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2. Books

Author

Sovka, David and Palmer, Donna

Published
2003

3. Mapping axon initial segment structure and function by multiplexed proximity biotinylation.

Author

Hamdan, Hamdan, Lim, Brian C, Torii, Tomohiro, Joshi, Abhijeet, Konning, Matthias, Smith, Cameron, Palmer, Donna J, Ng, Philip, Leterrier, Christophe, Oses-Prieto, Juan A, Burlingame, Alma L, and Rasband, Matthew N

Subjects
Neurons, Axons, Animals, Humans, Mice, Rats, Rats, Sprague-Dawley, Proteome, Biotinylation, Protein Transport, Mass Spectrometry, Axon Initial Segment, Sprague-Dawley
Abstract

Axon initial segments (AISs) generate action potentials and regulate the polarized distribution of proteins, lipids, and organelles in neurons. While the mechanisms of AIS Na+ and K+ channel clustering are understood, the molecular mechanisms that stabilize the AIS and control neuronal polarity remain obscure. Here, we use proximity biotinylation and mass spectrometry to identify the AIS proteome. We target the biotin-ligase BirA* to the AIS by generating fusion proteins of BirA* with NF186, Ndel1, and Trim46; these chimeras map the molecular organization of AIS intracellular membrane, cytosolic, and microtubule compartments. Our experiments reveal a diverse set of biotinylated proteins not previously reported at the AIS. We show many are located at the AIS, interact with known AIS proteins, and their loss disrupts AIS structure and function. Our results provide conceptual insights and a resource for AIS molecular organization, the mechanisms of AIS stability, and polarized trafficking in neurons.

Published
2020

4. Brainmarker-I Differentially Predicts Remission to Various Attention-Deficit/Hyperactivity Disorder Treatments: A Discovery, Transfer, and Blinded Validation Study

Author

Voetterl, Helena, van Wingen, Guido, Michelini, Giorgia, Griffiths, Kristi R., Gordon, Evian, DeBeus, Roger, Korgaonkar, Mayuresh S., Loo, Sandra K., Palmer, Donna, Breteler, Rien, Denys, Damiaan, Arnold, L. Eugene, du Jour, Paul, van Ruth, Rosalinde, Jansen, Jeanine, van Dijk, Hanneke, and Arns, Martijn

Published
2023
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6. Conditional disruption of hepatic carbamoyl phosphate synthetase 1 in mice results in hyperammonemia without orotic aciduria and can be corrected by liver-directed gene therapy

Author

Khoja, Suhail, Nitzahn, Matt, Hermann, Kip, Truong, Brian, Borzone, Roberta, Willis, Brandon, Rudd, Mitchell, Palmer, Donna J, Ng, Philip, Brunetti-Pierri, Nicola, and Lipshutz, Gerald S

Subjects
Medical Biotechnology, Biomedical and Clinical Sciences, Nutrition, Gene Therapy, Liver Disease, Biotechnology, Digestive Diseases, Genetics, Neurosciences, Development of treatments and therapeutic interventions, 5.2 Cellular and gene therapies, Ammonia, Animals, Carbamoyl-Phosphate Synthase (Ammonia), Carbamoyl-Phosphate Synthase I Deficiency Disease, Carbamyl Phosphate, Female, Gene Expression Regulation, Enzymologic, Genetic Therapy, Glutamine, Humans, Hyperammonemia, Liver, Male, Mice, Mice, Knockout, Mutation, Orotate Phosphoribosyltransferase, Orotidine-5'-Phosphate Decarboxylase, Purine-Pyrimidine Metabolism, Inborn Errors, Carbamoyl phosphate, synthetase deficiency, Gene therapy, Clinical Sciences, Genetics & Heredity, Clinical sciences
Abstract

Carbamoyl phosphate synthetase 1 (CPS1) is a urea cycle enzyme that forms carbamoyl phosphate from bicarbonate, ammonia and ATP. Bi-allelic mutations of the CPS1 gene result in a urea cycle disorder presenting with hyperammonemia, often with reduced citrulline, and without orotic aciduria. CPS1 deficiency is particularly challenging to treat and lack of early recognition typically results in early neonatal death. Therapeutic interventions have limited efficacy and most patients develop long-term neurologic sequelae. Using transgenic techniques, we generated a conditional Cps1 knockout mouse. By loxP/Cre recombinase technology, deletion of the Cps1 locus was achieved in adult transgenic animals using a Cre recombinase-expressing adeno-associated viral vector. Within four weeks from vector injection, all animals developed hyperammonemia without orotic aciduria and died. Minimal CPS1 protein was detectable in livers. To investigate the efficacy of gene therapy for CPS deficiency following knock-down of hepatic endogenous CPS1 expression, we injected these mice with a helper-dependent adenoviral vector (HDAd) expressing the large murine CPS1 cDNA under control of the phosphoenolpyruvate carboxykinase promoter. Liver-directed HDAd-mediated gene therapy resulted in survival, normalization of plasma ammonia and glutamine, and 13% of normal Cps1 expression. A gender difference in survival suggests that female mice may require higher hepatic CPS1 expression. We conclude that this conditional murine model recapitulates the clinical and biochemical phenotype detected in human patients with CPS1 deficiency and will be useful to investigate ammonia-mediated neurotoxicity and for the development of cell- and gene-based therapeutic approaches.

