foote, Trevor R. | Ralston, Rick | Boulanger, Karen | Özbe, Dominik | Gräßel, Elmar | Luttenberger, Katharina | Pendergrass, Anna | Pach, Daniel | Bellmann-Strobl, Judit | Chang, Yinhui | Pasura, Laura | Liu, Bin | Jäger, Sven F. | Loerch, Ronny | Jin, Li | Brinkhaus, Benno | Ortiz, Miriam | Reinhold, Thomas | Roll, Stephanie | Binting, Sylvia | Icke, Katja | Shi, Xuemin | Paul, Friedemann | Witt, Claudia M. | Rütz, Michaela | Lynen, Andreas | Schömitz, Meike | Vahle, Maik | Salomon, Nir | Lang, Alon | Lahat, Adi | Kopylov, Uri | Ben-Horin, Shomron | Har-Noi, Ofir | Avidan, Benjamin | Elyakim, Rami | Gamus, Dorit | NG, Siew | Chang, Jessica | Wu, Justin | Kaimiklotis, John | Schumann, Dania | Buttó, Ludovica | Langhorst, Jost | Dobos, Gustav | Haller, Dirk | Cramer, Holger | Smith, Caroline | de Lacey, Sheryl | Chapman, Michael | Ratcliffe, Julie | Johnson, Neil | Lyttleton, Jane | Boothroyd, Clare | Fahey, Paul | Tjaden, Bram | van Vliet, Marja | van Wietmarschen, Herman | Jong, Miek | Tröger, Wilfried | Vuolanto, Pia | Aarva, Paulina | Sorsa, Minna | Helin, Kaija | Wenzel, Claudia | Zoderer, Iris | Pammer, Patricia | Simon, Patrick | Tucek, Gerhard | Wode, Kathrin | Henriksson, Roger | Sharp, Lena | Stoltenberg, Anna | Nordberg, Johanna Hök | Xiao-ying, Yang | Wang, Li-qiong | Li, Jin-gen | Liang, Ning | Wang, Ying | Liu, Jian-ping | Balneaves, Lynda | Capler, Rielle | Bocci, Chiara | Guffi, Marta | Paolini, Marina | Meaglia, Ilaria | Porcu, Patrizia | Ivaldi, Giovanni B. | Dragan, Simona | Bucuras, Petru | Pah, Ana M. | Badalica-Petrescu, Marius | Buleu, Florina | Hogea-Stoichescu, Gheorghe | Christodorescu, Ruxandra | Kao, Lan | Cho, Yumin | Klafke, Nadja | Mahler, Cornelia | von Hagens, Cornelia | Uhlmann, Lorenz | Bentner, Martina | Schneeweiss, Andreas | Mueller, Andreas | Szecsenyi, Joachim | Joos, Stefanie | Neri, Isabella | Ortiz, Miriam | Schnabel, Katharina | Teut, Michael | Rotter, Gabriele | Binting, Sylvia | Cree, Margit | Lotz, Fabian | Suhr, Ralf | Brinkhaus, Benno | Rossi, Elio | Baccetti, Sonia | Firenzuoli, Fabio | Monechi, Maria V. | Di Stefano, Mariella | Amunni, Gianni | Wong, Wendy | Chen, Bingzhong | Wu, Justin | Amri, Hakima | Haramati, Aviad | Kotlyanskaya, Lucy | Anderson, Belinda | Evans, Roni | Kligler, Ben | Marantz, Paul | Bradley, Ryan | Booth-LaForce, Cathryn | Zwickey, Heather | Kligler, Benjamin | Brooks, Audrey | Kreitzer, Mary J. | Lebensohn, Patricia | Goldblatt, Elisabeth | Esmel-Esmel, Neus | Jiménez-Herrera, Maria | Ijaz, Nadine | Boon, Heather | Jocham, Alexandra | Stock-Schröer, Beate | Berberat, Pascal O. | Schneider, Antonius | Linde, Klaus | Masetti, Morgana | Murakozy, Henriette | Van Vliet, Marja | Jong, Mats | Jong, Miek | Agdal, Rita | Atarzadeh, Fatemeh | Jaladat, Amir M. | Hoseini, Leila | Amini, Fatemeh | Bai, Chen | Liu, Tiegang | Zheng, Zian | Wan, Yuxiang | Xu, Jingnan | Wang, Xuan | Yu, He | Gu, Xiaohong | Daneshfard, Babak | Nimrouzi, Majid | Tafazoli, Vahid | Alorizi, Seyed M. Emami | Saghebi, Seyed A. | Fattahi, Mohammad R. | Salehi, Alireza | Rezaeizadeh, Hossein | Zarshenas, Mohammad M. | Nimrouzi, Majid | Fox, Kealoha | Hughes, John | Kostanjsek, Nenad | Espinosa, Stéphane | Lewith, George | Fisher, Peter | Latif, Abdul | Lefeber, Donald | Paske, William | Öztürk, Ali Ö. | Öztürk, Gizemnur | Boers, Inge | Tissing, Wim | Naafs, Marianne | Busch, Martine | Jong, Miek | Daneshfard, Babak | Sanaye, Mohammad R. | Dräger, Kilian | Fisher, Peter | Kreitzer, Mary J. | Evans, Roni | Leininger, Brent | Shafto, Kate | Breen, Jenny | Sanaye, Mohammad R. | Daneshfard, Babak | Simões-Wüst, Ana P. | Moltó-Puigmartí, Carolina | van Dongen, Martien | Dagnelie, Pieter | Thijs, Carel | White, Shelley | Wiesener, Solveig | Salamonsen, Anita | Stub, Trine | Fønnebø, Vinjar | Abanades, Sergio | Blanco, Mar | Masllorens, Laia | Sala, Roser | Al-Ahnoumy, Shafekah | Han, Dongwoon | He, Luzhu | Kim, Ha Yun | In Choi, Da | Alræk, Terje | Stub, Trine | Kristoffersen, Agnete | von Sceidt, Christel | Michalsen, Andreas | Bruset, Stig | Musial, Frauke | Anheyer, Dennis | Cramer, Holger | Lauche, Romy | Saha, Felix J. | Dobos, Gustav | Anheyer, Dennis | Haller, Heidemarie | Lauche, Romy | Dobos, Gustav | Cramer, Holger | Azizi, Hoda | Khadem, Nayereh | Hassanzadeh, Malihe | Estiri, Nazanin | Azizi, Hamideh | Tavassoli, Fatemeh | Lotfalizadeh, Marzieh | Zabihi, Reza | Esmaily, Habibollah | Azizi, Hoda | Shabestari, Mahmoud Mohammadzadeh | Paeizi, Reza | Azari, Masoumeh Alvandi | Bahrami-Taghanaki, Hamidreza | Zabihi, Reza | Azizi, Hamideh | Esmaily, Habibollah | Baars, Erik | De Bruin, Anja | Ponstein, Anne | Baccetti, Sonia | Di Stefano, Mariella | Rossi, Elio | Firenzuoli, Fabio | Segantini, Sergio | Monechi, Maria Valeria | Voller, Fabio | Barth, Jürgen | Kern, Alexandra | Lüthi, Sebastian | Witt, Claudia | Barth, Jürgen | Zieger, Anja | Otto, Fabius | Witt, Claudia | Beccia, Ariel | Dunlap, Corina | Courneene, Brendan | Bedregal, Paula | Passi, Alvaro | Rodríguez, Alfredo | Chang, Mayling | Gutiérrez, Soledad | Beissner, Florian | Beissner, Florian | Preibisch, Christine | Schweizer-Arau, Annemarie | Popovici, Roxana | Meissner, Karin | Beljanski, Sylvie | Belland, Laura | Rivera-Reyes, Laura | Hwang, Ula | Berger, Bettina | Sethe, Dominik | Hilgard, Dörte | Heusser, Peter | Bishop, Felicity | Al-Abbadey, Miznah | Bradbury, Katherine | Carnes, Dawn | Dimitrov, Borislav | Fawkes, Carol | Foster, Jo | MacPherson, Hugh | Roberts, Lisa | Yardley, Lucy | Lewith, George | Bishop, Felicity | Al-Abbadey, Miznah | Bradbury, Katherine | Carnes, Dawn | Dimitrov, Borislav | Fawkes, Carol | Foster, Jo | MacPherson, Hugh | Roberts, Lisa | Yardley, Lucy | Lewith, George | Bishop, Felicity | Holmes, Michelle | Lewith, George | Yardley, Lucy | Little, Paul | Cooper, Cyrus | Bogani, Patrizia | Maggini, Valentina | Gallo, Eugenia | Miceli, Elisangela | Biffi, Sauro | Mengoni, Alessio | Fani, Renato | Firenzuoli, Fabio | Brands-Guendling, Nadine | Guendling, Peter W. | Bronfort, Gert | Evans, Roni | Haas, Mitch | Leininger, Brent | Schulz, Craig | Bu, Xiangwei | Wang, J. | Fang, T. | Shen, Z. | He, Y. | Zhang, X. | Zhang, Zhengju | Wang, Dali | Meng, Fengxian | Büssing, Arndt | Baumann, Klaus | Frick, Eckhard | Jacobs, Christoph | Büssing, Arndt | Grünther, Ralph-Achim | Lötzke, Désirée | Büssing, Arndt | Jung, Sonny | Lötzke, Désirée | Recchia, Daniela R. | Robens, Sibylle | Ostermann, Thomas | Berger, Bettina | Stankewitz, Josephin | Kröz, Matthias | Jeitler, Mika | Kessler, Christian | Michalsen, Andreas | Cheon, Chunhoo | Jang, Bo H. | Ko, Seong G. | Huang, Ching W. | Sasaki, Yui | Ko, Youme | Cheshire, Anna | Ridge, Damien | Hughes, John | Peters, David | Panagioti, Maria | Simon, Chantal | Lewith, George | Cho, Hyun J. | Han, Dongwoon | Choi, Soo J. | Jung, Young S. | Im, Hyea B | Cooley, Kieran | Tummon-Simmons, Laura | Cotton, Sian | Luberto, Christina M. | Wasson, Rachel | Kraemer, Kristen | Sears, Richard | Hueber, Carly | Derk, Gwendolyn | Lill, JR | An, Ruopeng | Steinberg, Lois | Rodriguez, Lourdes Diaz | la Fuente, Francisca García-de | De la Vega, Miguel | Vargas-Román, Keyla | Fernández-Ruiz, Jonatan | Cantarero-Villanueva, Irene | Rodriguez, Lourdes Diaz | García-De la Fuente, Francisca | Jiménez-Guerrero, Fanny | Vargas-Román, Keyla | Fernández-Ruiz, Jonatan | Galiano-Castillo, Noelia | Diaz-Saez, Gualberto | Torres-Jimenez, José I. | Garcia-Gomez, Olga | Hortal-Muñoz, Luis | Diaz-Diez, Camino | Dicen, Demijon | Diezel, Helene | Adams, Jon | Steel, Amie | Wardle, Jon | Diezel, Helene | Steel, Amie | Frawley, Jane | Wardle, Jon | Broom, Alex | Adams, Jon | Dong, Fei | Yu, He | Liu, Tiegang | Ma, Xueyan | Yan, Liyi | Wan, Yuxiang | Zheng, Zian | Gu, Xiaohong | Dong, Fei | Yu, He | Wu, Liqun | Liu, Tiegang | Ma, Xueyan | Ma, Jiaju | Yan, Liyi | Wan, Yuxiang | Zheng, Zian | Zhen, Jianhua | Gu, Xiaohong | Dubois, Julie | Rodondi, Pierre-Yves | Edelhäuser, Friedrich | Schwartze, Sophia | Trapp, Barbara | Cysarz, Dirk
doi:10.1186/s12906-017-1782-4
PMCID: PMC5498855
2.  Mindfulness-based Intervention for Perinatal Grief Education and Reduction among Poor Women in Chhattisgarh, India: a Pilot Study 
Introduction
Stillbirth is a significant public health problem in low-to-middle-income countries and results in perinatal grief, often with negative psychosocial impact. In low-resource settings, such as Chhattisgarh, India, where needs are high, it is imperative to utilize low-cost, effective interventions. Mindfulness-based stress reduction (MBSR) is an empirically sound intervention that has been utilized for a broad range of physical and mental health problems, and is adaptable to specific populations. The main objective of this pilot study was to explore the feasibility and effectiveness of a shortened, culturally adapted mindfulness-based intervention to address complex grief after stillbirth.