Published
2018

11. Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial

Author

Scarborough, Matthew, Kamfose, Musa, de Veciana, Ana, Gordon, Nicola Claire, Peto, Leon, Pill, Gemma, Clarke, Tiphanie, Watson, Laura, Young, Bernadette, Griffiths, Dai, Vaughn, Ali, Anson, Luke, Liu, Elian, Perera, Sanuki, Rylance-Knight, Lydia, Cantell, Carmen, Moroney, Ruth, Edgeworth, Jonathan D, Thwaites, Guy, Bisnauthsing, Karen, Querol-Rubiera, Antonio, Gibbs, Charlotte, Patel, Amita, Hemsley, Carolyn, Goodman, Anna L, Wyncoll, Duncan, Biswas, Jason, Fitzpatrick, Jennifer, Roberts, Lizzie, Millard, James, Stone, Neil, Cape, Angela, Hurley, Lisa, Tam, Chi Kai, Nsutebu, Emmanuel, Hoyle, Marie-Claire, Maitland, Kate, Trainor, Leona, Reynolds, Helen, Harrison, Jennifer, Anson, Jim, Lewis, Joseph, Folb, Jonathan, Goodwin, Lynsey, Beeching, Nicholas, Dyas, Sarah, Winslow, Helen, Foote, Elizabeth, Roberts, Paul, Natarajan, Pavithra, Chrdle, Alex, Fenech, Manuel, Allsop, Hannah, Tilley, Robert, Austin-Hutchison, Rachel, Barrett, Louise, Brookes, Karen, Carwithen, Leanne, Conbeer, Andrew, Cunningham, Richard, Eglinton, Charlotte, Fok, Rosie, Gott, Hannah, Hughes, Shona, Jones, Lewis, Kalita, Maggie, King, Angela, March, Linda, Marner, Mike, Mynes, Tracey, Plant, Aiden, Price, Suzanne, Sercombe, Judy, Stolton, Alison, Wallis, Mark, West, Marie-Claire, Westcott, Jackie, Williams, Claire, Wosley, Rob, Yabsley, Leona, Greig, Julia, Butland, Laura, Sorrell, Julie, Mitchell, Tamara, Alli, Abiola, Meiring, James, Masake, Boingotlo, Rowson, Carlene, Smart, Lynne, Makey, Laura, Moll, Sarah, Cunningham, Jane, Ryalls, Kim, Birchall, Kathryn, Middle, Janet, Jackson, Yvonne, Swift, Diane, Cole, Joby, Subramanian, Bala, Okhuoya, Faith, Edwards, Maria, Bailey, Cheryl, Warren, Rebecca, Islam, Gayti, Ankcorn, Michael, Birchall, Sarah, Jones, Paul, Humphries, John, Booth, Stephen, Evan, Cariad, Wyllie, Sarah, Flatt, Andrew, Strakova, Lenka, Hayes, Maria, Valentine, Stacey, James, Clare, Wands, Mary, Cortes, Nicolas, Khan, Nisa, Porter, Robert, Martin, Zoe, Yip, Keith, Preedy, Helen, Chesterfield, Helen, Dobson, Tracey, Walker, Colin, Llewelyn, Martin, Dunne, Angela, Latter, Laura, Porges, Alison, Price, James, Paul, John, Behar, Laura, Robinson, Louise, Murray, Amy, Sargent, Tenessa, Ridley, Carrie, de Gordoa, Laura Ortiz-Ruiz, Gilliam, Deborah, McPherson, Carole, Matthews, Simon, Foreman, Emma, Jarghese, Rajesh, Beddoe, Alisha, Martin, Sebastien, Shaw, Sephora, Wlazly, Dominika, Cole, Maggie, Gihawi, Abraham, Cole, Kevin, Török, M Estée, Gouliouris, Theodore, Bedford, Luke, Saunderson, Rebecca B, Mariolis, Ilias, Bousfield, Rachel, Ramsay, Isobel, Greaves, Daniel, Aliyu, Sani, Cox, Kim, Mlemba, Lois, Whitehead, Lynne, Vyse, Naval, Bolton, Mark, Williams, John, Lambert, Pauline, Chadwick, David, Baillie, Kirsty, Cain, Martyn, Bellamy, Richard, Wong, Jason, Thompson, Jane, Vassallo, Helen, Skotnicka, Agnieszka, Boyce, Andrea, Donnelly, Anthony, Wilson, Peter, FitzGerald, Graham, Dean, Victoria, Warnes, Kristian, Reyes, Anna, Rahman, Saadia, Tsang, Lillian, Williams, Joanne, Morris-Jones, Stephen, Hopkins, Susan, Witness, Elen, Brady, Orla, Woodford, Elizabeth, Pettifer, Teresa, McCadden, Angela, Marks, Ben, Collier, Sophie, Mack, Damien, Warren, Simon, Brown, Colin, Lyons, Adrian, Taiyari, Sara, Mepham, Stephen, Sweeney, Anna, Brown, Li-An, Auckland, Cressida, Potter, Alison, Mandiza, Jess, Hough, Maxine, Williams, Sue, Renton, Caroline, Walters, Fiona, Nadolski, Maria, Evans, Andree, Tarrant, Polly, Curley, Katherine, Whiteley, Sophie, Halpin, Julia, Hutchings, Melanie, Todd, Shirley, Lohan, Christop, Chapter, Tamika, Folland, Emma, Colville, Alaric, Marden, Katy, Morgan, Marina, Porter, Rob, Baxter, Mel, Minton, Jane, Rippon, Sarah, Cevik, Muge, Chapman, Judith, Kemp, Tim, Vincent, Rachel, Osborne, Dave, Platt, Tracey, Calderwood, James, Cook, Bernadette, Bedford, Caroline, Galloway-Browne, Leanne, Abberley, Nadine, Attack, Kelly, Allen, Joanna, Lal, Pankaj, Harrison, Melanie, Stevenson, Sarah, Brooks, Carol, Harlow, Paula, Ewing, Jordan, Cooper, Shirley, Balancio-Tolentino, Roderick, O'Neil, Laura, Tagney, Rebecca, Shackcloth, Daniela, Planche, Tim, Fellows, James, Millett, Ruth, Studham, Jo, de Souza, Cherrelle, Howell, Geoffrey, Greaves, Hezron, Foncel, Ella, Kurup, Rahul, Briggs, Jack, Smith, Melody, Suarez, Cristina, Sorrentino, Giordana, Scobie, Antonia, Houston, Angela, Ahmad, Fozia, Breathnach, Aodhan, Chahuan, Rakhee, Wilkins, Katie, Guleri, Achyut, Waddington, Natalia, Sharma, Rashmi, Flegg, Peter, Kollipara, Veenu, Alam, Mazhar, Potter, Andrew, Donaldson, Stacey, Armer, Charlote, Frudd, Julie, Jeyaratnam, Dakshika, Joy, Manju, Mathews, Asha, Glass, Stephen K, Ajayi, Ayodele, Fife, Amanda, Qaiser, Saba, Sheehan, Sharon, Muñoz-Villaverde, Sergio, Yogo, Noah, De Abreu, Ines, Notcheva, Gaynor, Flanagan, Joanna, Watson, Cordelia, Sais, Efisia, Adedayo, Adetunji, Chu, Vicky, Shaw, Georgina, Graver, Michelle A, Palmer, Rebecca, Palmer, Donna, Haile, Senait, Gordon, Joanne, Mandar, Kirandip, Szypura, Weronika, Jenkins, Neil, Marange, Josephine, Shabangu, Vusumuzi, Moore, Katy, Lyons, Jill, Munang, Melinda, Sangombe, Mirriam, Moran, Ed, Hussain, Abid, Wiselka, Martin, Lewszuk, Adam, Batham, Sally, Ellis, Kate, Bahadur, Leila, White, Helena, Pareek, Manish, Sahota, Amandip, Coleman, Stephen, Pateman, Hilary, Kotecha, Atul, Sim, Christopher, Rosser, Andrew, Deane, Jill, Nendick, Richard, Aldridge, Catherine, Clarke, Anne, Wood, Michelle, Marshall, Adele, Stephenson, Lynsey, Matheson-Smith, Tracy, Sloss, John, Potts, Kathryn, Malkin, Joanne, Ftika, Lemonia, Raviprakash, Veena, Sutton, Julian, Malachira, Ahalya, Kean, Miranda, Criste, Kristine, Gladas, Kirsty, Andrews, Caroline, Hutchison, Clare, Adams, Ellen, Andrews, Janet, Romans, Belinda, Ridley, Nicola, Ekani, Melanie, Mitchell, Julie, Smith, Nicola, Clark, Tristan, Glover, Sarah, Reed, Robert, Yam, Tat, Burton, Holly, Said, Rasha, Harvey, David, Janvier, Amy, Jacob, Reni, Smalley, Chris, Fair, Alison, Lord, Susan, Ripalda, Kate, Wooldridge, Helen, Cotter, Luis, Cardoso, Gus, Strachan, Elaine, Kaler, Gagan, Mohamoodally, Adam, Lawrence, Emma, Prime, Zoe, Abrahams, Rachel, Price, David Ashley, Rigden, Lesley, Shewan, Laura, Cullen, Katherine, Emmerson, Ingrid, Martin, Karen, Wilson, Hesther, Higham, Charley, Taylor, Kathryn Louise, Ong, Edmund, Patel, Bijal, Bond, Helena, Gradwell, Janine, Widdrington, John, Graham, Clive, Thornthwaite, Sarah, Prentice, Scott, Poultney, Una, Crowther, Hannah, Fairlamb, Helen, Hetherington, Emily, Brewer, Chris, Banerjee, Suryabrata, Hamson, Clare, McSkeane, Anna, McWhinney, Paul, Sharratt, Paula, Thorpe, Joanne, Kimachia, Sue, Wilson, Helen, Jeffs, Benjamin, Masters, Leslie, Wilson, Jonathan, Platt, Judith, Burgess, Lisa, Chadwick, Paul, Jeans, Adam, Keatley, Claire, Moran, Amanda, Swann, Zoe, Pagett, Katherine, Peel, Alex, Howard, Jason, Meisner, Sarah, Maloney, Kate, Masdin, Avril, Wright, Louise, Barlow, Gavin, Crossman, Samantha, Lowthorpe, Vicki, Moore, Emma, Moss, Peter, Parkin, Angela, Wolstencroft, Adam, Warner, Bev, Tarbotton, Clare, Eyre, Alison, Anderson, Anne, Burdett, Tina, Driffill, Amy, Walker, Ann Sarah, Hudson, Fleur, Szubert, Alex, Cairns, Janet, Ward, Denise, Webb, Helen, Russell, Charlotte, Jackson, Brooke, Otiko, Damilola, Borg, Chiara, Masters, Lindsey, Islam, Zaheer, Díaz-Montaña, Carlos, Johnson, Debbie, Thwaites, Guy E, Szubert, Alexander, Wyllie, Sarah A, Armando, Gonzalez-Ruiz, Chadwick, Paul R, Gordon, N Claire, Price, David A, Nayar, Deepa, Török, M Estee, Llewelyn, Martin J, and Walker, A Sarah