Methods
We used an observational, pre-post-6-week post study design. The study instrument was made up of descriptive demographic questions and validated scales and was administered as a structured interview due to low literacy rates. We used a community participatory approach to culturally adapt the five-week mindfulness-based intervention and delivered it through two trained local nurses. Quantitative and qualitative data analyses explored study outcomes as well as acceptability and feasibility of the intervention.
Results
29 women with a history of stillbirth enrolled, completed the pretest and began the intervention; 26 completed the five-week intervention and post-test (89.7%), and 23 completed the six-week follow-up assessment (88.5%). Pretest results included elevated psychological symptoms and high levels of perinatal grief, including the active grief, difficulty coping, and despair subscales. General linear modeling repeated measures was used to explore posttest and six-week follow up changes from baseline, controlling for significantly correlated demographic variables. These longitudinal results included significant reduction in psychological symptoms; four of the five facets of mindfulness changed in the desired direction, two significantly; as well as significant reduction in overall perinatal grief and on each of the three subscales.
Discussion
The shortened, culturally adapted, mindfulness-based intervention pilot study was well received and had very low attrition. We also found significant reductions of perinatal grief and mental health symptoms over time, as well as a high degree of practice of mindfulness skills by participants. This study not only sheds light on the tremendous mental health needs among rural women of various castes who have experienced stillbirth in Chhattisgarh, it also points to a promising effective intervention with potential to be taken to scale for wider delivery.
PMCID: PMC5367631
Perinatal grief; mental health; stillbirth; India; mindfulness-based intervention
3.  India’s Distorted Sex Ratio: Dire Consequences for Girls 
Female gender discrimination related to cultural preference for males is a common global problem, especially in Asian countries. Numerous laws intended to prevent discrimination on the basis of gender have been passed in India, yet the distorted female-to-male sex ratio seems to show worsening tendencies. Using detailed, two-year longitudinal chart abstraction data about delivery records of a private mission hospital in rural India, we explored if hospital birth ratio data differed in comparison to regional data, and what demographic and contextual variables may have influenced these outcomes. Using quantitative chart abstraction and qualitative contextual data, study results showed the female-to-male ratio was lower than the reported state ratio at birth. In the context of India’s patriarchal structure, with its strong son preference, women are under tremendous pressure or coerced to access community-based, sex-selective identification and female fetus abortion. Nurses may be key to turning the tide.
doi:10.1097/CNJ.0000000000000244
PMCID: PMC5341607
feticide; gender discrimination; India; nursing; prenatal sex identification; selective abortion; sex ratio
4.  Social and Cultural Factors Associated with Perinatal Grief in Chhattisgarh, India 
Journal of community health  2012;37(3):572-582.
Stillbirth is a globally significant public health problem with many medical causes. There are also indirect causal pathways including social and cultural factors which are particularly salient in India's traditional society. The purpose of this study was to explore women's perceptions of stillbirth and to determine how issues of gender and power, social support, coping efforts, and religious beliefs influence perinatal grief outcomes among poor women in rural Chhattisgarh, India. Structured interviews were done face-to-face in 21 randomly selected villages among women of reproductive age (N = 355) who had experienced stillbirth (n = 178) and compared to those who had not (n = 177), in the Christian Hospital, Mungeli catchment area. Perinatal grief was significantly higher among women with a history of stillbirth. Greater perinatal grief was associated with lack of support, maternal agreement with social norms, and younger maternal age. These predictors must be understood in light of an additional finding—distorted sex ratios, which reflect gender discrimination in the context of Indian society. The findings of this study will allow the development of a culturally appropriate health education program which should be designed to increase social support and address social norms, thereby reducing psychological distress to prevent complicated perinatal grief. Perinatal grief is a significant social burden which impacts the health women.
doi:10.1007/s10900-011-9485-0
PMCID: PMC5321201  PMID: 21956647
Perinatal grief; Social provision of support; Social norms; India
5.  Molecular Diagnosis of Inherited Retinal Diseases in Indigenous African Populations by Whole-Exome Sequencing 
Purpose
A majority of genes associated with inherited retinal diseases (IRDs) have been identified in patients of European origin. Indigenous African populations exhibit rich genomic diversity, and evaluation of reported genetic mutations has yielded low returns so far. Our goal was to perform whole-exome sequencing (WES) to examine variants in known IRD genes in underrepresented African cohorts.
Methods
Whole-exome sequencing was performed on 56 samples from 16 families with diverse IRD phenotypes that had remained undiagnosed after screening for known mutations using genotyping-based microarrays (Asper Ophthalmics). Variants in reported IRD genes were identified using WES and validated by Sanger sequencing. Custom TaqMan assays were used to screen for identified mutations in 193 unrelated indigenous Africans with IRDs.
Results
A total of 3494 variants were identified in 217 known IRD genes, leading to the identification of seven different mutations (including six novel) in six genes (RHO, PRPF3, PRPF31, ABCA4, CERKL, and PDE6B) in six distinct families. TaqMan screening in additional probands revealed identical homozygous CERKL and PDE6B variants in four more patients.
Conclusions
This is the first report of WES of patients with IRDs in indigenous African populations. Our study identified genetic defects in almost 40% of the families analyzed, significantly enhancing the molecular diagnosis of IRD in South Africa. Thus, WES of understudied cohorts seems to present an effective strategy for determining novel mutations in heterogeneous retinal diseases.
doi:10.1167/iovs.16-19785
PMCID: PMC5132076  PMID: 27898983
next generation sequencing; genetic testing; photoreceptor dysfunction; South Africa; vision loss; inherited blindness; retinal degeneration; clinical genetics
6.  Feline Calicivirus Infection Disrupts Assembly of Cytoplasmic Stress Granules and Induces G3BP1 Cleavage 
Journal of Virology  2016;90(14):6489-6501.