Published
2018
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12. Solute effects on the properties of supercritical solutions

Author

Palmer, Donna Jade

Subjects
543.86
Abstract

Supercritical (sc) fluids are extensively used for material processing and carbon dioxide is the most commonly used solvent. In these solutions, solute-solvent interactions consist primarily of Van der Waals forces and the small amount of data published shows that the solute has only a small effect on solution structure. The use of more polar solvents allows high concentrations of polar solutes to be dissolved resulting in more ordered solutions. This has an effect on clustering and mass transport. The aim of this thesis is to investigate solute-solute-solvent interactions in sc difluoromethane and to quantify the effect on solution viscosity for the first time. The local composition about the solvatochromic probe has been measured as a function of pressure and solute polarity and the Kamlet-Taft polarisability/dipolarity and hydrogen bond donor parameters determined. Variations in these solvent properties are understood in terms of solute aggregation and a model for solvation is proposed. The use of a piezoelectric quartz crystal as a reliable high-pressure viscometer is proposed and used to determine the viscosity of sc solutions as a function of pressure and solute polarity. A modification of the Dole-Jones equation is used to model the viscosity of simple sc solutions and the volume fraction of solute is shown to be the key factor affecting solution viscosity. Rapid expansion of supercritical solutions (RESS) is a technique used to reduce particle size and alter morphology of pharmaceuticals. As with most sc processes carbon dioxide has been the solvent of choice, but many pharmaceuticals are polar compounds or salts, which suffer from low solubility. Here the applicability of sc difluoromethane for precipitation of materials by RESS is presented.

Published
2006

16. Nitric oxide modulates bone anabolism through regulation of osteoblast glycolysis and differentiation

Author

Jin, Zixue, Kho, Jordan, Dawson, Brian, Jiang, Ming-Ming, Chen, Yuqing, Ali, Saima, Burrage, Lindsay C., Grover, Monica, Palmer, Donna J., Turner, Dustin L., Ng, Philip, Nagamani, Sandesh C.S., and Lee, Brendan

Subjects
Osteoblasts -- Growth, Nitric oxide -- Health aspects, Cell differentiation -- Health aspects, Glycolysis -- Health aspects, Lyases -- Health aspects, Company growth, Health care industry
Abstract

Previous studies have shown that nitric oxide (NO) supplements may prevent bone loss and fractures in preclinical models of estrogen deficiency. However, the mechanisms by which NO modulates bone anabolism remain largely unclear. Argininosuccinate lyase (ASL) is the only mammalian enzyme capable of synthesizing arginine, the sole precursor for nitric oxide synthase-dependent (NOS-dependent) NO synthesis. Moreover, ASL is also required for channeling extracellular arginine to NOS for NO production. ASL deficiency (ASLD) is thus a model to study cell-autonomous, NOS-dependent NO deficiency. Here, we report that loss of ASL led to decreased NO production and impairment of osteoblast differentiation. Mechanistically, the bone phenotype was at least in part driven by the loss of NO-mediated activation of the glycolysis pathway in osteoblasts that led to decreased osteoblast differentiation and function. Heterozygous deletion of caveolin 1, a negative regulator of NO synthesis, restored NO production, osteoblast differentiation, glycolysis, and bone mass in a hypomorphic mouse model of ASLD. The translational significance of these preclinical studies was further reiterated by studies conducted in induced pluripotent stem cells from an individual with ASLD. Taken together, our findings suggest that ASLD is a unique genetic model for studying NO-dependent osteoblast function and that the NO/glycolysis pathway may be a new target to modulate bone anabolism., Introduction Nitric oxide (NO) is an important signaling molecule that influences a wide range of physiological processes, including bone metabolism. Bone is a highly dynamic tissue that is maintained by [...]