ABSTRACT
In response to stress such as virus infection, cells can stall translation by storing mRNAs away in cellular compartments called stress granules (SGs). This defense mechanism favors cell survival by limiting the use of energy and nutrients until the stress is resolved. In some cases it may also block viral propagation as viruses are dependent on the host cell resources to produce viral proteins. Human norovirus is a member of the Caliciviridae family responsible for gastroenteritis outbreaks worldwide. Previous studies on caliciviruses have identified mechanisms by which they can usurp the host translational machinery, using the viral protein genome-linked VPg, or regulate host protein synthesis through the mitogen-activated protein kinase (MAPK) pathway. Here, we examined the effect of feline calicivirus (FCV) infection on SG accumulation. We show that FCV infection impairs the assembly of SGs despite an increased phosphorylation of eukaryotic initiation factor eIF2α, a hallmark of stress pathway activation. Furthermore, SGs did not accumulate in FCV-infected cells that were stressed with arsenite or hydrogen peroxide. FCV infection resulted in the cleavage of the SG-nucleating protein Ras-GTPase activating SH3 domain-binding protein (G3BP1), which is mediated by the viral 3C-like proteinase NS6Pro. Using mutational analysis, we identified the FCV-induced cleavage site within G3BP1, which differs from the poliovirus 3C proteinase cleavage site previously identified. Finally, we showed that NS6Pro-mediated G3BP1 cleavage impairs SG assembly. In contrast, murine norovirus (MNV) infection did not impact arsenite-induced SG assembly or G3BP1 integrity, suggesting that related caliciviruses have distinct effects on the stress response pathway.
IMPORTANCE Human noroviruses are a major cause of viral gastroenteritis, and it is important to understand how they interact with the infected host cell. Feline calicivirus (FCV) and murine norovirus (MNV) are used as models to understand norovirus biology. Recent studies have suggested that the assembly of stress granules is central in orchestrating stress and antiviral responses to restrict viral replication. Overall, our study provides the first insight on how caliciviruses impair stress granule assembly by targeting the nucleating factor G3BP1 via the viral proteinase NS6Pro. This work provides new insights into host-pathogen interactions that regulate stress pathways during FCV infection.
doi:10.1128/JVI.00647-16
PMCID: PMC4936126  PMID: 27147742
7.  Non-specific mechanisms in orthodox and CAM management of low back pain (MOCAM): theoretical framework and protocol for a prospective cohort study 
BMJ Open  2016;6(5):e012209.
Introduction
Components other than the active ingredients of treatment can have substantial effects on pain and disability. Such ‘non-specific’ components include: the therapeutic relationship, the healthcare environment, incidental treatment characteristics, patients’ beliefs and practitioners’ beliefs. This study aims to: identify the most powerful non-specific treatment components for low back pain (LBP), compare their effects on patient outcomes across orthodox (physiotherapy) and complementary (osteopathy, acupuncture) therapies, test which theoretically derived mechanistic pathways explain the effects of non-specific components and identify similarities and differences between the therapies on patient–practitioner interactions.
Methods and analysis
This research comprises a prospective questionnaire-based cohort study with a nested mixed-methods study. A minimum of 144 practitioners will be recruited from public and private sector settings (48 physiotherapists, 48 osteopaths and 48 acupuncturists). Practitioners are asked to recruit 10–30 patients each, by handing out invitation packs to adult patients presenting with a new episode of LBP. The planned multilevel analysis requires a final sample size of 690 patients to detect correlations between predictors, hypothesised mediators and the primary outcome (self-reported back-related disability on the Roland-Morris Disability Questionnaire). Practitioners and patients complete questionnaires measuring non-specific treatment components, mediators and outcomes at: baseline (time 1: after the first consultation for a new episode of LBP), during treatment (time 2: 2 weeks post-baseline) and short-term outcome (time 3: 3 months post-baseline). A randomly selected subsample of participants in the questionnaire study will be invited to take part in a nested mixed-methods study of patient–practitioner interactions. In the nested study, 63 consultations (21/therapy) will be audio-recorded and analysed quantitatively and qualitatively, to identify communication practices associated with patient outcomes.
Ethics and dissemination
The protocol is approved by the host institution's ethics committee and the NHS Health Research Authority Research Ethics Committee. Results will be disseminated via peer-reviewed journal articles, conferences and a stakeholder workshop.
doi:10.1136/bmjopen-2016-012209
PMCID: PMC4885467  PMID: 27235304
COMPLEMENTARY MEDICINE; PAIN MANAGEMENT; PRIMARY CARE; RHEUMATOLOGY
8.  Exploring Experiences and Perceptions of Aging and Cognitive Decline Across Diverse Racial and Ethnic Groups 
Gerontology & geriatric medicine  2015;1:2333721415596101.
Objective
To explore how older adults from three prominent ethnoracial groups experience cognitive decline and aging.
Method
Semistructured key informant interviews (KIIs) and focus groups (FGs) were conducted with caregivers, experts, and older adults.
Results
(N = 75). Fifteen KIIs regarding cognitive aging issues were conducted among health care professionals and community-based agencies serving older adults. Eight FGs included family caregivers and physicians, and six FGs with Latino, African American, and White older adult community members. Major themes included (a) personal expectations about aging, (b) societal value of older adults, (c) model of care preferred, and (d) community concerns. An overarching theme was a sense of loss associated with aging; however, how this loss was experienced and dealt with varied.
Discussion
Distinct patterns of concerns and views are important to understand for the development of programs aimed at meeting the needs of diverse older adult community members to improve health outcomes.
doi:10.1177/2333721415596101
PMCID: PMC4766862  PMID: 26925436
perceptions of aging; cognitive decline; diverse racial and ethnic groups
9.  Mental Health and Sociocultural Determinants in an Asian Indian Community 
Family & community health  2016;39(1):31-39.
In a US population of adult male and female Sikh immigrant participants (N = 350), we explored sociocultural factors related to depression, giving participants a choice between English or Punjabi surveys. Language preference pointed to a subgroup with higher levels of depression and lower satisfaction with life. Underreporting of depression suggests a general reluctance to discuss depression. While multiple sociocultural variables were associated with depression bivariably, multivariate analysis identified negative religious coping and anxiety as unique predictors of depression. Community interventions should tap into the protective close-knit social fabric of this community as an opportunity to change the stigma of mental health.
doi:10.1097/FCH.0000000000000087
PMCID: PMC4682551  PMID: 26605953
Asian Indian immigrants; depression; sociocultural determinants
10.  Depression, a Hidden Mental Health Disparity in an Asian Indian Immigrant Community 
Cultural influences are deeply rooted, and continue to affect the lives of Asian-Indian (AI) immigrants living in Western culture. Emerging literature suggests the powerful nature of traditions and culture on the lives, mental and physical health of AI immigrants, particularly women. The purpose of this study was to explore depression among AI women in Central California (CC). This mixed-methods research was conducted in collaboration with the CC Punjabi community and the support of local religious leaders. All interviews were conducted in Punjabi and English. Whenever possible we utilized validated scales aligned with emerging themes from the qualitative data, which also provided contextualization to survey responses. In all we conducted 11 key informant interviews, four focus groups (n = 47) and a rigorously developed anonymous survey (n = 350). Social dynamics and traditional expectations including gendered roles significantly affected mental health among women participants. Subgroups along the lines of language choice (Punjabi vs. English) experience and report depression differently in part due to the highly stigmatized nature of mental health issues in this model minority community. The findings of this study highlight the importance of utilizing mixed methods to access hard to reach populations regarding sensitive topics such as mental health.
doi:10.3390/ijerph13010027
PMCID: PMC4730418  PMID: 26703654
Asian-Indian; immigrants; gender; mental health; acculturation; Punjabi Sikhs
11.  Mindfulness-based Intervention for Perinatal Grief after Stillbirth in Rural India 
Issues in mental health nursing  2015;36(3):222-230.
We explored the concept of using a Mindfulness-based intervention to reduce perinatal grief among Indian women. Data were collected using mixed methods to explore concept acceptability, receptivity, modality, and feasibility of the intervention. The intervention was piloted and evaluated with measures of perinatal grief, psychosocial wellbeing, religious coping, perceived social provision of support, and mindfulness. The intervention was well received and effective in teaching skills to help women deal with high levels of grief and subsequent mental health challenges. To overcome attendance barriers modification is necessary. Partnership with a local nursing school is critical to enhance sustainability of the intervention.
doi:10.3109/01612840.2014.962676
PMCID: PMC4682546  PMID: 25898268
12.  Grief and Women: Stillbirth in the Social Context of India 
INTRODUCTION
Few in Western society would argue the potentially devastating impact of stillbirth related grief; but in many developing countries where stillbirth remains the highest in the world, perinatal grief is barely recognized as an issue. The purpose of this study was to explore how poor, rural central Indian women perceive and cope with stillbirths.
METHODS
Seventeen key informant interviews and two focus groups (N = 33) with local health care providers, family members, and women who experienced stillbirth were conducted over a 1-month period in 2011 and then systematically coded for emerging themes using grounded theory methods to explore how women experienced stillbirth.
RESULTS
Although usually never talked about and not recognized as an issue, perinatal grief emerged as a significant shared experience by all. The perceptions of stillbirth-related grief emerged in three major themes and bear evidence of gender and power issues and indicate that local social norms negatively factor heavily into their perinatal grief experiences.
DISCUSSION
The findings in this richly textured study add to the limited literature regarding rural, central Indian women's experiences with stillbirth and factors influencing their resulting perinatal grief. In light of the void of recognition of this phenomenon in Indian society, a better understanding of the context in which poor Indian women experience perinatal grief will be a first step toward developing much needed culturally rooted interventions to positively impact the women's abilities to better cope with stillbirth in the context of their realities.
doi:10.1891/2156-5287.2.3.187
PMCID: PMC4652937  PMID: 26594592
perinatal grief; gender; power (psychology); social conformity; India
13.  Using an internet intervention to support self-management of low back pain in primary care: protocol for a randomised controlled feasibility trial (SupportBack) 
BMJ Open  2015;5(9):e009524.
Introduction
Low back pain (LBP) is a prevalent and costly condition. The majority of patients experiencing LBP are managed in primary care, where first-line care recommendations consist of advice to self-manage and remain active. Internet interventions present a potential means of providing patients with tailored self-management advice and evidence-based support for increasing physical activity.
Methods/analysis
This protocol describes a single-blind, randomised controlled feasibility trial of an internet intervention developed to support the self-management of LBP in primary care. Patients are being randomised to 1 of 3 groups receiving either usual primary care, usual primary care with the addition of an internet intervention or an internet intervention with physiotherapist telephone support. Patients are followed up at 3 months. Primary outcomes are the feasibility of (1) the trial design/methods, (2) the delivery of the internet intervention and (3) the provision of telephone support by physiotherapists. Secondary outcomes will include exploratory analysis of estimates and variation in clinical outcomes of pain and disability, in order to inform a future main trial.
Ethics/dissemination
This feasibility trial has undergone ethical scrutiny and been approved by the National Health Service (NHS) Research Ethics Committee, REC Reference 13/SC/0202. The feasibility findings will be disseminated to the research community through presentations at conferences and publication in peer review journals. Broader dissemination will come following a definitive trial.
Trial registration number
ISRCTN 31034004.
doi:10.1136/bmjopen-2015-009524
PMCID: PMC4593135  PMID: 26399575
PRIMARY CARE; REHABILITATION MEDICINE
14.  Exploring Experiences and Perceptions of Aging and Cognitive Decline Across Diverse Racial and Ethnic Groups 
Gerontology and geriatric medicine  2015;1:2333721415596101.