Published
2021
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21. Dynamic Dossier in the Cloud: A Sociotechnical Architecture for a Real-Time and Metrics-Based Data Tracking System with Gene and Cell Therapies as a Case Study

Author

Lincoln Laboratory, Massachusetts Institute of Technology. Center for Biomedical Innovation, Nam, Kevin, Larholt, Kay, Hirsch, Gigi, Beninger, Paul, Fritsche, David, Shoda, Diane, Ferguson, John, Bourgeois, Florence T., Palmer, Donna, Katz, Karen, Courtney, Matt W., Lincoln Laboratory, Massachusetts Institute of Technology. Center for Biomedical Innovation, Nam, Kevin, Larholt, Kay, Hirsch, Gigi, Beninger, Paul, Fritsche, David, Shoda, Diane, Ferguson, John, Bourgeois, Florence T., Palmer, Donna, Katz, Karen, and Courtney, Matt W.

Abstract

Background Data sharing among stakeholders in the development, access, and use of drug therapies is critical but the current system and process are inefficient. Methods We take a Systems Engineering approach with a realistic use case to propose a scalable design for multi-stakeholder data sharing. Results We make three major contributions to the drug development and healthcare communities: first, a methodology for developing a multi-stakeholder data sharing system, with its focus on high-level requirements that influence the design of the system architecture and technology choice; second, the development of a realistic use case for long-term patient and therapy data tracking and sharing in the use of potentially curative and durable gene and cell therapies. Further, a bridge for the ‘awareness gap’ was found between the payer (Payer is organization which takes care of financial and operational aspects (which include insurance plans, provider network) of providing health care to US citizens. Or refer to health care insurers.) and the regulator communities by illustrating the common data tracking needs, which highlights the need for coordinated data activities; and third, a proposed system architecture for scalable, multi-stakeholder data sharing. Next steps are briefly discussed. Conclusion We present a system design for multiple stakeholders such as the payer, the regulator, the developer (drug manufacturer), and the healthcare provider to share data for their decision-making. The stakeholder community would benefit from collaboratively moving the system development proposal forward for efficient and cost-effective data sharing.

Published
2022

24. Disruption of MeCP2–TCF20 complex underlies distinct neurodevelopmental disorders

Author

Zhou, Jian, primary, Hamdan, Hamdan, additional, Yalamanchili, Hari Krishna, additional, Pang, Kaifang, additional, Pohodich, Amy E., additional, Lopez, Joanna, additional, Shao, Yingyao, additional, Oses-Prieto, Juan A., additional, Li, Lifang, additional, Kim, Wonho, additional, Durham, Mark A., additional, Bajikar, Sameer S., additional, Palmer, Donna J., additional, Ng, Philip, additional, Thompson, Michelle L., additional, Bebin, E. Martina, additional, Müller, Amelie J., additional, Kuechler, Alma, additional, Kampmeier, Antje, additional, Haack, Tobias B., additional, Burlingame, Alma L., additional, Liu, Zhandong, additional, Rasband, Matthew N., additional, and Zoghbi, Huda Y., additional

Published
2022
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26. Gene transfer of master autophagy regulator TFEB results in clearance of toxic protein and correction of hepatic disease in alpha‐1‐anti‐trypsin deficiency

Author

Pastore, Nunzia, Blomenkamp, Keith, Annunziata, Fabio, Piccolo, Pasquale, Mithbaokar, Pratibha, Maria Sepe, Rosa, Vetrini, Francesco, Palmer, Donna, Ng, Philip, Polishchuk, Elena, Iacobacci, Simona, Polishchuk, Roman, Teckman, Jeffrey, Ballabio, Andrea, and Brunetti‐Pierri, Nicola

Published
2013
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27. Biomarker-based treatment stratification in ADHD: An out-of-sample validation

Author

Voetterl, Helena, primary, Wingen, Guido van, additional, Michelini, Giorgia, additional, Griffiths, Kristi, additional, Gordon, Evian, additional, deBeus, Roger, additional, Korgaonkar, Mayuresh, additional, Loo, Sandra, additional, Palmer, Donna, additional, Breteler, Rien, additional, Denys, Damiaan, additional, Arnold, Eugene, additional, du Jour, Paul, additional, Ruth, Rosalinde van, additional, Jansen, Jeanine, additional, Dijk, Hanneke van, additional, and Arns, Martijn, additional

Published
2021
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28. Dynamic Dossier in the Cloud: A Sociotechnical Architecture for a Real-Time and Metrics-Based Data Tracking System with Gene and Cell Therapies as a Case Study