Objective: To explore how older adults from three prominent ethnoracial groups experience cognitive decline and aging. Method: Semistructured key informant interviews (KIIs) and focus groups (FGs) were conducted with caregivers, experts, and older adults. Results: (N = 75). Fifteen KIIs regarding cognitive aging issues were conducted among health care professionals and community-based agencies serving older adults. Eight FGs included family caregivers and physicians, and six FGs with Latino, African American, and White older adult community members. Major themes included (a) personal expectations about aging, (b) societal value of older adults, (c) model of care preferred, and (d) community concerns. An overarching theme was a sense of loss associated with aging; however, how this loss was experienced and dealt with varied. Discussion: Distinct patterns of concerns and views are important to understand for the development of programs aimed at meeting the needs of diverse older adult community members to improve health outcomes.
doi:10.1177/2333721415596101
PMCID: PMC4766862  PMID: 26925436
perceptions of aging; cognitive decline; diverse racial and ethnic groups
15.  JAK2V617F Drives Mcl-1 Expression and Sensitizes Hematologic Cell Lines to Dual Inhibition of JAK2 and Bcl-xL 
PLoS ONE  2015;10(3):e0114363.
Constitutive activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) axis is fundamental to the molecular pathogenesis of a host of hematological disorders, including acute leukemias and myeloproliferative neoplasms (MPN). We demonstrate here that the major JAK2 mutation observed in these diseases (JAK2V617F) enforces Mcl-1 transcription via STAT3 signaling. Targeting this lesion with JAK inhibitor I (JAKi-I) attenuates STAT3 binding to the Mcl-1 promoter and suppresses Mcl-1 transcript and protein expression. The neutralization of Mcl-1 in JAK2V617F-harboring myelodyssplastic syndrome cell lines sensitizes them to apoptosis induced by the BH3-mimetic and Bcl-xL/Bcl-2 inhibitor, ABT-263. Moreover, simultaneously targeting JAK and Bcl-xL/-2 is synergistic in the presence of the JAK2V617F mutation. These findings suggest that JAK/Bcl-xL/-2 inhibitor combination therapy may have applicability in a range of hematological disorders characterized by activating JAK2 mutations.
doi:10.1371/journal.pone.0114363
PMCID: PMC4362760  PMID: 25781882
16.  Screening of a large cohort of Leber congenital amaurosis and retinitis pigmentosa patients identifies novel LCA5 mutations and new genotype-phenotype correlations 
Human mutation  2013;34(11):1537-1546.
To investigate the prevalence of sequence variants in LCA5 in patients with Leber congenital amaurosis (LCA), early onset rod-cone dystrophy (EORD) and autosomal recessive retinitis pigmentosa (RP), to delineate the ocular phenotypes, and to provide an overview of all published LCA5 variants in an online database._Patients underwent standard ophthalmic evaluations after providing informed consent. In selected patients, optical coherence tomography (OCT) and fundus autofluorescence imaging was possible. DNA samples from 797 unrelated patients with LCA and 211 with the various types of RP were screened by Sanger sequence analysis of all LCA5 exons and intron/exon junctions. Some LCA patients were pre-screened by APEX technology or selected based on homozygosity mapping. In silico analyses were performed to assess the pathogenicity of the variants. Segregation analysis was performed where possible. Published and novel LCA5 variants were collected, amended for their correct nomenclature, and listed in a Leiden Open Variation Database (LOVD). Sequence analysis identified 18 new probands with 19 different LCA5 variants. Seventeen of the 19 LCA5 variants were novel. Except for two missense variants and one splice site variant, all variants were protein-truncating mutations. Most patients expressed a severe phenotype, typical of LCA. However, some LCA subjects had better vision and intact inner segment/outer segment (IS/OS) junctions on OCT imaging. In two families with LCA5 variants, the phenotype was more compatible with EORD with affected individuals displaying preserved islands of RPE. One of these milder families harbored a homozygous splice site mutation, a second family was found to have a combination of a stop mutation and a missense mutation. This is the largest LCA5 study to date. We sequenced 1008 patients (797 with LCA, 211 with arRP) and identified 18 probands with LCA5 mutations. Mutations in LCA5 are a rare cause of childhood retinal dystrophy accounting for ~2% of disease in this cohort and the majority of LCA5 mutations are likely null. The LCA5 protein truncating mutations are predominantly associated with LCA. However, in two families with the milder EORD, the LCA5 gene analysis revealed a homozygous splice site mutation in one and a stop mutation in combination with a missense mutation in a second family, suggesting that this milder phenotype is due to residual function of lebercilin and expanding the currently known phenotypic spectrum to include the milder early onset RP. Some patients have remaining foveal cone structures (intact IS/OS junctions on OCT imaging) and remaining visual acuities, which may bode well for upcoming treatment trials.
doi:10.1002/humu.22398
PMCID: PMC4337959  PMID: 23946133
LCA; RP; retinal dystrophy; blindness; LCA5; lebercilin
17.  Murine Norovirus 1 (MNV1) Replication Induces Translational Control of the Host by Regulating eIF4E Activity during Infection* 
The Journal of Biological Chemistry  2015;290(8):4748-4758.
Background: The phosphorylation of eIF4E plays a critical role in controlling protein translation.
Results: MNV1 infection results in activation of p-eIF4E, its relocation to polysomes, and translational regulation.
Conclusion: MNV1 manipulates the host cell translation machinery by controlling eIF4E activity.
Significance: Regulation of cellular response to infection may contribute to viral pathogenesis and persistence.
Protein synthesis is a tightly controlled process responding to several stimuli, including viral infection. As obligate intracellular parasites, viruses depend on the translation machinery of the host and can manipulate it by affecting the availability and function of specific eukaryotic initiation factors (eIFs). Human norovirus is a member of the Caliciviridae family and is responsible for gastroenteritis outbreaks. Previous studies on feline calicivirus and murine norovirus 1 (MNV1) demonstrated that the viral protein, genome-linked (VPg), acts to direct translation by hijacking the host protein synthesis machinery. Here we report that MNV1 infection modulates the MAPK pathway to activate eIF4E phosphorylation. Our results show that the activation of p38 and Mnk during MNV1 infection is important for MNV1 replication. Furthermore, phosphorylated eIF4E relocates to the polysomes, and this contributes to changes in the translational state of specific host mRNAs. We propose that global translational control of the host by eIF4E phosphorylation is a key component of the host-pathogen interaction.
doi:10.1074/jbc.M114.602649
PMCID: PMC4335213  PMID: 25561727
Eukaryotic Translation Initiation Factor 4E (eIF4E); Host-Pathogen Interaction; Mitogen-activated Protein Kinase (MAPK); Protein Synthesis; RNA Virus; Translation Control
19.  Stargardt Disease: towards developing a model to predict phenotype 
European Journal of Human Genetics  2013;21(10):1173-1176.
Stargardt disease is an ABCA4-associated retinopathy, which generally follows an autosomal recessive inheritance pattern and is a frequent cause of macular degeneration in childhood. ABCA4 displays significant allelic heterogeneity whereby different mutations can cause retinal diseases with varying severity and age of onset. A genotype–phenotype model has been proposed linking ABCA4 mutations, purported ABCA4 functional protein activity and severity of disease, as measured by degree of visual loss and the age of onset. It has, however, been difficult to verify this model statistically in observational studies, as the number of individuals sharing any particular mutation combination is typically low. Seven founder mutations have been identified in a large number of Caucasian Afrikaner patients in South Africa, making it possible to test the genotype–phenotype model. A generalised linear model was developed to predict and assess the relative pathogenic contribution of the seven mutations to the age of onset of Stargardt disease. It is shown that the pathogenicity of an individual mutation can differ significantly depending on the genetic context in which it occurs. The results reported here may be used to identify suitable candidates for inclusion in clinical trials, as well as guide the genetic counselling of affected individuals and families.
doi:10.1038/ejhg.2013.92
PMCID: PMC3778365  PMID: 23695285
ABCA4; age of onset; generalised linear model; genotype–phenotype; Stargardt disease
20.  Opening clinical encounters in an adult musculoskeletal setting 
Manual Therapy  2014;19(4):306-310.
Effective communication between healthcare professionals and their patients is crucial for successful consultations, and can profoundly affect patients' adherence to treatment. Despite this evidence, communication within the physiotherapy profession is still underexplored, in particular, how ‘best’ to open clinical encounters. This study explores the issue by seeking the preferences of physiotherapists for opening encounters in the adult musculoskeletal outpatient setting. Initially, 42 consultations and 17 first follow-up encounters were observed between qualified physiotherapists and patients with back pain. These encounters were audio-recorded, analysed and used to develop a questionnaire to determine clinicians' preferences for opening encounters. From these findings, a synopsis of the questionnaire was posted on the four most-relevant professional networks of the national, interactive Chartered Society of Physiotherapy (iCSP) website, to canvass opinion more widely. Among the 43 physiotherapists who responded, the preferred ‘key clinical question’ for an initial encounter was: “Do you want to just tell me a little bit about [your ‘problem presentation’] first of all?”; and for follow-up encounters: ‘How have you been since I last saw you?’ These results provide an important and novel contribution to the profession, as debate on this issue has not previously been published. Although the sample size in this study is small, the aim of this paper is to generate reflection and debate among clinicians on their preferences for opening patient encounters and optimising the non-specific treatment effects.
doi:10.1016/j.math.2014.03.011
PMCID: PMC4077240  PMID: 24809241
Communication; Interaction; History-taking; Musculoskeletal; Physiotherapy
21.  A Design to Investigate the Feasibility and Effects of Partnered Ballroom Dancing on People With Parkinson Disease: Randomized Controlled Trial Protocol 
JMIR Research Protocols  2014;3(3):e34.
Background
Self-help and physical leisure activities has become increasingly important in the maintenance of safe and functional mobility among an increasingly elderly population. Preventing the cycle of deterioration, falling, inactivity, dependency, and secondary complications in people with Parkinson disease (PD) is a priority. Research has shown that people with PD are interested in dance and although the few existing trials are small, initial proof of principle trials from the United States have demonstrated beneficial effects on balance control, gait, and activity levels. To our knowledge, there has been no research into long-term effects, cost effectiveness, the influence on spinal posture and turning, or the personal insights of dance participants.
Objective
The purpose of this study was to determine the methodological feasibility of conducting a definitive phase III trial to evaluate the benefits of dance in people with PD. We will build on the proof of principle trials by addressing gaps in knowledge, focusing on areas of greatest methodological uncertainty; the choice of dances and intensity of the program; for the main trial, the availability of partners, the suitability of the currently envisaged primary outcomes, balance and spinal posture; and the key costs of delivering and participating in a dance program to inform economic evaluation.
Methods
Fifty participants (mild-to-moderate condition) will be randomized to the control (usual care) or experimental (dance plus usual care) groups at a ratio of 15:35. Dance will be taught by professional teachers in a dance center in the South of England. Each participant in the experimental group will dance with his or her spouse, a friend, or a partner from a bank of volunteers. A blinded assessor will complete clinical measures and self-reported ability at baseline, and at 3 and 6 months after randomization. A qualitative study of a subgroup of participants and partners will examine user’s views about the appropriateness and acceptability of the intervention, assessment protocol, and general trial procedures. Procedures for an economic evaluation of dance for health care will be developed for the main trial.
Results
Recruitment began in January 2013 and the last participant is expected to complete the trial follow-up in June 2014.
Conclusions
Findings from our study may provide novel insights into the way people with PD become involved in dance, their views and opinions, and the suitability of our primary and secondary outcomes.
Trial Registration
International Standard Randomized Controlled Trial Number (ISRCTN): 63088686; http://www.controlled-trials.com/ISRCTN63088686/63088686 (Archived by WebCite at http://www.webcitation.org/6QYyjehP7).
doi:10.2196/resprot.3184
PMCID: PMC4137144  PMID: 25051989
Parkinson disease; ballroom dancing; balance; posture
22.  A mutation in a splicing factor that causes retinitis pigmentosa has a transcriptome-wide effect on mRNA splicing 
BMC Research Notes  2014;7:401.
Background
Substantial progress has been made in the identification of sequence elements that control mRNA splicing and the genetic variants in these elements that alter mRNA splicing (referred to as splicing quantitative trait loci – sQTLs). Genetic variants that affect mRNA splicing in trans are harder to identify because their effects can be more subtle and diffuse, and the variants are not co-located with their targets. We carried out a transcriptome-wide analysis of the effects of a mutation in a ubiquitous splicing factor that causes retinitis pigmentosa (RP) on mRNA splicing, using exon microarrays.