Author

Nam, Kevin, Larholt, Kay, Hirsch, Gigi, Beninger, Paul, Fritsche, David, Shoda, Diane, Ferguson, John, Bourgeois, Florence T, Palmer, Donna, Katz, Karen, Courtney, Matt W, Nam, Kevin, Larholt, Kay, Hirsch, Gigi, Beninger, Paul, Fritsche, David, Shoda, Diane, Ferguson, John, Bourgeois, Florence T, Palmer, Donna, Katz, Karen, and Courtney, Matt W

Abstract

Background Data sharing among stakeholders in the development, access, and use of drug therapies is critical but the current system and process are inefficient. Methods We take a Systems Engineering approach with a realistic use case to propose a scalable design for multi-stakeholder data sharing. Results We make three major contributions to the drug development and healthcare communities: first, a methodology for developing a multi-stakeholder data sharing system, with its focus on high-level requirements that influence the design of the system architecture and technology choice; second, the development of a realistic use case for long-term patient and therapy data tracking and sharing in the use of potentially curative and durable gene and cell therapies. Further, a bridge for the ‘awareness gap’ was found between the payer (Payer is organization which takes care of financial and operational aspects (which include insurance plans, provider network) of providing health care to US citizens. Or refer to health care insurers.) and the regulator communities by illustrating the common data tracking needs, which highlights the need for coordinated data activities; and third, a proposed system architecture for scalable, multi-stakeholder data sharing. Next steps are briefly discussed. Conclusion We present a system design for multiple stakeholders such as the payer, the regulator, the developer (drug manufacturer), and the healthcare provider to share data for their decision-making. The stakeholder community would benefit from collaboratively moving the system development proposal forward for efficient and cost-effective data sharing.

Published
2021

29. Dynamic Dossier in the Cloud: A Sociotechnical Architecture for a Real-Time and Metrics-Based Data Tracking System with Gene and Cell Therapies as a Case Study

Author

Lincoln Laboratory, Massachusetts Institute of Technology. Center for Biomedical Innovation, Nam, Kevin, Larholt, Kay, Hirsch, Gigi, Fritsche, David, Bourgeois, Florence T., Palmer, Donna, Lincoln Laboratory, Massachusetts Institute of Technology. Center for Biomedical Innovation, Nam, Kevin, Larholt, Kay, Hirsch, Gigi, Fritsche, David, Bourgeois, Florence T., and Palmer, Donna

Abstract

Background Data sharing among stakeholders in the development, access, and use of drug therapies is critical but the cur-rent system and process are inefficient. Methods We take a Systems Engineering approach with a realistic use case to propose a scalable design for multi-stakeholder data sharing. Results We make three major contributions to the drug development and healthcare communities: first, a methodology for developing a multi-stakeholder data sharing system, with its focus on high-level requirements that influence the design of the system architecture and technology choice; second, the development of a realistic use case for long-term patient and therapy data tracking and sharing in the use of potentially curative and durable gene and cell therapies. Further, a bridge for the ‘awareness gap’ was found between the payer (Payer is organization which takes care of financial and operational aspects (which include insurance plans, provider network) of providing health care to US citizens. Or refer to health care insurers.) and the regulator communities by illustrating the common data tracking needs, which highlights the need for coordinated data activities; and third, a proposed system architecture for scalable, multi-stakeholder data sharing. Next steps are briefly discussed. Conclusion We present a system design for multiple stakeholders such as the payer, the regulator, the developer (drug manu-facturer), and the healthcare provider to share data for their decision-making. The stakeholder community would benefit from collaboratively moving the system development proposal forward for efficient and cost-effective data sharing.

Published
2021

32. Annual variation in attentional response after methylphenidate treatment

Author

Leerstoel Kenemans, Experimental Psychology (onderzoeksprogramma PF), Helmholtz Institute, Vollebregt, Madelon A., Kenemans, J. Leon, Buitelaar, Jan K., Deboer, Tom, Cain, Sean W., Palmer, Donna, Elliott, Glen R., Gordon, Evian, Fallahpour, Kamran, Arns, Martijn, Leerstoel Kenemans, Experimental Psychology (onderzoeksprogramma PF), Helmholtz Institute, Vollebregt, Madelon A., Kenemans, J. Leon, Buitelaar, Jan K., Deboer, Tom, Cain, Sean W., Palmer, Donna, Elliott, Glen R., Gordon, Evian, Fallahpour, Kamran, and Arns, Martijn

Published
2020

34. Gene transfer of CFTR to airway epithelia: low levels of expression are sufficient to correct [Cl.sup.-] transport and overexpression can generate basolateral CFFR

Author

Farmen, Sara L., Karp, Philip H., Ng, Philip, Palmer, Donna J., Koehler, David R., Hu, Jim, Beaudet, Arthur L., Zabner, Joseph, and Welsh, Michael J.