Results
Exon microarray data was generated from whole blood samples obtained from four individuals with a mutation in the splicing factor PRPF8 and four sibling controls. Although the mutation has no known phenotype in blood, there was evidence of widespread differences in splicing between cases and controls (affecting approximately 20% of exons). Most probesets with significantly different inclusion (defined as the expression intensity of the exon divided by the expression of the corresponding transcript) between cases and controls had higher inclusion in cases and corresponded to exons that were shorter than average, AT rich, located towards the 5’ end of the gene and flanked by long introns. Introns flanking affected probesets were particularly depleted for the shortest category of introns, associated with splicing via intron definition.
Conclusions
Our results show that a mutation in a splicing factor, with a phenotype that is restricted to retinal tissue, acts as a trans-sQTL cluster in whole blood samples. Characteristics of the affected exons suggest that they are spliced co-transcriptionally and via exon definition. However, due to the small sample size available for this study, further studies are required to confirm the widespread impact of this PRPF8 mutation on mRNA splicing outside the retina.
doi:10.1186/1756-0500-7-401
PMCID: PMC4084799  PMID: 24969741
mRNA splicing; Retinitis pigmentosa; Exon array; PRPF8
23.  Norovirus Translation Requires an Interaction between the C Terminus of the Genome-linked Viral Protein VPg and Eukaryotic Translation Initiation Factor 4G* 
The Journal of Biological Chemistry  2014;289(31):21738-21750.
Background: Noroviruses use a virus-encoded protein, VPg, covalently linked to the viral RNA for translation.
Results: The direct interaction of VPg with the central domain of eIF4G is required for norovirus translation.
Conclusion: eIF4G plays a central role in norovirus VPg-dependent translation initiation.
Significance: The VPg-eIF4G interaction may provide a suitable target for the specific inhibition of norovirus translation.
Viruses have evolved a variety of mechanisms to usurp the host cell translation machinery to enable translation of the viral genome in the presence of high levels of cellular mRNAs. Noroviruses, a major cause of gastroenteritis in man, have evolved a mechanism that relies on the interaction of translation initiation factors with the virus-encoded VPg protein covalently linked to the 5′ end of the viral RNA. To further characterize this novel mechanism of translation initiation, we have used proteomics to identify the components of the norovirus translation initiation factor complex. This approach revealed that VPg binds directly to the eIF4F complex, with a high affinity interaction occurring between VPg and eIF4G. Mutational analyses indicated that the C-terminal region of VPg is important for the VPg-eIF4G interaction; viruses with mutations that alter or disrupt this interaction are debilitated or non-viable. Our results shed new light on the unusual mechanisms of protein-directed translation initiation.
doi:10.1074/jbc.M114.550657
PMCID: PMC4118132  PMID: 24928504
Eukaryotic Translation Initiation Factor 4E (eIF4E); Plus-stranded RNA Virus; Translation; Translation Initiation Factor; Virus; VPg; eIF4G; Norovirus
24.  IRES-Mediated Translation of Membrane Proteins and Glycoproteins in Eukaryotic Cell-Free Systems 
PLoS ONE  2013;8(12):e82234.
Internal ribosome entry site (IRES) elements found in the 5′ untranslated region of mRNAs enable translation initiation in a cap-independent manner, thereby representing an alternative to cap-dependent translation in cell-free protein expression systems. However, IRES function is largely species-dependent so their utility in cell-free systems from different species is rather limited. A promising approach to overcome these limitations would be the use of IRESs that are able to recruit components of the translation initiation apparatus from diverse origins. Here, we present a solution to this technical problem and describe the ability of a number of viral IRESs to direct efficient protein expression in different eukaryotic cell-free expression systems. The IRES from the intergenic region (IGR) of the Cricket paralysis virus (CrPV) genome was shown to function efficiently in four different cell-free systems based on lysates derived from cultured Sf21, CHO and K562 cells as well as wheat germ. Our results suggest that the CrPV IGR IRES-based expression vector is universally applicable for a broad range of eukaryotic cell lysates. Sf21, CHO and K562 cell-free expression systems are particularly promising platforms for the production of glycoproteins and membrane proteins since they contain endogenous microsomes that facilitate the incorporation of membrane-spanning proteins and the formation of post-translational modifications. We demonstrate the use of the CrPV IGR IRES-based expression vector for the enhanced synthesis of various target proteins including the glycoprotein erythropoietin and the membrane proteins heparin-binding EGF-like growth factor receptor as well as epidermal growth factor receptor in the above mentioned eukaryotic cell-free systems. CrPV IGR IRES-mediated translation will facilitate the development of novel eukaryotic cell-free expression platforms as well as the high-yield synthesis of desired proteins in already established systems.
doi:10.1371/journal.pone.0082234
PMCID: PMC3869664  PMID: 24376523
25.  Structures of the Compact Helical Core Domains of Feline Calicivirus and Murine Norovirus VPg Proteins 
Journal of Virology  2013;87(10):5318-5330.
We report the solution structures of the VPg proteins from feline calicivirus (FCV) and murine norovirus (MNV), which have been determined by nuclear magnetic resonance spectroscopy. In both cases, the core of the protein adopts a compact helical structure flanked by flexible N and C termini. Remarkably, while the core of FCV VPg contains a well-defined three-helix bundle, the MNV VPg core has just the first two of these secondary structure elements. In both cases, the VPg cores are stabilized by networks of hydrophobic and salt bridge interactions. The Tyr residue in VPg that is nucleotidylated by the viral NS7 polymerase (Y24 in FCV, Y26 in MNV) occurs in a conserved position within the first helix of the core. Intriguingly, given its structure, VPg would appear to be unable to bind to the viral polymerase so as to place this Tyr in the active site without a major conformation change to VPg or the polymerase. However, mutations that destabilized the VPg core either had no effect on or reduced both the ability of the protein to be nucleotidylated and virus infectivity and did not reveal a clear structure-activity relationship. The precise role of the calicivirus VPg core in virus replication remains to be determined, but knowledge of its structure will facilitate future investigations.
doi:10.1128/JVI.03151-12
PMCID: PMC3648151  PMID: 23487472

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