Subjects
Cystic fibrosis -- Research, Gene expression -- Research, Biological sciences
Abstract

Gene transfer of CFTR eDNA to airway epithelia is a promising approach to treat cystic fibrosis (CF). Most gene transfer vectors use strong viral promoters even though the endogenous CFTR promoter is very weak. To learn whether expressing CFTR at a low level in a fraction of cells would correct [Cl.sup.-] transport, we mixed freshly isolated wild-type and CF airway epithelial cells in varying proportions and generated differentiated epithelia. Epithelia with ~20% wild-type cells generated ~70% the transepithelial [Cl.sup.-] current of epithelia containing 100% wild-type cells. These data were nearly identical to those previously obtained with CFTR expressed under control of a strong promoter in a CF epithelial cell line. We also tested high level CFTR expression using the very strong cytomegalovirus (CMV) promoter as well as the cytokeratin-18 (K18) promoter. In differentiated airway epithelia, the CMV promoter generated 50-fold more transgene expression than the K18 promoter, but the K18 promoter generated more transepithelial [Cl.sup.-] current at high vector doses. Using functional studies, we found that with marked overexpression, some CFTR channels were present in the basolateral membrane where they shunted [Cl.sup.-] flow, thereby reducing net transepithelial [Cl.sup.-] transport. These results suggest that very little CFTR is required in a fraction of CF epithelial cells to complement [Cl.sup.-] transport because transepithelial [Cl.sup.-] flow is limited at the basolateral membrane. Thus they suggest a broad leeway in promoter strength for correcting the CF gene transfer, although at very high expression levels CFTR may be mislocalized to the basolateral membrane. cystic fibrosis; gene therapy; promoter; cytomegalovirus; cytokeratin-18

Published
2005

35. Effect of electrolyte concentration on the viscosity and voltammetry of supercritical solutions

Author

Abbott, Andrew P., Hope, Eric G., and Palmer, Donna J.

Subjects
Electrolytes -- Research, Chemistry
Abstract

The viscosity of a supercritical electrolyte solution is measured for the first time using a modified quartz crystal microbalance, and it is shown that ionic solvation leads to a significant structuring of the solvent and an appreciable increase in solution viscosity. Voltammetric investigations in the electrolyte solutions are used to confirm the magnitude of the viscosity changes, and these account for the appreciably lower than expected peak currents.

Published
2005

36. Safety profile, efficacy, and biodistribution of a bicistronic high-capacity adenovirus vector encoding a combined immunostimulation and cytotoxic gene therapy as a prelude to a phase I clinical trial for glioblastoma

Author

Puntel, Mariana, A.K.M., Ghulam Muhammad, Farrokhi, Catherine, VanderVeen, Nathan, Paran, Christopher, Appelhans, Ashley, Kroeger, Kurt M., Salem, Alireza, Lacayo, Liliana, Pechnick, Robert N., Kelson, Kyle R., Kaur, Sukhpreet, Kennedy, Sean, Palmer, Donna, Ng, Philip, Liu, Chunyan, Krasinkiewicz, Johnny, Lowenstein, Pedro R., and Castro, Maria G.

Published
2013
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40. Dynamic Dossier in the Cloud: A Sociotechnical Architecture for a Real-Time and Metrics-Based Data Tracking System with Gene and Cell Therapies as a Case Study

Author

Nam, Kevin, primary, Larholt, Kay, additional, Hirsch, Gigi, additional, Beninger, Paul, additional, Fritsche, David, additional, Shoda, Diane, additional, Ferguson, John, additional, Bourgeois, Florence T., additional, Palmer, Donna, additional, Katz, Karen, additional, and Courtney, Matt W., additional

Published
2020
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43. Disruption of MeCP2-TCF20 complex underlies distinct neurodevelopmental disorders.

Author

Jian Zhou, Hamdan, Hamdan, Yalamanchili, Hari Krishna, Kaifang Pang, Pohodich, Amy E., Lopez, Joanna, Yingyao Shao, Oses-Prieto, Juan A., Lifang Li, Wonho Kim, Durham, Mark A., Bajikar, Sameer S., Palmer, Donna J., Ng, Philip, Thompson, Michelle L., Bebin, E. Martina, Müller, Amelie J., Kuechler, Alma, Kampmeier, Antje, and Haack, Tobias B.

Subjects
RETT syndrome, NEURAL development, INTELLECTUAL disabilities, AUTISTIC children, MISSENSE mutation, TRANSCRIPTION factors
Abstract

MeCP2 is associated with Rett syndrome (RTT), MECP2 duplication syndrome, and a number of conditions with isolated features of these diseases, including autism, intellectual disability, and motor dysfunction. MeCP2 is known to broadly bind methylated DNA, but the precise molecular mechanism driving disease pathogenesis remains to be determined. Using proximity-dependent biotinylation (BioID), we identified a transcription factor 20 (TCF20) complex that interacts with MeCP2 at the chromatin interface. Importantly, RTT-causing mutations in MECP2 disrupt this interaction. TCF20 and MeCP2 are highly coexpressed in neurons and coregulate the expression of key neuronal genes. Reducing Tcf20 partially rescued the behavioral deficits caused by MECP2 overexpression, demonstrating a functional relationship between MeCP2 and TCF20 in MECP2 duplication syndrome pathogenesis. We identified a patient exhibiting RTT-like neurological features with a missense mutation in the PHF14 subunit of the TCF20 complex that abolishes the MeCP2-PHF14-TCF20 interaction. Our data demonstrate the critical role of the MeCP2-TCF20 complex for brain function. [ABSTRACT FROM AUTHOR]

Published
2022
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45. Annual variation in attentional response after methylphenidate treatment

Author

Vollebregt, Madelon A., Kenemans, J. Leon, Buitelaar, Jan K., Deboer, Tom, Cain, Sean W., Palmer, Donna, Elliott, Glen R., Gordon, Evian, Fallahpour, Kamran, Arns, Martijn, Leerstoel Kenemans, Experimental Psychology (onderzoeksprogramma PF), Helmholtz Institute, Leerstoel Kenemans, Experimental Psychology (onderzoeksprogramma PF), and Helmholtz Institute

Subjects
DISORDER, Male, Time Factors, Circadian clock, Audiology, Pediatrics, 0302 clinical medicine, Continuous performance task, Developmental and Educational Psychology, Prevalence, Medicine, Annual variation, Child, medicine.diagnostic_test, Methylphenidate, 05 social sciences, General Medicine, Perinatology, and Child Health, Psychiatry and Mental health, Treatment Outcome, CIRCADIAN CLOCKS, Sunlight, Female, Entrainment (chronobiology), 050104 developmental & child psychology, medicine.drug, medicine.medical_specialty, Adolescent, 03 medical and health sciences, Humans, ADHD, 0501 psychology and cognitive sciences, Daylight, Circadian rhythm, Pediatrics, Perinatology, and Child Health, CHRONOTYPE, business.industry, 030227 psychiatry, Inattention, Attention Deficit Disorder with Hyperactivity, Pediatrics, Perinatology and Child Health, Central Nervous System Stimulants, sense organs, business, SYSTEM
Abstract

Prevalence rates of attention-deficit/hyperactivity disorder (ADHD) differ with geographical areas varying in sunlight intensity. Sun- or daylight reaching the retina establishes entrainment of the circadian clock to daylight. Changes herein, hence, alterations in clock alignment, could be reflected indirectly in inattention via sleep duration. We here studied (1) annual variation in inattention at treatment initiation; (2) annual variation in response to ADHD treatment [methylphenidate (MPH)] by day of treatment initiation; and (3) dose dependence. We predicted least baseline inattention during a period of high sunlight intensity implying more room for improvement (i.e., a better treatment response) when sunlight intensity is low. These hypotheses were not confirmed. High-dose treated patients, however, had significantly better attention after treatment than low-dosed treated patients, only when treated in the period from winter to summer solstice. Change in solar irradiance (SI) during low-dosed treatment period was negatively related to attentional improvement. The above described findings were primarily found in inattention ratings and replicated in omission errors on a continuous performance task. Daylight and inattention have been proposed to be related via mediation of the circadian system. One mechanism of MPH may be to enhance sensitivity to the diurnal entrainment to sunlight and the question can be raised whether appropriate lighting could potentiate the effects of stimulants.

Published
2019

46. Supplementary_Material_6MAR19 – Supplemental material for Characterising anxiety in major depressive disorder and its use in predicting antidepressant treatment outcome: An iSPOT-D report

Author

Braund, Taylor A, Palmer, Donna M, Williams, Leanne M, and Harris, Anthony WF

Subjects
FOS: Psychology, FOS: Clinical medicine, 170199 Psychology not elsewhere classified, 110319 Psychiatry (incl. Psychotherapy), humanities, Neuroscience
Abstract

Supplemental material, Supplementary_Material_6MAR19 for Characterising anxiety in major depressive disorder and its use in predicting antidepressant treatment outcome: An iSPOT-D report by Taylor A Braund, Donna M Palmer, Leanne M Williams and Anthony WF Harris in Australian & New Zealand Journal of Psychiatry

Published
2019
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47. Supplement_material – Supplemental material for Probing the 'Default Network Interference Hypothesis' With EEG: An RDoC Approach Focused on Attention

Author

Berrie Gerrits, Vollebregt, Madelon A., Olbrich, Sebastian, Dijk, Hanneke Van, Palmer, Donna, Evian Gordon, Pascual-Marqui, Roberto, Kessels, Roy P. C., and Arns, Martijn

Subjects
FOS: Clinical medicine, 110904 Neurology and Neuromuscular Diseases, Neuroscience
Abstract

Supplemental material, Supplement_material for Probing the “Default Network Interference Hypothesis” With EEG: An RDoC Approach Focused on Attention by Berrie Gerrits, Madelon A. Vollebregt, Sebastian Olbrich, Hanneke van Dijk, Donna Palmer, Evian Gordon, Roberto Pascual-Marqui, Roy P. C. Kessels and Martijn Arns in Clinical EEG and Neuroscience

Published
2019
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